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cardiac&#44; and smooth muscle4 &#40;Cav 1&#46;2 &#91;a<span class="elsevierStyleInf">1C</span>&#93;&#41;&#46; They are responsible for muscle tone in arterial smooth muscles&#44; and have become a target for drugs to treat hypertension and angina&#46; In the kidney &#40;Cav1&#46;2 &#91;a<span class="elsevierStyleInf">1C</span>&#93; and Cav1&#46;3 &#91;a<span class="elsevierStyleInf">1D</span>&#93;&#41;&#44; these channels promote the dilation of preglomerular &#40;afferent&#41; arterioles&#44; ostensibly increasing intraglomerular pressure&#46; Additionally&#44; other L-type channels are found in the skeletal muscle &#40;Cav1&#46;1 &#91;a<span class="elsevierStyleInf">1S</span>&#93;&#41;&#44; brain and kidney &#40;Cav1&#46;2 &#91;a<span class="elsevierStyleInf">1C</span>&#93;&#44; Cav1&#46;3 &#91;a<span class="elsevierStyleInf">1D</span>&#93;&#41;&#44; pancreas &#40;Cav1&#46;3 &#91;a<span class="elsevierStyleInf">1D</span>&#93;&#41;&#44; and retina &#40;Cav1&#46;4 &#91;a1F&#93;&#41;&#46;<span class="elsevierStyleSup">1</span></p><p class="elsevierStylePara">Other lesser-known channel types are P&#47;Q&#44; 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aldosterone&#44; atrial natriuretic peptide&#44; and insulin&#46; Only T-type channels &#40;not L-type&#41; are found in postglomerular &#40;efferent&#41; arterioles&#44; and so the tone of these vascular muscles must be controlled by T-type channels and angiotensin II AT1 receptors&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">In principle&#44; L-type channel blocking is considered to be the most important type in the regulation of vascular functioning&#44; since Cav1&#46;2 is the major route of calcium entry into skeletal muscle&#44; heart&#44; and kidney cells&#46;<span class="elsevierStyleSup">1&#44;6 </span>However&#44; the non-haemodynamic action of T-type channel blockers could have multiple beneficial effects by inhibiting inflammatory processes &#40;inhibition of Rho kinases&#44; NF-kB&#44; leukocyte adhesion&#41;&#44; blocking the renin-angiotensin system&#44; and blocking the sympathetic nervous system &#40;Table 1&#41;&#46;<span class="elsevierStyleInf">7</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">TYPES OF CALCIUM CHANNEL BLOCKERS </span></p><p class="elsevierStylePara">Calcium channel blockers &#40;CCB&#41; are highly heterogeneous molecules that can be grouped into&#58; derived from phenylalkylamine&#44; such as verapamil&#59; derived from benzodiazepines&#44; whose prototype is diltiazem&#59; and derived from 1&#44;4-dihydropyridines&#44; such as manidipine&#46;<span class="elsevierStyleSup">8 </span>These molecules mainly block L-type channels&#46;</p><p class="elsevierStylePara">The first generation of dihydropyridine calcium channel blockers&#44; such as nifedipine&#44; are characterised by instantaneous release&#44; a short lifetime&#44; and quick absorption&#46; In spite of a favourable metabolic profile&#44; these drugs cause some adverse effects such as sharp drops in blood pressure&#44; tachycardia&#44; and sympathetic activation&#46; In the second generation of drugs&#44; including nimodipine&#44; the release of the molecule is slower&#46;<span class="elsevierStyleSup">9 </span></p><p class="elsevierStylePara">The latest-generation CCB have a long lifetime and prolonged action that significantly reduces blood pressure&#44; thus notably diminishing the secondary side effects of the drug &#40;Table 2&#41;&#46; In contrast with traditional blockers&#44; this new group of molecules&#44; including manidipine&#44; blocks both L-type and T-type channels&#46;<span class="elsevierStyleSup">10 </span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">THE EFFECTS OF CCB ON CARDIOVASCULAR MORBIDITY </span></p><p class="elsevierStylePara">Cardiovascular disease is clearly and consistently related to blood pressure&#46; The main objective of antihypertensive therapy is to reduce both cardiovascular and renal morbidity and mortality&#46; In order to achieve this&#44; a target blood pressure level was established at below 140&#47;90mm Hg&#44; although in patients with diabetes or kidney disease&#44; it appears that this limit should be less than 130&#47;80mm Hg&#46;<span class="elsevierStyleSup">11 </span></p><p class="elsevierStylePara">According to the guidelines for the management of arterial hypertension&#44;<span class="elsevierStyleSup">12 </span>thiazide diuretics should be the treatment of choice&#44; although certain high-risk cases could be treated with angiotensin II receptor antagonists &#40;ARA-II&#41;&#44; CCB&#44; or angiotensin-converting enzyme &#40;ACE&#41; inhibitors as a first choice&#46;<span class="elsevierStyleSup">11 </span>Precise indications exist for the use of antihypertensive agents such as CCB&#44; ACE inhibitors&#44; and ARA-II in order to prevent the development of diabetes in hypertensive patients&#46;<span class="elsevierStyleSup">11 </span></p><p class="elsevierStylePara">The CAMELOT study concluded that&#44; as a monotherapy&#44; CCB are more efficient at diminishing cardiovascular events and slowing the progression of atherosclerosis than ACE inhibitors&#46;<span class="elsevierStyleSup">13 </span>With regard to CCB combined with other drugs&#44; Fogari et al&#46; demonstrated that manidipine &#40;CCB&#41; and delapril &#40;ACE inhibitor&#41; provide increased benefit over olmesartan &#40;ARA II&#41; and hydrochlorothiazide&#44; as this combination reduces orthostatic blood pressure and does not cause adverse metabolic effects&#46;<span class="elsevierStyleSup">14 </span></p><p class="elsevierStylePara">Other studies&#44; such as the one carried out by the Japanese Hypertension Society&#44; affirm that CCB possess greater antihypertensive efficacy than all other preferred antihypertensive drugs available&#44; without affecting blood flow to the body&#8217;s organs&#46; This characteristic makes this group of drugs particularly indicated in elderly patients and those with complications such as left ventricular hypertrophy&#44; tachycardia&#44; angina pectoris&#44; and chronic