amlodipine Norvasc
Effects of chronic treatment with amlodipine in streptozotocin-diabetic and spontaneously hypertensive rats.

Srinivasan PS, Hakim ZS, Santani DD, Goyal RK.

Department of Pharmacology, L.M. College of Pharmacy, Navrangpura, Ahmedabad, India.

Calcium antagonists have been reported to alter insulin secretion and insulin sensitivity. However, there still exists a controversy over the benefits of calcium antagonists in the conditions when diabetes mellitus and hypertension coexist. In the present study the effects of six-week chronic amlodipine treatment (5 mg kg-1 p.o.) on insulin sensitivity and serum lipid levels in streptozotocin (STZ)-diabetic and spontaneously hypertensive (SH) rats were investigated. Intravenous injection of STZ produced glucosuria (> 2%). hyperglycaemia, hypoinsulinemia, polydipsia, polyphagia, loss of body weight, hypercholesterolemia, hypertriglyceridaemia, hypertension and bradycardia. SH rats were found to have significantly higher insulin levels compared to their Wistar controls. Treatment of rats with amlodipine in diabetic and diabetic-hypertensive animals significantly prevented STZ-induced loss of body weight, hypertension and bradycardia. It also significantly prevented STZ-induced hyperglycaemia in both STZ-diabetic Wistar and SH rats. The insulin levels were decreased in the non-diabetic treated Wistar rats but were unaltered in the non-diabetic SH and the diabetic Wistar and SH rats. There was a significant reduction in cholesterol levels in diabetic Wistar and SH rats. In conclusion the present study revealed beneficial effects of amlodipine treatment in hyperinsulinemic, diabetic and/or hypertensive rats.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9299205&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Analgesic effects of amlodipine and its interaction with morphine and ketorolac-induced analgesia.

Dogrul A, Yesilyurt O, Deniz G, Isimer A.

Department of Pharmacology, Faculty of Medicine, Gulhane Medical Military Academy, Ankara, Turkey.

1. The antinociceptive effects of amlodipine, administered subcutaneously (s.c.), intracerebroventricularly (i.c.v.) and intrathecally (i.t.) were examined with the acetic acid writhing and tail-flick tests in mice. Amlodipine was also tested in combination with morphine and ketorolac. Isobolographic analyses were used to define the nature of functional interactions between amlodipine and morphine or ketorolac. 2. The s.c. (0.1, 1.25, 2.5, 5 and 10 mg/kg), i.c.v. (2.5, 5, 10 and 20 micrograms/mice) and i.t. (2.5, 5, 10 and 20 micrograms/mice) administration of amlodipine exhibited a dose-dependent antinociceptive effect in the writhing test but had no effect on the tail-flick latency. Isobolographic analyses revealed an additive interaction between amlodipine and morphine or ketorolac in the writhing test. 3. These results suggest that amlodipine induces antinociception and increases antinociceptive action of morphine and ketorolac, possibly through a decrease in cellular calcium availability.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9347336&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Combined effects of an angiotensin converting enzyme inhibitor and a calcium antagonist on renal injury.

Bakris GL, Griffin KA, Picken MM, Bidani AK.

Department of Preventive Medicine, Rush Hypertension Center, Rush-Presbyterian-St Luke's Medical Center, Chicago, Illinois 60612, USA.

