amlodipine Norvasc
Synergistic effect of Nicorandil and Amlodipine on tissue defense system during experimental myocardial infarction in rats.

Sathish V, Ebenezar KK, Devaki T.

Department of Biochemistry and Molecular Biology, University of Madras, Guindy Campus, Chennai, India.

The synergistic protective effect of Nicorandil (K(ATP) channel opener) and Amlodipine (calcium channel blocker) on heart tissue antioxidant defense system and lipid profile were examined on isoproterenol induced myocardial infarction in rats. The rats given isoproterenol (150 mg kg(-1) daily, i.p.) for 2 days showed significant changes in antioxidant defense system and lipid profile levels. Pretreatment with Nicorandil (2.5 mg kg(-1) daily, p.o.) and Amlodipine (5.0 mg kg(-1) daily, p.o.) for 3 days significantly prevented these alterations and restored the enzyme activities to near normal. These findings indicate the synergistic protective effect of Nicorandil and Amlodipine on tissue defense system and lipid metabolism during isoproterenol induced cardiac damage.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12619898&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Improvement of insulin sensitivity for glucose metabolism with the long-acting Ca-channel blocker amlodipine in essential hypertensive subjects.

Harano Y, Kageyama A, Hirose J, Asakura Y, Yokota T, Ikebuchi M, Suzuki M, Omae T.

Department of Medicine, National Cardiovascular Center, Osaka, Japan.

To clarify whether the long-acting calcium-channel blocker amlodipine restores insulin insensitivity in essential hypertension, insulin sensitivity tests were performed at the physiological steady-state insulin level (45 to 55 microU/mL) before and after amlodipine (2.5 to 7.5 mg/d) administration for 2 to 4 months in borderline and mild essential hypertensive subjects. Instead of somatostatin, Sandostatin (Sandoz, Basel, Switzerland) was used for the determination of steady-state plasma glucose (SSPG) in the same way as previously described. SSPG, which was initially high (212.9 +/- 18.0 mg/dL, mean +/- SE), was significantly reduced to 169.8 +/- 14.7 after amlodipine treatment. Responses of ketone bodies during the test at 30 minutes, which reflect the insulin effect on lipolysis in adipose tissue and hepatic fatty acid oxidation, also improved after amlodipine treatment. Norepinephrine, noted to be mildly elevated after amlodipine treatment, decreased during the sensitivity test at 2 hours probably due to the sedative effect, without any change in the fractional extraction of Na. This indicates that the physiological level of insulin does not activate sympathetic nerve activity or stimulate Na reabsorption. The long-acting calcium-channel blocker amlodipine has significantly improved the initially decreased insulin sensitivity for glucose metabolism at least partially in borderline or mild essential hypertension.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7885275&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Effects of amlodipine on coronary hemodynamics and vascular responses to sympathetic stimulation in patients with coronary heart disease.

Saino A, Pomidossi G, Perondi R, Gregorini L, Rimini A, Alessio P, Zanchetti A, Mancia G.

Cattedra di Medicina Interna, Universita di Milano, Italy.

Dihydropyridines (DHPs) exert a powerful coronary vasodilator action, but whether they actually affect the coronary vasomotor effects elicited by an increase in cardiac sympathetic drive is controversial. We assessed the effects of the DHP calcium antagonist amlodipine on coronary hemodynamics and vascular response to sympathetic activation in patients with coronary heart disease. In the control condition, mean arterial pressure (MAP, aortic catheter), heart rate (HR, ECG), rate-pressure product (RPP), coronary sinus blood flow (CBF, thermodilution) and coronary vascular resistance (CVR) (ratio between MAP and CBF) were measured in all our case series (13 patients with angiographically documented severe coronary artery disease) before and during a 2-min cold pressor test (CPT) and a 30-s diving (D) and, in the 8 patients of this case series who were smokers, also before and during smoking a cigarette (S, nicotine content 1.0 mg for 10 min). The same protocol used in control condition was repeated 30 min after intravenous (i.v.) bolus administration of 11 mg amlodipine. CPT, diving, and smoking increased MAP and RPP and caused a marked and significant increase in CVR (+12.1 +/- 4.8, +30.4 +/- 6.8, and +16.8 +/- 7.2%, respectively). Amlodipine reduced MAP, increased CBF, and caused a marked decrease in CBF. The drug did not modify responses to CPT and diving or pressure and HR responses to smoking, whereas the smoking-induced increase in coronary vascular resistance was attenuated after amlodipine administration (+3.2 +/- 2.7%, p < 0.05 vs. control condition). Thus, amlodipine does not attenuate the sympathetic coronary vasoconstrictor effects of CPT and diving.(ABSTRACT TRUNCATED AT 250 WORDS)

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amlodipine Norvasc
Effects of amlodipine on glomerular filtration, growth, and injury in experimental hypertension.

Dworkin LD, Tolbert E, Recht PA, Hersch JC, Feiner H, Levin RI.