cerebrovascular disease&#46;<span class="elsevierStyleSup">15 </span></p><p class="elsevierStylePara">In this respect&#44; one trial treated 30 obese hypertensive patients with amlodipine&#44; manidipine&#44; and cilnidipine&#44; revealing that these long-acting CCB reduce blood pressure and also diminish resistance to insulin&#44; suggesting valuable cardio-metabolic properties&#46;<span class="elsevierStyleSup">16 </span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">However&#44; other studies have not observed significant differences in the efficacy of reducing blood pressure between different latest generation calcium channel blockers&#46;<span class="elsevierStyleSup">17&#44;18 </span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">CCB AND INSULIN RESISTANCE&#46; MANIDIPINE AND THE EXPRESSION OF AP2 </span></p><p class="elsevierStylePara">In terms of cardiovascular morbidity and mortality&#44; arterial hypertension and diabetes are key risk factors&#46; These are interrelated in a complex and multifactorial manner&#46; Hypertensive patients with metabolic syndromes &#40;MS&#41; have an elevated risk of diabetes mellitus &#40;DM&#41;&#46; The incidence of DM appears to increase in patients with AHT&#44; partly due to the high percentage of obese patients in both groups&#46; The UKPDS study demonstrated that high blood pressure and glycaemia independently and additively increase the risk of cardiovascular disease&#46;<span class="elsevierStyleSup">19&#44;20 </span></p><p class="elsevierStylePara">In this respect&#44; the MARIMBA study compared the effects of administering manidipine and amlodipine<span class="elsevierStyleSup">21 </span>in non-diabetic MS patients&#44; and found that blood pressure and C-reactive protein &#40;CRP&#41; levels decreased with both types of treatment&#44; although manidipine also significantly reduced albuminuria and insulin resistance&#44; associated with an increase in serum adiponectin levels&#46; Manidipine also caused fewer adverse effects&#46;</p><p class="elsevierStylePara">By comparing manidipine with another CCB with similar kinetic and lipophilic characteristics&#44; such as lercanidipine&#44; manidipine is more effective in reducing insulin resistance in obese and hypertensive patients&#46;<span class="elsevierStyleSup">22 </span>In other studies&#44; manidipine proves itself to be just as effective as pioglitazone in reducing the expression of RAGE and the production of ROS&#44; as well as reducing CRP levels&#46; These experiments with specific inhibitors have concluded that the mechanism depends on PPAR-&#947;&#46; This mechanism could explain the reduced inflammatory effect of hyperglycaemia and vascular damage&#46;<span class="elsevierStyleSup">23 </span></p><p class="elsevierStylePara">The &#8220;lipotoxicity hypothesis&#8221; correlates type 2 diabetes with a loss in capacity of adipose tissue to accommodate excess calories&#46; The loss in adipocyte differentiation makes the excess calories accumulate primarily in the liver&#44; pancreas&#44; and muscles&#44; contributing to the development of insulin resistance&#46;<span class="elsevierStyleSup">24 </span>We know that small adipocytes are sensitive to insulin&#44; as opposed to mature cells&#44; which undergo hypertrophy and become resistant to the hormone&#46; For this reason&#44; favouring adipogenesis would contribute to reducing insulin resistance in type 2 diabetes patients&#46;</p><p class="elsevierStylePara">The improvement produced in insulin sensitivity by dihydropyrimidine CCB is almost imperceptible&#46; In the case of nifedipine&#44; which blocks only L-type channels&#44; the body becomes even more desensitised to insulin&#44; and glucose release is inhibited&#46;<span class="elsevierStyleSup">16 </span>However&#44; studies with manidipine have reported surprising results in this respect&#46; Although some of these studies were already taken into account&#44; a clinical trial performed with 64 hypertensive MS patients&#46; The patients were evaluated using NCEP&#47;ATPIII criteria and randomly assigned to manidipine or amlodipine treatments for 12 weeks&#46; Similar reductions in blood pressure were observed with both treatments&#44; and the patients treated with manidipine also experienced significant reductions in insulin resistance&#46;<span class="elsevierStyleSup">25 </span>In this same manner&#44; a more recent analysis on insulin sensitivity and plasma fibrinogen in obese and hypertensive patients compared the combination of manidipine and delapril versus olmesartan and hydrochlorothiazide&#46; It demonstrated that the first combination significantly reduced insulin resistance and plasma fibrinogen levels&#44; in spite of the fact that the reduction in blood pressure values would indicate similar efficacy between both combinations&#46;<span class="elsevierStyleSup">26 </span>A later study compared the combination of manidipine and delapril with losartan and hydrochlorothiazide in patients with diabetes and microalbuminuria&#44; and concluded that the first combination was the more useful therapeutic option for these patients&#46;<span class="elsevierStyleSup">27 </span></p><p class="elsevierStylePara">Experiments have shown that manidipine&#44; but not amlodipine or lercanidipine&#44; activates PPAR-&#947;in 3T3-L1 rat adipocytes&#46;<span class="elsevierStyleSup">23&#44;28 </span>In our studies&#44; we have observed that NIH3T3 cells treated with manidipine<span class="elsevierStyleSup">29 </span>experience increased PPAR-&#947;&#40;Peroxisome Proliferator-activated Receptor gamma&#41; expression and adipocyte differentiation 2 &#40;aP2&#41; gene expression&#44; which can be considered as evidence of the expression of the first &#40;Figure 1&#41;&#46; These results indicate mechanisms that link manidipine to the increase observed in insulin sensitivity in hypertensive&#44; diabetic patients and with <span class="elsevierStyleItalic">de novo </span>adipocyte formation&#46; In this sense&#44; the increase in intracellular calcium levels has been observed to inhibit preadipocyte differentiation&#46;<span