BACKGROUND: Angiotensin converting enzyme inhibitors have uniformly been shown to prevent the development both of proteinuria and of glomerulosclerosis in rats with a remnant kidney. Conversely, dihydropyridine calcium antagonists (DCA) have failed to demonstrate such a benefit in spite of causing an equivalent reduction in blood pressure. OBJECTIVE: To test the hypothesis that concomitant administration of an angiotensin converting enzyme inhibitor and a DCA would lead to a smaller increase both in proteinuria and in glomerulosclerosis relative to that caused by administration of a DCA alone at similar levels of blood pressure. METHODS: Experiments were carried out using Sprague-Dawley rats that had been subjected to five-sixths renal ablation. Animals were allocated randomly to one of four groups: control (no treatment), amlodipine (A rats), benazepril (B rats), or a combination of benazepril and amlodipine (B + A rats). We implanted intraperitoneal sensors for telemetric monitoring of the animal's blood pressure. Other parameters measured at baseline included proteinuria and inulin clearance. After approximately 7 weeks all of the parameters were remeasured and animals killed for morphologic assessment of the kidney. RESULTS: The B + A rats had lower levels of proteinuria than did the rats in group A (21 +/- 12 mg/day for B + A rats versus 59 +/- 24 mg/day for A rats, P < 0.05). The degree of glomerulosclerosis in the B + A rats was also reduced markedly compared with that in A rats (12 +/- 4% for B + A rats versus 43 +/- 12% for A rats, P < 0.05). Moreover, the results on proteinuria and glomerulosclerosis of B + A rats were similar to those for B rats. These differences could not be explained totally in terms of differences in blood pressure control (144 +/- 12 mmHg in A rats versus 132 +/- 13 mmHg in B + A rats, NS). CONCLUSION: The results were consistent with the observation that a combination of benzepril and amlodipine provides additional protection against renal injury compared with that provided by amlodipine alone. The mechanism for this benefit is not known.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9350593&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
The effect of cyclosporine A and amlodipine on the activity of gamma-glutamyl transpeptidase in mouse cerebral cortex.

Maj JG, Tomaszewski JJ.

Department of Clinical Biochemistry and Environmental Toxicology, School of Medicine, Lublin, Poland.

The effect of cyclosporine A (CsA) and dihydropyridine calcium channel blocker (CCB) amlodipine on gamma-glutamyl transpeptidase (GGT; EC 2.3.2.2) activity in mouse cerebral cortex was investigated. Mice received amlodipine (0.07 mg kg-1), CsA (10, 20 and 40 mg kg-1) and CsA in the above doses combined with amlodipine (0.07 mg kg-1) once daily, intraperitoneally for 5 days. The control group received saline. Amlodipine decreased GGT activity when compared to the control group. GGT activity in the cerebral cortex was decreased after treatment with CsA (20 and 40 mg kg-1), but was not changed after treatment with CsA in the 10 mg kg-1 dose as compared to the control group. CsA in doses of 20 and 40 mg kg-1, combined with amlodipine, increased GGT activity as compared to the control group groups received the same doses of CsA without amlodipine and received only amlodipine. However, CsA in the 10 mg kg-1 dose combined with amlodipine decreased GGT activity when compared to the control group, but did not show any statistical difference when compared to the groups treated only with amlodipine or CsA in the same doses. These results suggest that CsA and amlodipine may modulate GGT activity in mouse cerebral cortex.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9368918&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Effects of amlodipine versus enalapril on left ventricular remodelling after reperfused anterior myocardial canine infarction.

Jugdutt BI.

Department of Medicine, University of Alberta, Edmonton. jugdutt tachy.uah.ualberta.ca

OBJECTIVE: To compare the effects of the calcium channel blocker amlodipine with those of the angiotensin-converting enzyme (ACE) inhibitor enalapril on left ventricular (LV) remodelling and dysfunction during healing after reperfused anterior myocardial infarction (MI). ACE inhibitors and reperfusion are known to limit LV remodelling after MI. However, the effects of ACE inhibitors and calcium channel blockers on LV remodelling after reperfused MI have not been compared. METHODS: Changes in LV topography and function (quantitative echocardiograms) and hemodynamics were measured over six weeks in dogs that were randomized 24 h after reperfusion, done after 2 h of anterior MI, to oral amlodipine (5 mg bid; n = 7), enalapril (5 mg bid; n = 6) or no drug (controls; n = 6) for six weeks. Postmortem LV topography was measured at six weeks. RESULTS: Scar sizes after six weeks were similar in the three groups. Both enalapril and amlodipine reduced the rate pressure product, but decreases in mean arterial and left atrial pressures were more sustained over six weeks with enalapril. Compared with controls over six weeks, both enalapril and amlodipine preserved LV volumes, global ejection fraction, regional function and infarct segment length, but enalapril blocked the increase in non-infarct wall thickness, attenuated the infarct wall thickness, preserved shape and decreased global LV mass more than amlodipine. Sham-operated dogs (n = 3) showed no significant structural changes. CONCLUSIONS: Both enalapril and amlodipine preserve LV volumes and function during healing after reperfused MI, but enalapril more effectively limits hypertrophy, attenuates infarct wall thickness and preserves shape.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9374951&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Effects of amlodipine on endothelial function in rats with chronic heart failure after experimental myocardial infarction.

