UMLS:C0406810 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the ability of the angiotensin converting enzyme (ACE) inhibitor imidapril hydrochloride, and of the calcium channel blocker amlodipine besilate, to prevent nephrosclerosis and left ventricular hypertrophy (LVH) in rats with hypertension induced by chronic inhibition of nitric oxide (NO). Male Wistar rats were given distilled water (control), NG-nitro-L-arginine methyl ester (L-NAME) 500 mg/L, L-NAME plus imidapril 10 mg/L or 100 mg/L, or L-NAME plus amlodipine 50 mg/L or 100 mg/L in the drinking water (n = 10-12). We then collected 24-h urine samples at 2, 4, and 6 weeks, obtained blood samples at 6 weeks, and histologically examined the kidney and heart. L-NAME markedly reduced the levels of NO metabolites in serum and urine while increasing the tail-cuff blood pressure, the urinary albumin level (1.90 +/- 0.65 v 0.05 +/- 0.02 mg/day/100 g in control), and the area of the left ventricular wall (83.3 +/- 3.0 v 69.8 +/- 1.8 mm2 in control). Nephrosclerosis and myocardial interstitial fibrosis were documented histologically. The plasma renin activity was significantly higher in rats treated with L-NAME than in the control rats. The concomitant administration of imidapril (10 mg/L) with L-NAME completely normalized the tail-cuff pressure, the LVH (70.8 +/- 1.8 mm2), the albuminuria (0.05 +/- 0.01 mg/day/100 g), and the histologic changes. Amlodipine (50 mg/L) also ameliorated the L-NAME-induced effects, but to a lesser extent. Thus, the chronic inhibition of NO synthesis in rats produced nephrosclerosis and LVH that were effectively prevented by giving imidapril at a dose lower than that of amlodipine. We conclude that ACE inhibitors can prevent nephrosclerosis and LVH even in the presence of a reduction in NO production, implying that in rats the inhibition of the renin-angiotensin system is more effective than the blockade of calcium channels in preventing hypertensive tissue injury.
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PMID:Antihypertensive agents prevent nephrosclerosis and left ventricular hypertrophy induced in rats by prolonged inhibition of nitric oxide synthesis. 965 29

Our previous study found that angiotensin-converting enzyme (ACE) inhibitors and amlodipine induce NO release from coronary microvessels through a kinin-dependent mechanism. The goal of this study was to determine whether amlodipine could potentiate NO formation during ACE inhibition. Coronary microvessels were isolated from 16 mongrel dogs. Nitrite, the hydration product of NO, from coronary microvessels was quantified by using the Griess reaction. Bradykinin and kallikrein all significantly increased nitrite release from coronary microvessels in a concentration-dependent manner. The ACE inhibitor, ramiprilat, potentiated these effects. Amlodipine also markedly potentiated nitrite production by ramiprilat. For instance, amlodipine (10(-10) M) enhanced nitrite release induced by ramiprilat (10(-7) M) from 122 +/- 9 to 168 +/- 14 pmol/mg (p < 0.05 vs. ramiprilat). Nitrite release potentiated by ramiprilat and amlodipine was entirely blocked by N(omega)-nitro-L-arginine methyl ester (L-NAME, an inhibitor of NO synthase), HOE 140 (Icatibant, a specific B2-kinin receptor antagonist), and dichloroisocoumarin (DCIC, a serine protease inhibitor that blocks local kinin formation). These results clearly show that there is a synergistic effect on NO formation when amlodipine is combined with ACE inhibition. Our data suggest that kinin-mediated coronary NO production may contribute importantly to the beneficial therapeutic action of ACE inhibitors, especially in combination with amlodipine in the treatment of heart disease.
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PMID:Amlodipine enhances NO production induced by an ACE inhibitor through a kinin-mediated mechanism in canine coronary microvessels. 1067 50