class="elsevierStyleSup">30 </span>This contrasts with the normal role of calcium in faster processes&#44; such as neurosecretion&#44; excitation&#44; and contraction&#46;</p><p class="elsevierStylePara">Adipogenesis&#44; as other differentiation processes&#44; depends on stimulating transcription factors&#44; such as PPAR-&#947;&#44; and inhibitors such as the GATA family&#44; which in turn is activated by extracellular signals&#46; Calcium homeostasis has been studied with special emphasis on calreticulin&#44; which is one of the main calcium binding proteins in the lumen of the endoplasmic reticulum&#44; and is largely responsible for a rapid calcium exchange&#46; One study performed with stem cells and 3T3-L1 preadipocytes demonstrated how calreticulin can modulate adipogenesis through a negative feedback mechanism&#46; PPAR-&#947;is a potent transcription activator for calreticulin&#44; as it binds to its promoter&#46; In this manner&#44; it increases the expression of calreticulin&#44; but once this protein is over-expressed&#44; calreticulin inhibits the <span class="elsevierStyleItalic">cis</span>-bond of the PPAR-&#947;-RxR heterodimer to PPAR-&#947;response elements &#40;PPRE&#41;&#44; thus cancelling the transcriptional activation of PPAR-&#947;by fatty acids&#46; Through this mechanism&#44; calreticulin negatively regulates both the expression of PPAR-&#947;and other critical proadipogenic transcription factors such as C&#47;EBPa&#46;<span class="elsevierStyleSup">31 </span></p><p class="elsevierStylePara">Manidipine&#8217;s calcium channel blocking activity could impede the entrance of calcium into the cells&#44; thus reducing calcium concentrations in the endoplasmic reticulum&#44; and in turn&#44; that of calreticulin&#44; favouring the differentiation of adipocytes&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">EFFECTS OF CCB ON MICROALBUMINURIA </span></p><p class="elsevierStylePara">The renal protection is associated with cardiovascular protection as well&#44; and the evolution of albuminuria is an excellent predictor of both the evolution of renal function and the development of cardiovascular complications&#46;<span class="elsevierStyleSup">32 </span>The presence of microalbuminuria makes the use of ACE inhibitors or ARA-II necessary&#44; even as CCB are still considered for combined therapy&#46; In the absence of albuminuria&#44; and with maintained or diminished glomerular filtration rate&#44; CCB could be the first pharmacological option&#46; However&#44; a high percentage of patients do require ACE inhibitors and&#47;or ARA-II&#46;<span class="elsevierStyleSup">33 </span></p><p class="elsevierStylePara">Contrary to other dihydropyridines&#44; manidipine blocks T-type channels of efferent arterioles&#44; which diminishes glomerular pressure and&#44; consequently&#44; albumin excretion&#44; but at the same time it blocks L-type channels&#44; thus favouring the dilation of the afferent arteriole&#46; In this manner&#44; T-type calcium channel blockers &#40;CCB&#41;<span class="elsevierStyleSup">1&#44;7&#44;34 </span>influence haemodynamics through their antihypertensive effect&#46; Thus&#44; we could consider their effect as protective against kidney damage&#44; since the kidney is one of the target organs in hypertensive and diabetic patients&#46; The AMANDHA study &#40;Efficacy and Safety Assessment of Manidipine in Type 2 Diabetic Patients with Hypertension and Microalbuminuria Uncontrolled with Renin-Angiotensin System Blockers&#41;<span class="elsevierStyleSup">35 </span>compared manidipine and amlodipine in diabetic patients with uncontrolled hypertension and microalbuminuria&#46; Although both CCB are equally effective in reducing CRP and blood pressure&#44; the first implies fewer adverse effects&#46; Also&#44; the reduction in albuminuria and insulin resistance was significantly higher in patients treated with manidipine&#46; A recent study demonstrated yet again that manidipine is capable of significantly reducing albumin urine excretion in patients with essential hypertension without causing adverse effects&#44; and so the combination of manidipine with renin-angiotensin antagonists could be beneficial in these cases&#46;<span class="elsevierStyleSup">36 </span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">MANIDIPINE AND OXIDATIVE STRESS </span></p><p class="elsevierStylePara">Endothelial structure and function could improve considerably with the use of CCB&#46; Research such as the INSIGHT study &#40;International Nifedipine Intervention as a Goal in Hypertension Treatment&#41; and MIDAS study &#40;Myocardial Infarction Data Acquisition System&#41; demonstrates the superiority of these drugs as compared to thiazide diuretics in terms of lower increases in intimal thickness&#46;<span class="elsevierStyleSup">33&#44;37&#44;38 </span></p><p class="elsevierStylePara">The beneficial effects of calcium blockers in macrovascular endothelial cells must be demonstrated and justified through mechanisms that do not include calcium channels&#44; since these are not expressed in endothelial cells&#46;<span class="elsevierStyleSup">39&#44;40 </span>To this end&#44; some authors have postulated that the action of DHP in this type of tissue are related to their lipophilicity&#46;<span class="elsevierStyleSup">41 </span></p><p class="elsevierStylePara">Oxidative stress plays a fundamental role in the development of atherosclerosis&#46; Toba et al&#46; pointed out the antioxidant and anti-inflammatory effects of manidipine and other CCB such as amlodipine&#44; mediated by the increased expression of endothelial nitric oxide synthase &#40;eNOS&#41; and the inhibition of angiotensin converting enzyme &#40;ACE&#41; expression&#44; but not their possible activity in reducing blood pressure&#46; In this study&#44; the authors observed how manidipine normalises the reduction in the expression of both the eNOS gene and protein&#44; and reduces the over-expression of NADPH oxidase&#44; VCAM&#44; and MCP-1 in hypertensive rat aortas&#46;<span class="elsevierStyleSup">41 </span>Furthermore&#44; manidipine has another beneficial effect on