Department of Medicine, Brown University, Rhode Island Hospital, Providence 02903, USA.

The objective of this study was to determine whether the calcium antagonist amlodipine could slow the progression of chronic renal disease. We examined the effects of amlodipine on kidney structure and function in two experimental models of hypertension. In the first study, adult, male Munich Wistar rats underwent uninephrectomy and were given weekly injections of desoxycorticosterone and 1% saline for drinking. Rats ingested normal chow or chow containing amlodipine for 8 weeks. The drug reduced systemic blood pressure, but glomerular filtration rate, kidney weight, proteinuria, and morphological evidence of glomerular injury were not affected. In the second study, male spontaneously hypertensive rats underwent uninephrectomy at 5 weeks of age and were followed for 6 months, during which they received no therapy or amlodipine. The drug dose was determined in preliminary studies to be the highest dose not associated with marked growth retardation. Again, although systemic blood pressure was significantly reduced by amlodipine, proteinuria and the prevalence of glomerulosclerosis were similar in amlodipine-treated and control spontaneously hypertensive rats. Micropuncture studies revealed that glomerular pressure remained elevated in amlodipine-treated spontaneously hypertensive rats. Kidney weight and glomerular volume were also similar in amlodipine-treated and control rats. Amlodipine also failed to inhibit platelet aggregation. Therefore, antihypertensive therapy with amlodipine fails to reduce glomerular pressure in spontaneously hypertensive rats as well as glomerular size and injury in spontaneously hypertension rats and desoxycorticosterone-salt hypertension. Although other dihydropyridine calcium antagonists have been found to reduce experimental glomerular injury, these data suggest that amlodipine may not prevent hypertensive nephrosclerosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8567047&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Effects of amlodipine, atorvastatin and combination of both on advanced atherosclerotic plaque in APOE*3-Leiden transgenic mice.

van de Poll SW, Delsing DJ, Wouter Jukema J, Princen HM, Havekes LM, Puppels GJ, van der Laarse A.

Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.

Combined treatment of statins and calcium channel blockers has been suggested to be superior to statin therapy alone. We quantified the anti-atherosclerotic potential of amlodipine, atorvastatin and their combination on existing atherosclerotic plaques in the aorta of APOE*3-Leiden transgenic mice. Sixty-two mice were fed a high cholesterol containing diet for 18 weeks. A subgroup of 10 mice was then killed. All other mice received the diet for another 18 weeks, alone (late control group), along with 0.01% atorvastatin, 0.002% w/w amlodipine, or their combination (all groups, n = 13). Atherosclerotic lesions, collagen content and monocyte adherence were quantified using standard histology (aortic root). Raman spectroscopy was used to quantify the content of cholesterol and calcification (aortic arch). Compared to the late control group, treatment with amlodipine, atorvastatin or the combination, reduced atherosclerostic lesion area by, respectively, 25%, 39% and 46% in the aortic root (P < 0.01) and by 53%, 55% and 60% in the aortic arch (P < 0.05). Atorvastatin, but not amlodipine reduced the adherence of monocytes in the intima. Lesion severity and plaque contents of collagen, cholesterol and calcification were equal for all treatment groups. Neither treatment resulted in regression of atherosclerotic plaque size. In conclusion, both atorvastatin and amlodipine significantly retard the progression of existing atherosclerotic lesions. No additive effect of the combination of amlodipine and atorvastatin could be observed in this study.

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amlodipine Norvasc
Structure-function relationships of calcium antagonists. Effect on oxidative modification of low density lipoprotein.

Rojstaczer N, Triggle DJ.

School of Pharmacy, State University of New York at Buffalo, NY 14260, USA.

Human low density lipoprotein (LDL) incubated with active Ca2+ antagonists from three different chemical groups, 1,4-dihydropyridines that are of reduced activity as Ca2+ antagonists, vitamin E, and probucol, was more resistant than control to copper- or human monocyte-induced oxidation, as assessed by thiobarbituric acid reactive substance (TBARS) content, degradation by J774 macrophages, and relative electrophoretic mobility on agarose gel. In the copper-induced oxidation system, the drugs tested reduced the TBARS levels of LDL in a concentration-dependent manner. The order of potency was vitamin E > felodipine > 2-chloro analog of nifedipine > nifedipine > amlodipine, nitrendipine, verapamil > diltiazem. In agreement with the results of the TBARS assay, felodipine (25 microM) was also the most effective calcium antagonist in the degradation assay, inducing a significant (P<0.05) 97 +/- 2% reduction in the amount of oxidized [125I]LDL degraded by J774 macrophages compared with nifedipine and its 4-nitro analog, amlodipine, and verapamil. The relative mobility of oxidized LDL on agarose gel was reduced significantly (P<0.05) by felodipine (50 microM) and amlodipine (25 and 50 microM) when compared with control, and was similar to that of native LDL, suggesting an effect of these drugs on the net negative charge of oxidized LDL. In the cell-induced oxidation system, both nifedipine and felodipine (25 microM) induced significant (P<0.05) reductions in the TBARS content of LDL (96 +/- 2 and 65 +/- 9%, respectively) compared with amlodipine, verapamil and the 4-nitro analog of nifedipine. However, in this oxidation system nifedipine was a more effective antioxidant than felodipine. Analysis of the structure-function relationships for the effect of 1,4-dihydropyridines on the oxidative modification of LDL suggests an important role for the 2-substitution of the phenyl ring, and an essential role for the dihydropyridine ring. This study clearly shows that Ca2+ antagonists from different chemical groups have a concentration-dependent effect as antioxidants against LDL oxidation. However, the order of potency of the drug depends on the oxidation system and the assay used to measure the antioxidant effect. Our data suggest that such a protective effect of Ca2+ antagonists against LDL oxidation could play a role in the antiatherosclerotic effect of these drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8615882&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Mechanism of the antiischemic effect of mibefradil, a selective T calcium channel blocker in dogs: comparison with amlodipine.