The production of endogenous nitric oxide, which regulates myocardial oxygen consumption, is decreased in heart failure. As with angiotensin-converting enzyme (ACE) inhibitors, amlodipine, a calcium antagonist, increases kinin-mediated nitric oxide production in coronary microvessels. We investigated the possibility of synergy between ACE inhibitors and amlodipine in regulating myocardial oxygen consumption. Left ventricular myocardium was isolated from 6 healthy dog hearts and 5 human hearts with end-stage heart failure at the time of orthotopic heart transplantation. Myocardial oxygen consumption was measured before and after administration of bradykinin, S-nitroso N-acetyl penicillamine (SNAP, a nitric oxide donor), ramiprilat (an ACE inhibitor), amlodipine, and the combination of a sub-threshold dose of ramiprilat (10(-8) md/L) + amlodipine. These experiments were repeated with L-nitro-arginine methyl ester (L-NAME, an inhibitor of nitric oxide synthesis), dichloroisocoumarin (an inhibitor of kinin synthesis), and HOE 140 (a B2 kinin-receptor antagonist). Baseline myocardial oxygen consumption in canine hearts was 182 +/- 21 nmol/g/min. Bradykinin and SNAP caused dose-dependent reductions in myocardial oxygen consumption (p <0.05). Ramiprilat and amlodipine caused a 10 +/- 3.2% and 11 +/- 0.8% reduction in myocardial oxygen consumption, respectively, when used alone (p <0.05). In the presence of a subthreshold dose of ramiprilat, amlodipine caused a larger (15 +/- 1.7%) reduction in myocardial oxygen consumption compared with either drug used alone (p <0.05). In human hearts, baseline myocardial oxygen consumption was 248 +/- 57 nmol/g/min. Amlodipine caused a larger reduction in myocardial oxygen consumption when used with ramiprilat (22 +/- 3.2%) as compared with amlodipine alone (15 +/- 2.6%). The effect of both drugs was attenuated by L-NAME, dichloroisocoumarin, and HOE 140 (p <0.05). In conclusion, ACE inhibitors and amlodipine act synergistically to regulate myocardial oxygen consumption by modulating kinin-mediated nitric oxide release, and this combination of drugs may be useful in the treatment of heart failure.
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PMID:Synergy of amlodipine and angiotensin-converting enzyme inhibitors in regulating myocardial oxygen consumption in normal canine and failing human hearts. 1075 May 96

Amlodipine increases NO levels in coronary vessels and aorta via bradykinin-dependent mechanisms in vitro. We have previously reported that a long-acting Ca channel blocker, benidipine, increases cardiac NO levels in ischemic canine hearts, suggesting that benidipine may also protect against ischemia and reperfusion injury via bradykinin- and NO-dependent mechanisms. We examined this possibility. In open chest dogs, the left anterior descending coronary artery was perfused with blood through a bypass tube and was occluded for 90 min followed by 6 hours of reperfusion. Infarct size was assessed by TTC staining at 6 hours of reperfusion. When benidipine doses of 50, 100, and 200 ng/kg/min were infused via the bypass tube between 10 min prior to the onset of ischemia and after 60 min of reperfusion, systemic blood pressure did not change significantly. Infarct size decreased with the administration of benidipine (50, 100, and 200 ng/kg/min) when compared to the untreated condition (24.8+/-2.5, 17.3+/-3.1, and 16.5+/-2.0 vs. 43.4+/-5.6%, respectively) associated with the increased release of NO and bradykinin in the coronary venous blood upon reperfusion. Myeloperoxidase activity of the myocardium increased after 6 hours of reperfusion, which was attenuated by benidipine. The limitation of infarct size and the increase in myeloperoxidase activity were completely blunted by either L-NAME or HOE140. There were no significant differences in collateral blood flow assessed by the microsphere method after 45 min of ischemia for any of the groups. Thus, we conclude that the Ca channel blocker, benidipine, limits infarct size via bradykinin- and NO-dependent mechanisms.
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PMID:Benidipine, a long-acting Ca channel blocker, limits infarct size via bradykinin- and NO-dependent mechanisms in canine hearts. 1171 85

Amlodipine is a mixture of two enantiomers, one having L-type channel blocking activity (S-) and the other about 1,000-fold weaker activity and of little known other activity (R+). To determine whether the R+ enantiomer releases nitric oxide, the ability of amlodipine, its enantiomers, and nitrendipine to release nitric oxide in isolated coronary microvessels and to regulate cardiac tissue oxygen consumption via nitric oxide release was studied in vitro. Amlodipine and the R+ enantiomer released nitric oxide in a concentration-dependent fashion, increasing nitrite release from coronary microvessels by 57 +/- 12 and 45 +/- 5 pmol/mg/20 min at 10(-6) M (p < 0.05 from control). Nitrite release was entirely blocked by N(omega)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, and HOE-140, a B2-kinin receptor antagonist. The S- enantiomer had no effect on nitrite release at any concentration. Amlodipine and the R+ enantiomer also reduced oxygen consumption in canine cardiac tissue in vitro and this was in an L-NAME-blockable manner. The S- enantiomer of amlodipine had no effect. This study shows that the R+ enantiomer of amlodipine is responsible for the release of nitric oxide and not the S- enantiomer (the L-type calcium channel blocking portion of amlodipine). Interestingly, nitric oxide release is dependent on the production of kinins because it is blocked by HOE-140. This study defines a potentially important property by which calcium channel blockers may release nitric oxide and may contribute to their use in the treatment of cardiovascular disease.
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PMID:Paradoxical release of nitric oxide by an L-type calcium channel antagonist, the R+ enantiomer of amlodipine. 1179 Oct 6