atherogenesis&#44; as it inhibits the expression of LOX-1&#44; a low-density lipoprotein receptor induced into action by angiotensin II&#46;<span class="elsevierStyleSup">43 </span></p><p class="elsevierStylePara">Sun X et al&#46;<span class="elsevierStyleSup">44 </span>recently demonstrated that both in mature differentiated adipocytes and 3T3-L1 cells&#44; and in co-cultures of both cell types&#44; calcitrol increases the expression of inflammatory molecules such as MCP-1&#44; MIF&#44; M-CSF&#44; MIP&#44; IL-6<span class="elsevierStyleSup">45</span>&#44; TNF and CD14&#46; Treatment with nifedipine or dinitrophenol inhibits the activity of calcitrol&#44; which could reveal a calcium-dependent mechanism that requires mitochondrial uncoupling&#46; As such&#44; we could expect the blockage of calcium channels with manidipine to also show anti-oxidative and &#183; anti-inflammatory effect by reducing intracellular calcium levels&#46;</p><p class="elsevierStylePara">Our preliminary studies on smooth muscle cells revealed an increase in endothelial nitric oxide synthase &#40;eNOS&#41; gene after being treated with manidipine&#46; In response to many types of aggression&#44; the expression of eNOS in cells treated with manidipine is essentially stable&#44; compared to the control culture&#46; This data may reveal a beneficial effect of CCB against endothelial dysfunction &#40;Figure 2&#41;&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">CONCLUSIONS </span></p><p class="elsevierStylePara">T-type calcium channel blockers provide protection to the kidneys&#44; as they improve glomerular microcirculation due to their vasodilatory effect both on afferent and efferent arterioles&#46; Manidipine stands out from among these types of calcium channel blockers due to its anti-inflammatory activity&#44; which does not rely on the renin-angiotensin system&#44; and because of its possible beneficial effects against endothelial dysfunction&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Acknowledgements </span></p><p class="elsevierStylePara">This manuscript was developed with the aid of authors from the Fundaci&#243;n Mapfre-Guanarteme &#40;Mapfre-Guanarteme Foundation&#41; and Laboratorios Chiesi &#40;Chiesi Laboratories&#41;&#44; who we thank for their support and collaboration&#46; The authors declare a Research Agreement between Chiesi Farmaceuti&#173;ca S&#46;p&#46;A&#46; and the Research Unit of the Dr&#46; Negr&#237;n Gran Canaria</p><p class="elsevierStylePara"><a href="grande&#47;10643&#95;108&#95;14369&#95;en&#95;10643&#95;f1&#46;jpg" class="elsevierStyleCrossRefs"><img src="10643_108_14369_en_10643_f1.jpg" alt="Exposure of NIH-3T3 preadipocyte cells to manidipine activates the expression of the aP2 gene in a time-dependent manner&#46;"></img></a></p><p class="elsevierStylePara">Figure 1&#46; Exposure of NIH-3T3 preadipocyte cells to manidipine activates the expression of the aP2 gene in a time-dependent manner&#46;</p><p class="elsevierStylePara"><a href="grande&#47;10643&#95;108&#95;14370&#95;en&#95;10643&#95;f2&#46;jpg" class="elsevierStyleCrossRefs"><img src="10643_108_14370_en_10643_f2.jpg" alt="The Expression of eNOS in cells treated with angiotensin II and manidipine is significantly greater than in cells treated with just angiotensin II "></img></a></p><p class="elsevierStylePara">Figure 2&#46; The Expression of eNOS in cells treated with angiotensin II and manidipine is significantly greater than in cells treated with just angiotensin II </p><p class="elsevierStylePara"><a href="10643&#95;108&#95;14367&#95;en&#95;10643tabla&#95;1&#46;doc" class="elsevierStyleCrossRefs">10643&#95;108&#95;14367&#95;en&#95;10643tabla&#95;1&#46;doc</a></p><p class="elsevierStylePara">Table 1&#46; Calcium channels </p><p class="elsevierStylePara"><a href="10643&#95;108&#95;14368&#95;en&#95;10643tabla&#95;2&#46;doc" class="elsevierStyleCrossRefs">10643&#95;108&#95;14368&#95;en&#95;10643tabla&#95;2&#46;doc</a></p><p class="elsevierStylePara">Table 2&#46; Calcium channel blockers </p>"
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Vascular and metabolic properties of manidipine
Aspectos vasculares y metabólicos de manidipino
, Nisa Buset Ríosb, N.. Buset Ríosc, Francisco Rodríguez Esparragónb, F.. Rodríguez Esparragónc, Carlos Fernández-Andrade Rodríguezd, C.. Fernández-Andrade Rodrígueze, José Carlos Rodríguez Pérezf, J.C.. Rodríguez Pérezg
b Unidad de Investigación, Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria Las Palmas, Spain,
c Unidad de Investigación, Hospital Universitario de Gran Canaria Dr. Negrín, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria
d Servicio de Nefrología, Hospital Universitario Virgen del Rocío, Sevilla, Sevilla, Spain,
e Servicio de Nefrología, Hospital Universitario Virgen del Rocío, Sevilla,
f Servicio de Nefrología y Unidad de Investigación, Hospital Universitario de Gran Canaria Dr. Negrín, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria Las Palmas Spain,
g Servicio de Nefrología y Unidad de Investigación, Hospital Universitario de Gran Canaria Dr. Negrín, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria
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    "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">CALCIUM CHANNELS </span></p><p class="elsevierStylePara">Voltage-dependent calcium channels mediate the flow of calcium in response to the depolarisation of the cell membrane and regulate intracellular processes such as contraction&#44; secretion&#44; neurotransmission&#44; and gene expression&#44; in which calcium acts as a second messenger&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The channels are composed of multiple heteromeric subunits&#58; &#945;&#44; &#946;&#44; &#947; and &#948;&#44; which are coded for by several different genes&#46; They are named using the chemical symbol of the principal ion they regulate the passage of &#40;Ca&#41; and the primary physiological regulator&#44; voltage &#40;v&#41;&#46; The numerical identifier corresponds to the gene subfamily to which the channel corresponds &#40;1-3&#41;&#44; and the letter &#40;A-I&#41; indicates the order in which