Roux S, Buhler M, Clozel JP.

Pharma Division, Hoffmann-La Roche Ltd., Basel, Switzerland.

Calcium channel blockers are active in variant angina principally by preventing coronary vasospasm. However, a direct antiischemic effect may also occur. In open-chest dogs, an attack of variant angina was mimicked by a 2-min critical coronary stenosis, and the following reversible myocardial ischemia was assessed by measuring the decrease of segmental shortening. We compared the antiischemic mechanism of mibefradil, a T and L calcium channel blocker, with that of amlodipine, a pure L channel blocker. Both drugs showed a similar relationship between the decrease of the rate-pressure product and the antiischemic effect, but only mibefradil reduced heart rate. Amlodipine and mibefradil at the highest doses tested (20 and 70 micrograms/kg/min, respectively) restored 68 +/- 8 and 76 +/- 5% of segmental shortening in the ischemic area, respectively, as compared with preischemic values. Matching blood pressure (by intraaortic balloon) or heart rate (by atrial pacing) to predrug values showed that the antiischemic effect was mainly afterload-dependent for amlodipine and heart rate-dependent for mibefradil. We conclude that in variant angina, in addition to their antivasospastic effects, calcium channel blockers may be antiischemic by a direct myocardial effect associated with a decrease of the rate pressure product. Blockade of the T channel does not seem to participate in the direct antiischemic effect of mibefradil but could explain the decrease of heart rate.

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amlodipine Norvasc
Cardiac implications of amlodipine-dantrolene combinations.

Freysz M, Timour Q, Bernaud C, Bertrix L, Faucon G.

Department of Anesthesiology and Intensive Care, General Hospital, Dijon.

PURPOSE: Cardiac disorders, cardiac arrest and ventricular fibrillation in the most severe cases, have been observed after the administration of dantrolene to patients treated by verapamil for coronary artery disease. This study was designed to examine the interaction of dantrolene with amlodipine, a dihydropyridine. METHODS: In 12 anaesthetized, open-chest pigs, the effects of the interaction have been studied on heart rate, atrioventricular conduction, monophasic action potential duration, intraventricular conduction time, left ventricular dP/dt max and mean blood pressure. The study was performed with normal coronary circulation and ischaemia of a large area of the left ventricule, obtained by complete occlusion of the left anterior descending coronary artery near its origin, under pacing at a constant high rate, 180 beats.min-1. The drugs were injected iv, amlodipine 0.4 mg.kg-1 first and dantrolene 3.0 mg.kg-1 20 min later in six animals and the order was reversed in the other animals. RESULTS: Sinus rate and atrioventricular conduction were not affected by amlodipine, but were slowed by dantrolene added (145 +/- 9 to 131 +/- 7 beats.min-1, P < 0.01 and 150 +/- 15 to 180 +/- 20 msec, P < 0.01). In contrast, amlodipine or amlodipine plus dantrolene did not change MAP duration or conduction time in the normal heart. Similarly, they did not alter the maximal variations due to ischaemia, but delayed them, while prolonging the time to onset of fibrillation (111 +/- 8 to 343 +/- 33 sec. P < 0.001 with amlodipine alone, 289 +/- 11 to 323 +/- 16 sec, P < 0.05 with dantrolene). Left ventricular dP/dt max was lowered from 1670 +/- 86 to 1532 +/- 50 mmHg.sec-1 (P < 0.001) and mean blood pressure from 79 +/- 4 to 70 +/- 3 mmHg (P < 0.01) by amlodipine, but dantrolene did not enhance and even counteracted these effects. Finally, potassium plasma concentration did not increase above 5.1 +/- 0.2 mmol.L-1 under the dual influence of amlodipine and dantrolene. CONCLUSION: In usual clinical doses, dantrolene may be safely administered concurrently with amlodipine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8665636&dopt=Abstract amlodipine Norvasc