1. We investigated the nitric oxide (NO) dependence of vasorelaxation in response to different calcium channel blockers (CCB), in rabbit femoral artery in vivo. 2. Anaesthetized rabbits underwent femoral artery ligation, and blood from the proximal artery was returned distal to the ligature through a constant infusion pump. The effects of local injection of CCB on perfusion pressure and plasma nitrite+nitrate (NO(x), which reflects local NO biosynthesis) concentration in this system were determined. 3. Intra-arterial verapamil, nifedipine or amlodipine 10 micromol x kg(-1) each reduced perfusion pressure. Pre-treatment with intra-arterial N(G)-nitro-L-arginine methyl ester (L-NAME, a NO synthase inhibitor) 1 micromol x kg(-1) did not affect responses to verapamil or nifedipine, but attenuated the reduction in perfusion pressure to amlodipine, from 33.2+/-2.1% to 22.5+/-1.6% (P=0.002). 4. Intra-arterial amlodipine--unlike verapamil or nifedipine--increased femoral venous NO(x), from 9.1+/-0.4 microM to 14.1+/-0.5 microM (P=0.005). 5. The bradykinin B2 receptor antagonist HOE 140, 30 mg x kg(-1), attenuated the reduction in perfusion pressure and abolished the rise in venous NO(x) concentration, following intra-arterial amlodipine. 6. Amlodipine potently inhibited serum angiotensin converting-enzyme (ACE) activity in vitro, as effectively as enalapril at similar concentrations. 7. These results suggest that the vasorelaxant effects of nifedipine and verapamil are NO-independent, whereas those of amlodipine are partly NO-dependent, in rabbit femoral artery in vivo. This effect of amlodipine occurs through B2 receptor activation, and may be related to an increase in local bradykinin through inhibition of ACE.
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PMID:Amlodipine, but not verapamil or nifedipine, dilates rabbit femoral artery largely through a nitric oxide- and kinin-dependent mechanism. 1202 40

Chronic inhibition of nitric oxide (NO) synthesis induces cardiac remodeling independent of systemic hemodynamic changes in rats. We examined whether long-acting dihydropyridine calcium channel blockers block myocardial remodeling and whether the activation of 70-kDa S6 kinase (p70S6K) and extracellular signal-regulated kinase (ERK) are involved. Ten groups of Wistar-Kyoto rats underwent 8 weeks of drug treatment consisting of a combination of NO synthase inhibitor NG-nitro-l-arginine methyl ester (L-NAME), an inactive isomer (D-NAME), amlodipine (1 or 3 mg/kg per day), or benidipine (3 or 10 mg/kg per day). In other groups, L-NAME was also used in combination with a p70S6K inhibitor (rapamycin), a MEK inhibitor (PD98059), and hydralazine. Systolic blood pressure (SBP), heart rate, and left ventricular weight (LVW) were measured, together with histological examinations and kinase assay. L-NAME increased SBP and LVW (1048+/-22 versus 780+/-18 mg, P<0.01) compared with the control, showing a significant increase in cross-sectional area of cardiomyocytes after 8 weeks. Amlodipine, benidipine, or hydralazine equally attenuated the increase in SBP induced by L-NAME. However, both amlodipine and benidipine but not hydralazine attenuated the increase in LVW by L-NAME (789+/-27, 825+/-20 mg, P<0.01, and 1118+/-29 mg, NS, respectively), also confirmed by histological analysis. L-NAME caused a 2.2-fold/1.8-fold increase in p70S6K/ERK activity in myocardium compared with the control, both of which were attenuated by both amlodipine and benidipine but not hydralazine. Both rapamycin and PD98059 attenuated cardiac hypertrophy in this model. Thus, long-acting dihydropyridine calcium channel blockers inhibited cardiac hypertrophy induced by chronic inhibition of NO synthesis by inhibiting both p70S6K and ERK in vivo.
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PMID:Long-acting Ca2+ blockers prevent myocardial remodeling induced by chronic NO inhibition in rats. 1262 37