it was identified&#44; except subunit a1S&#44; which was assigned the letter S due to its presence in skeletal muscle&#46;</p><p class="elsevierStylePara">Subunit &#945;<span class="elsevierStyleSup">1</span>&#44; which is coded for by CACNA1&#44; appears to be responsible for the main characteristics of these channels&#44; since it is involved in ion selectivity and conductivity and sensitivity to voltage&#46;<span class="elsevierStyleSup">1-3 </span></p><p class="elsevierStylePara">The calcium currents registered in different cell types have multiple pharmacological and physiological properties&#44; so it is possible to group calcium channels into L&#44; P&#47;Q&#44; N&#44; R&#44; and T types&#46;<span class="elsevierStyleSup">1 </span></p><p class="elsevierStylePara">L-type &#40;long-lasting&#41; calcium channels are activated by strong depolarisations&#44; mediated by the prolonged flow of calcium into a wide variety of cell types&#46; In this manner&#44; these channels play a central role in the contraction and excitation of skeletal&#44; cardiac&#44; and smooth muscle4 &#40;Cav 1&#46;2 &#91;a<span class="elsevierStyleInf">1C</span>&#93;&#41;&#46; They are responsible for muscle tone in arterial smooth muscles&#44; and have become a target for drugs to treat hypertension and angina&#46; In the kidney &#40;Cav1&#46;2 &#91;a<span class="elsevierStyleInf">1C</span>&#93; and Cav1&#46;3 &#91;a<span class="elsevierStyleInf">1D</span>&#93;&#41;&#44; these channels promote the dilation of preglomerular &#40;afferent&#41; arterioles&#44; ostensibly increasing intraglomerular pressure&#46; Additionally&#44; other L-type channels are found in the skeletal muscle &#40;Cav1&#46;1 &#91;a<span class="elsevierStyleInf">1S</span>&#93;&#41;&#44; brain and kidney &#40;Cav1&#46;2 &#91;a<span class="elsevierStyleInf">1C</span>&#93;&#44; Cav1&#46;3 &#91;a<span class="elsevierStyleInf">1D</span>&#93;&#41;&#44; pancreas &#40;Cav1&#46;3 &#91;a<span class="elsevierStyleInf">1D</span>&#93;&#41;&#44; and retina &#40;Cav1&#46;4 &#91;a1F&#93;&#41;&#46;<span class="elsevierStyleSup">1</span></p><p class="elsevierStylePara">Other lesser-known channel types are P&#47;Q&#44; N&#44; and R&#44; and these also require strong depolarisation in order to be activated&#46;<span class="elsevierStyleSup">1</span></p><p class="elsevierStylePara">Contrary to the previously mentioned channel types&#44; T-type &#40;transient&#41; channels are activated by weak depolarisations&#44; and provoke a transitory flow of calcium&#46;5 T-type channels are present in the nervous system &#40;Cav3&#46;1 &#91;a<span class="elsevierStyleInf">1G</span>&#93;&#41;&#44; brain &#40;Cav3&#46;1 &#91;a1G&#44;&#93; Cav3&#46;2 &#91;a1H&#93; and &#40;Cav3&#46;3 &#91;a<span class="elsevierStyleInf">1D</span>&#93;&#41;&#44; heart &#40;Cav3&#46;2 &#91;&#40;a1H&#93;&#41;&#44; kidneys &#40;Cav3&#46;1 &#91;a<span class="elsevierStyleInf">1G</span>&#93;&#44; Cav3&#46;2 &#91;a<span class="elsevierStyleInf">1H</span>&#93;&#41; and liver &#40;Cav3&#46;2 &#91;a<span class="elsevierStyleInf">1H</span>&#93;&#41;&#46;1 These are involved in heart rate&#44; vascular smooth muscle contraction&#44; and cell growth&#46;4 T-type channels have been implicated on several occasions in the secretion of hormones such as renin&#44; aldosterone&#44; atrial natriuretic peptide&#44; and insulin&#46; Only T-type channels &#40;not L-type&#41; are found in postglomerular &#40;efferent&#41; arterioles&#44; and so the tone of these vascular muscles must be controlled by T-type channels and angiotensin II AT1 receptors&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">In principle&#44; L-type channel blocking is considered to be the most important type in the regulation of vascular functioning&#44; since Cav1&#46;2 is the major route of calcium entry into skeletal muscle&#44; heart&#44; and kidney cells&#46;<span class="elsevierStyleSup">1&#44;6 </span>However&#44; the non-haemodynamic action of T-type channel blockers could have multiple beneficial effects by inhibiting inflammatory processes &#40;inhibition of Rho kinases&#44; NF-kB&#44; leukocyte adhesion&#41;&#44; blocking the renin-angiotensin system&#44; and blocking the sympathetic nervous system &#40;Table 1&#41;&#46;<span class="elsevierStyleInf">7</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">TYPES OF CALCIUM CHANNEL BLOCKERS </span></p><p class="elsevierStylePara">Calcium channel blockers &#40;CCB&#41; are highly heterogeneous molecules that can be grouped into&#58; derived from phenylalkylamine&#44; such as verapamil&#59; derived from benzodiazepines&#44; whose prototype is diltiazem&#59; and derived from 1&#44;4-dihydropyridines&#44; such as manidipine&#46;<span class="elsevierStyleSup">8 </span>These molecules mainly block L-type channels&#46;</p><p class="elsevierStylePara">The first generation of dihydropyridine calcium channel blockers&#44; such as nifedipine&#44; are characterised by instantaneous release&#44; a short lifetime&#44; and quick absorption&#46; In spite of a favourable metabolic profile&#44; these drugs cause some adverse effects such as sharp drops in blood pressure&#44; tachycardia&#44; and sympathetic activation&#46; In the second generation of drugs&#44; including nimodipine&#44; the release of the molecule is slower&#46;<span class="elsevierStyleSup">9 </span></p><p class="elsevierStylePara">The latest-generation CCB have a long lifetime and prolonged action that significantly reduces blood pressure&#44; thus notably diminishing the secondary side effects of the drug &#40;Table 2&#41;&#46; In contrast with traditional blockers&#44; this new group of molecules&#44; including manidipine&#44; blocks both L-type and T-type channels&#46;<span class="elsevierStyleSup">10 </span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">THE EFFECTS OF CCB ON CARDIOVASCULAR MORBIDITY </span></p><p class="elsevierStylePara">Cardiovascular disease is clearly and consistently related to blood pressure&#46; The main objective of antihypertensive therapy is to reduce both cardiovascular and renal morbidity and mortality&#46; In order to achieve this&#44; a target