Amlodipine (a new class of calcium channel antagonist) has been shown to limit the progression of arteriosclerosis and decrease the incidence of cardiovascular events. The mechanisms underlying the beneficial effects of amlodipine, however, remain unclear. Therefore, we hypothesized that amlodipine attenuates the development of arteriosclerosis through the inhibition of inflammation in vivo. Long-term inhibition of nitric oxide (NO) by administration of a NO synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME), to rats induces coronary vascular inflammation [monocyte infiltration, monocyte chemoattractant protein-1 (MCP-1) expression, increased activity of angiotensin-converting enzyme (ACE)], and arteriosclerosis. Here, we used the rat model to investigate the anti-inflammatory effects of amlodipine in vivo. Treatment with amlodipine markedly inhibited the L-NAME-induced increase in vascular inflammation, oxidative stress, and local ACE and Rho activity and prevented arteriosclerosis. Interestingly, amlodipine prevented the L-NAME-induced increase in MCP-1 receptor CCR2 expression in circulating monocytes. Amlodipine markedly attenuated the high mortality rate at 8 wk of treatment. These data suggest that amlodipine attenuated arteriosclerosis through inhibiting inflammatory disorders in the rat model of long-term inhibition of NO synthesis. The anti-inflammatory effects of amlodipine seem to be mediated not only by the inhibition of local factors such as MCP-1 but also by the decrease in CCR2 in circulating monocytes. Inhibition of the MCP-1 to CCR2 pathway may represent novel anti-inflammatory actions of amlodipine beyond blood pressure lowering.
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PMID:Novel anti-inflammatory actions of amlodipine in a rat model of arteriosclerosis induced by long-term inhibition of nitric oxide synthesis. 1459 42

The cardiac effects of calcium channel blockers (CCBs) related to cardiac remodeling are inconsistent. Matrix metalloproteinases (MMPs) contribute to tissue remodeling. Cardiac fibroblasts play an important role in the regulation of collagen degradation by MMPs. Using gelatin zymography, Western blotting, Griess reagent, and a calcium kit-fluo 3, we investigated the effects of nifedipine, verapamil, diltiazem, and amlodipine on MMP-2 expression and further elucidate the mechanisms in cultured rat cardiac fibroblasts. Nifedipine increased and amlodipine decreased the expression of MMP-2; however, neither verapamil nor diltiazem altered MMP-2 expression. Nifedipine also increased nitrite production, and this increase was blunted by a nitric oxide (NO) synthases inhibitor (L-NAME). Nifedipine-induced MMP-2 expression was also blunted by L-NAME. An NO donor (sodium nitroprusside) induced MMP-2 expression. Data indicated that nifedipine might increase MMP-2 expression through a possible NO-dependent pathway. Amlodipine had no influence on nitrite production. The amlodipine-induced decrease of MMP-2 expression was abolished by two protein tyrosine kinase inhibitors, genistein and herbimycin A, indicating that amlodipine might decrease MMP-2 expression through a possible protein tyrosine kinase pathway. None of the four CCBs could alter the fluoscence intensity of fluo 3, indicating that the effects of CCBs on MMP-2 expression were independent of the variation in intracellular C2+ concentration. Our findings revealed that different CCBs exerted different effects on MMP-2 expression in cardiac fibroblasts.
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PMID:Different effects of calcium channel blockers on matrix metalloproteinase-2 expression in cultured rat cardiac fibroblasts. 1524 4

Amlodipine reduces oxidative stress that decreases NO and adenosine release. This study was undertaken to examine whether amlodipine mediates coronary vasodilation and improves myocardial metabolism and contractility in ischemic hearts via either adenosine- or NO-dependent mechanisms. In open-chest dogs, amlodipine (2 mug kg per min) was infused at the minimum dose that caused maximal coronary vasodilation. The perfusion pressure was reduced in the left anterior descending coronary artery so that coronary blood flow (CBF) decreased by 50%. Amlodipine increased the difference of the adenosine level (VAD (Ado): 119+/-14 to 281+/-46 nM) and the nitrate+nitrite level (VAD (NOx): 7.8+/-1.3 to 16.1+/-1.1 muM) between coronary venous and coronary arterial blood, and also increased CBF (50+/-3 to 69+/-6 ml/100 g/min). These changes were partially reversed by either 8-sulfophenyeltheophylline (8SPT) or l(omega)-nitro arginine methyl ester (l-NAME), and were completely blocked by both 8SPT and l-NAME. The reduction of CBF increased VAD (8-iso-prostaglandin F(2alpha)), and this increase was reduced by amlodipine (10.8+/-1.1 to 5.0+/-0.5 pg/ml). In addition, pretreatment with superoxide dismutase mimicked the coronary effects of amlodipine and blunted the response to amlodipine administration. Amlodipine-induced coronary vasodilation via both adenosine- and NO-dependent mechanisms. Adenosine and NO may interact in ischemic hearts to mediate coronary vasodilation by amlodipine.
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PMID:A calcium channel blocker amlodipine increases coronary blood flow via both adenosine- and NO-dependent mechanisms in ischemic hearts. 1608 89

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