blood pressure level was established at below 140&#47;90mm Hg&#44; although in patients with diabetes or kidney disease&#44; it appears that this limit should be less than 130&#47;80mm Hg&#46;<span class="elsevierStyleSup">11 </span></p><p class="elsevierStylePara">According to the guidelines for the management of arterial hypertension&#44;<span class="elsevierStyleSup">12 </span>thiazide diuretics should be the treatment of choice&#44; although certain high-risk cases could be treated with angiotensin II receptor antagonists &#40;ARA-II&#41;&#44; CCB&#44; or angiotensin-converting enzyme &#40;ACE&#41; inhibitors as a first choice&#46;<span class="elsevierStyleSup">11 </span>Precise indications exist for the use of antihypertensive agents such as CCB&#44; ACE inhibitors&#44; and ARA-II in order to prevent the development of diabetes in hypertensive patients&#46;<span class="elsevierStyleSup">11 </span></p><p class="elsevierStylePara">The CAMELOT study concluded that&#44; as a monotherapy&#44; CCB are more efficient at diminishing cardiovascular events and slowing the progression of atherosclerosis than ACE inhibitors&#46;<span class="elsevierStyleSup">13 </span>With regard to CCB combined with other drugs&#44; Fogari et al&#46; demonstrated that manidipine &#40;CCB&#41; and delapril &#40;ACE inhibitor&#41; provide increased benefit over olmesartan &#40;ARA II&#41; and hydrochlorothiazide&#44; as this combination reduces orthostatic blood pressure and does not cause adverse metabolic effects&#46;<span class="elsevierStyleSup">14 </span></p><p class="elsevierStylePara">Other studies&#44; such as the one carried out by the Japanese Hypertension Society&#44; affirm that CCB possess greater antihypertensive efficacy than all other preferred antihypertensive drugs available&#44; without affecting blood flow to the body&#8217;s organs&#46; This characteristic makes this group of drugs particularly indicated in elderly patients and those with complications such as left ventricular hypertrophy&#44; tachycardia&#44; angina pectoris&#44; and chronic cerebrovascular disease&#46;<span class="elsevierStyleSup">15 </span></p><p class="elsevierStylePara">In this respect&#44; one trial treated 30 obese hypertensive patients with amlodipine&#44; manidipine&#44; and cilnidipine&#44; revealing that these long-acting CCB reduce blood pressure and also diminish resistance to insulin&#44; suggesting valuable cardio-metabolic properties&#46;<span class="elsevierStyleSup">16 </span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">However&#44; other studies have not observed significant differences in the efficacy of reducing blood pressure between different latest generation calcium channel blockers&#46;<span class="elsevierStyleSup">17&#44;18 </span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">CCB AND INSULIN RESISTANCE&#46; MANIDIPINE AND THE EXPRESSION OF AP2 </span></p><p class="elsevierStylePara">In terms of cardiovascular morbidity and mortality&#44; arterial hypertension and diabetes are key risk factors&#46; These are interrelated in a complex and multifactorial manner&#46; Hypertensive patients with metabolic syndromes &#40;MS&#41; have an elevated risk of diabetes mellitus &#40;DM&#41;&#46; The incidence of DM appears to increase in patients with AHT&#44; partly due to the high percentage of obese patients in both groups&#46; The UKPDS study demonstrated that high blood pressure and glycaemia independently and additively increase the risk of cardiovascular disease&#46;<span class="elsevierStyleSup">19&#44;20 </span></p><p class="elsevierStylePara">In this respect&#44; the MARIMBA study compared the effects of administering manidipine and amlodipine<span class="elsevierStyleSup">21 </span>in non-diabetic MS patients&#44; and found that blood pressure and C-reactive protein &#40;CRP&#41; levels decreased with both types of treatment&#44; although manidipine also significantly reduced albuminuria and insulin resistance&#44; associated with an increase in serum adiponectin levels&#46; Manidipine also caused fewer adverse effects&#46;</p><p class="elsevierStylePara">By comparing manidipine with another CCB with similar kinetic and lipophilic characteristics&#44; such as lercanidipine&#44; manidipine is more effective in reducing insulin resistance in obese and hypertensive patients&#46;<span class="elsevierStyleSup">22 </span>In other studies&#44; manidipine proves itself to be just as effective as pioglitazone in reducing the expression of RAGE and the production of ROS&#44; as well as reducing CRP levels&#46; These experiments with specific inhibitors have concluded that the mechanism depends on PPAR-&#947;&#46; This mechanism could explain the reduced inflammatory effect of hyperglycaemia and vascular damage&#46;<span class="elsevierStyleSup">23 </span></p><p class="elsevierStylePara">The &#8220;lipotoxicity hypothesis&#8221; correlates type 2 diabetes with a loss in capacity of adipose tissue to accommodate excess calories&#46; The loss in adipocyte differentiation makes the excess calories accumulate primarily in the liver&#44; pancreas&#44; and muscles&#44; contributing to the development of insulin resistance&#46;<span class="elsevierStyleSup">24 </span>We know that small adipocytes are sensitive to insulin&#44; as opposed to mature cells&#44; which undergo hypertrophy and become resistant to the hormone&#46; For this reason&#44; favouring adipogenesis would contribute to reducing insulin resistance in type 2 diabetes patients&#46;</p><p class="elsevierStylePara">The improvement produced in insulin sensitivity by dihydropyrimidine CCB is almost imperceptible&#46; In the case of nifedipine&#44; which blocks only L-type channels&#44; the body becomes even more desensitised to insulin&#44; and glucose release is inhibited&#46;<span class="elsevierStyleSup">16 </span>However&#44; studies with manidipine have reported surprising results in this respect&#46; Although some of these studies were already taken into account&#44; a clinical trial performed with 64 hypertensive MS patients&#46; The patients were evaluated using NCEP&#47;ATPIII criteria and randomly assigned to manidipine or amlodipine treatments for 12 weeks&#46; Similar reductions in blood pressure were observed with both treatments&#44; and the patients treated with manidipine also experienced significant reductions in insulin resistance&#46;<span class="elsevierStyleSup">25 </span>In this same manner&#44; a more recent analysis on insulin sensitivity and plasma fibrinogen in obese and hypertensive patients compared the combination of manidipine and delapril versus olmesartan and hydrochlorothiazide&#46; It demonstrated that the first combination significantly reduced insulin resistance and plasma fibrinogen levels&#44; in spite of the fact that the reduction in blood pressure values would indicate similar efficacy between both combinations&#46;<span class="elsevierStyleSup">26 </span>A later study compared the combination of manidipine and delapril with losartan and hydrochlorothiazide in patients with diabetes and microalbuminuria&#44; and concluded that the first combination was the more useful therapeutic option for these patients&#46;<span class="elsevierStyleSup">27 </span></p><p class="elsevierStylePara">Experiments have shown that manidipine&#44; but not amlodipine or lercanidipine&#44; activates PPAR-&#947;in 3T3-L1 rat adipocytes&#46;<span class="elsevierStyleSup">23&#44;28 </span>In our studies&#44; we have observed that NIH3T3 cells treated with manidipine<span class="elsevierStyleSup">29 </span>experience increased PPAR-&#947;&#40;Peroxisome Proliferator-activated Receptor gamma&#41; expression and adipocyte differentiation 2 &#40;aP2&#41; gene expression&#44; which can be considered as evidence of the expression of the first &#40;Figure 1&#41;&#46; These results indicate mechanisms that link manidipine to the increase observed in insulin sensitivity in hypertensive&#44; diabetic patients and with <span class="elsevierStyleItalic">de novo </span>adipocyte formation&#46; In this sense&#44; the increase in intracellular calcium levels has been observed to inhibit preadipocyte differentiation&#46;<span class="elsevierStyleSup">30 </span>This contrasts with the normal role of calcium in faster processes&#44; such as neurosecretion&#44; excitation&#44; and contraction&#46;</p><p class="elsevierStylePara">Adipogenesis&#44; as other differentiation processes&#44; depends on stimulating transcription factors&#44; such as PPAR-&#947;&#44; and inhibitors such as the GATA family&#44; which in turn is activated by extracellular signals&#46; Calcium homeostasis has been studied with special emphasis on calreticulin&#44; which is one of the main calcium binding proteins in the lumen of the endoplasmic reticulum&#44; and is largely responsible for a rapid calcium exchange&#46; One study performed with stem cells and 3T3-L1 preadipocytes demonstrated how calreticulin can modulate adipogenesis through a negative feedback mechanism&#46; PPAR-&#947;is a potent transcription activator for calreticulin&#44; as it binds to its promoter&#46; In this manner&#44; it increases the expression of calreticulin&#44; but once this protein is over-expressed&#44; calreticulin inhibits the <span class="elsevierStyleItalic">cis</span>-bond of the PPAR-&#947;-RxR heterodimer to PPAR-&#947;response elements &#40;PPRE&#41;&#44; thus cancelling the transcriptional activation of PPAR-&#947;by fatty acids&#46; Through this mechanism&#44; calreticulin negatively regulates both the expression of PPAR-&#947;and other critical proadipogenic transcription factors such as C&#47;EBPa&#46;<span class="elsevierStyleSup">31 </span></p><p class="elsevierStylePara">Manidipine&#8217;s calcium channel blocking activity could impede the entrance of calcium into the cells&#44; thus reducing calcium concentrations in the endoplasmic reticulum&#44; and in turn&#44; that of calreticulin&#44; favouring the differentiation of adipocytes&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">EFFECTS OF CCB ON MICROALBUMINURIA </span></p><p class="elsevierStylePara">The renal protection is associated with cardiovascular protection as well&#44; and the evolution of albuminuria is an excellent predictor of both the evolution of renal function and the development of cardiovascular complications&#46;<span class="elsevierStyleSup">32 </span>The presence of microalbuminuria makes the use of ACE inhibitors or ARA-II necessary&#44; even as CCB are still considered for combined therapy&#46; In the absence of albuminuria&#44; and with maintained or diminished glomerular filtration rate&#44; CCB could be the first pharmacological option&#46; However&#44; a high percentage of patients do require ACE inhibitors and&#47;or ARA-II&#46;<span class="elsevierStyleSup">33 </span></p><p class="elsevierStylePara">Contrary to other dihydropyridines&#44; manidipine blocks T-type channels of efferent arterioles&#44; which diminishes glomerular pressure and&#44; consequently&#44; albumin excretion&#44; but at the same time it blocks L-type channels&#44; thus favouring the dilation of the afferent arteriole&#46; In this manner&#44; T-type calcium channel blockers &#40;CCB&#41;<span class="elsevierStyleSup">1&#44;7&#44;34 </span>influence haemodynamics through their antihypertensive effect&#46; Thus&#44; we could consider their effect as protective against kidney damage&#44; since the kidney is one of the target organs in hypertensive and diabetic patients&#46; The AMANDHA study &#40;Efficacy and Safety Assessment of Manidipine in Type 2 Diabetic Patients with Hypertension and Microalbuminuria Uncontrolled with Renin-Angiotensin System Blockers&#41;<span class="elsevierStyleSup">35 </span>compared manidipine and amlodipine in diabetic patients with uncontrolled hypertension and microalbuminuria&#46; Although both CCB are equally effective in reducing CRP and blood pressure&#44; the first implies fewer adverse effects&#46; Also&#44; the reduction in albuminuria and insulin resistance was significantly higher in patients treated with manidipine&#46; A recent study demonstrated yet again that manidipine is capable of significantly reducing albumin urine excretion in patients with essential hypertension without causing adverse effects&#44; and so the combination of manidipine with renin-angiotensin antagonists could be beneficial in these cases&#46;<span class="elsevierStyleSup">36 </span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">MANIDIPINE AND OXIDATIVE STRESS </span></p><p class="elsevierStylePara">Endothelial structure and function could improve considerably with the use of CCB&#46; Research such as the INSIGHT study &#40;International Nifedipine Intervention as a Goal in Hypertension Treatment&#41; and MIDAS study &#40;Myocardial Infarction Data Acquisition System&#41; demonstrates the superiority of these drugs as compared to thiazide diuretics in terms of lower increases in intimal thickness&#46;<span class="elsevierStyleSup">33&#44;37&#44;38 </span></p><p class="elsevierStylePara">The beneficial effects of calcium blockers in macrovascular endothelial cells must be demonstrated and justified through mechanisms that do not include calcium channels&#44; since these are not expressed in endothelial cells&#46;<span class="elsevierStyleSup">39&#44;40 </span>To this end&#44; some authors have postulated that the action of DHP in this type of tissue are related to their lipophilicity&#46;<span class="elsevierStyleSup">41 </span></p><p class="elsevierStylePara">Oxidative stress plays a fundamental role in the development of atherosclerosis&#46; Toba et al&#46; pointed out the antioxidant and anti-inflammatory effects of manidipine and other CCB such as amlodipine&#44; mediated by the increased expression of endothelial nitric oxide synthase &#40;eNOS&#41; and the inhibition of angiotensin converting enzyme &#40;ACE&#41; expression&#44; but not their possible activity in reducing blood pressure&#46; In this study&#44; the authors observed how manidipine normalises the reduction in the expression of both the eNOS gene and protein&#44; and reduces the over-expression of NADPH oxidase&#44; VCAM&#44; and MCP-1 in hypertensive rat aortas&#46;<span class="elsevierStyleSup">41 </span>Furthermore&#44; manidipine has another beneficial effect on atherogenesis&#44; as it inhibits the expression of LOX-1&#44; a low-density lipoprotein receptor induced into action by angiotensin II&#46;<span class="elsevierStyleSup">43 </span></p><p class="elsevierStylePara">Sun X et al&#46;<span class="elsevierStyleSup">44 </span>recently demonstrated that both in mature differentiated adipocytes and 3T3-L1 cells&#44; and in co-cultures of both cell types&#44; calcitrol increases the expression of inflammatory molecules such as MCP-1&#44; MIF&#44; M-CSF&#44; MIP&#44; IL-6<span class="elsevierStyleSup">45</span>&#44; TNF and CD14&#46; Treatment with nifedipine or dinitrophenol inhibits the activity of calcitrol&#44; which could reveal a calcium-dependent mechanism that requires mitochondrial uncoupling&#46; As such&#44; we could expect the blockage of calcium channels with manidipine to also show anti-oxidative and &#183; anti-inflammatory effect by reducing intracellular calcium levels&#46;</p><p class="elsevierStylePara">Our preliminary studies on smooth muscle cells revealed an increase in endothelial nitric oxide synthase &#40;eNOS&#41; gene after being treated with manidipine&#46; In response to many types of aggression&#44; the expression of eNOS in cells treated with manidipine is essentially stable&#44; compared to the control culture&#46; This data may reveal a beneficial effect of CCB against endothelial dysfunction &#40;Figure 2&#41;&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">CONCLUSIONS </span></p><p class="elsevierStylePara">T-type calcium channel blockers provide protection to the kidneys&#44; as they improve glomerular microcirculation due to their vasodilatory effect both on afferent and efferent arterioles&#46; Manidipine stands out from among these types of calcium channel blockers due to its anti-inflammatory activity&#44; which does not rely on the renin-angiotensin system&#44; and because of its possible beneficial effects against endothelial dysfunction&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Acknowledgements </span></p><p class="elsevierStylePara">This manuscript was developed with the aid of authors from the Fundaci&#243;n Mapfre-Guanarteme &#40;Mapfre-Guanarteme Foundation&#41; and Laboratorios Chiesi &#40;Chiesi Laboratories&#41;&#44; who we thank for their support and collaboration&#46; The authors declare a Research Agreement between Chiesi Farmaceuti&#173;ca S&#46;p&#46;A&#46; and the Research Unit of the Dr&#46; Negr&#237;n Gran Canaria</p><p class="elsevierStylePara"><a href="grande&#47;10643&#95;108&#95;14369&#95;en&#95;10643&#95;f1&#46;jpg" class="elsevierStyleCrossRefs"><img src="10643_108_14369_en_10643_f1.jpg" alt="Exposure of NIH-3T3 preadipocyte cells to manidipine activates the expression of the aP2 gene in a time-dependent manner&#46;"></img></a></p><p class="elsevierStylePara">Figure 1&#46; Exposure of NIH-3T3 preadipocyte cells to manidipine activates the expression of the aP2 gene in a time-dependent manner&#46;</p><p class="elsevierStylePara"><a href="grande&#47;10643&#95;108&#95;14370&#95;en&#95;10643&#95;f2&#46;jpg" class="elsevierStyleCrossRefs"><img src="10643_108_14370_en_10643_f2.jpg" alt="The Expression of eNOS in cells treated with angiotensin II and manidipine is significantly greater than in cells treated with just angiotensin II "></img></a></p><p class="elsevierStylePara">Figure 2&#46; The Expression of eNOS in cells treated with angiotensin II and manidipine is significantly greater than in cells treated with just angiotensin II </p><p class="elsevierStylePara"><a href="10643&#95;108&#95;14367&#95;en&#95;10643tabla&#95;1&#46;doc" class="elsevierStyleCrossRefs">10643&#95;108&#95;14367&#95;en&#95;10643tabla&#95;1&#46;doc</a></p><p class="elsevierStylePara">Table 1&#46; Calcium channels </p><p class="elsevierStylePara"><a href="10643&#95;108&#95;14368&#95;en&#95;10643tabla&#95;2&#46;doc" class="elsevierStyleCrossRefs">10643&#95;108&#95;14368&#95;en&#95;10643tabla&#95;2&#46;doc</a></p><p class="elsevierStylePara">Table 2&#46; Calcium channel blockers </p>"
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