de Vries RJ, Anthonio R, van Veldhuisen DJ, Scholtens E, Buikema H, van Gilst WH.

Department of Cardiology, University Hospital Groningen, The Netherlands.

In chronic heart failure, the role of endothelial dysfunction is not yet well established. As calcium metabolism plays an important role in the endothelium, it might be suggested that calcium channel blockers influence endothelial function. Although calcium channel blockers are generally contraindicated in chronic heart failure, because they are believed to stimulate neurohumoral mechanisms and to exert negative inotropic effects, recently it has been suggested that amlodipine might have a favorable affect on mortality in patients with heart failure. The mechanism of amlodipine that contributes to this beneficial effect is not known. Therefore we investigated whether 10 weeks of amlodipine treatment could influence endothelial function in rats with congestive heart failure induced by myocardial infarction. The main finding of our study was that amlodipine, when administered for 10 weeks to rats after a myocardial infarction had been induced, had no significant effects on in vitro and in vivo hemodynamics or neurohormones. The effect of amlodipine on endothelium-intact, norepinephrine-precontracted aortic rings appears to differ from the placebo treatment with respect to the endothelium-dependent relaxation, whereas no differences are seen in endothelium-independent relaxation. We conclude that our data do not support a beneficial role of amlodipine on endothelial function in chronic heart failure.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9388052&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Brain pharmacokinetics and in vivo receptor binding of 1,4-dihydropyridine calcium channel antagonists.

Uchida S, Yamada S, Nagai K, Deguchi Y, Kimura R.

Department of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka, Japan.

Brain pharmacokinetics of 1,4-dihydropyridine (DHP) calcium channel antagonists and their in vivo receptor binding in mice were characterized. The area under the concentration vs time curve (AUCbrain) for [3H]nifedipine, [3H]nimodipine and [3H]PN 200-110 in mouse brain after intravenous injection was higher than that for [3H]amlodipine. Brain/plasma concentration ratios (AUCbrain/AUCplasm) for [3H]nimodipine and [3H]PN 200-110 were 3 to 5 times higher than those for [ H]nifedipine and [3H]amlodipine. Further, brain/heart concentration ratios (AUCbrain/AUCheart) for [3H]nifedipine, [3H]nimodipine and [3H]PN 200-110 were about 20 times higher than the ratio for [3H]amlodipine. A significant amount of specific binding in particulate fractions of mouse brain was detected in vivo by intravenous injection of [3H]nifedipine, [3H]nimodipine and [3H]PN 200-110 but not [3H]amlodipine. These data suggest that [3H]nifedipine, [3H]nimodipine and [3H]PN 200-110 are more extensively taken up into brain from plasma than [3H]amlodipine and bind to the receptor sites in brain parenchymal cells in a significant amount in vivo. In conclusion, the present simultaneous measurement of pharmacokinetics and in vivo receptor binding in mouse brain suggests an usefulness of calcium channel antagonists such as nimodipine in the pharmacotherapy of brain diseases.

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amlodipine Norvasc
Amlodipine inhibits rat microsomal cytochrome P450-mediated drug biotransformation.

Drobitch RK, McLellan RA, Renton KW.

Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.

Calcium channel antagonists have been shown to inhibit cytochrome P-450-mediated metabolism both in vitro and in vivo. The purpose of the present study was to examine the effect of amlodipine on a suite of rat hepatic microsomal cytochrome P-450 activities to determine the potential for drug interactions. In this study, amlodipine (0.05 and 0.5 mM) decreased CYP1A-mediated ethoxyresorufin O-deethylase activity in microsomes prepared from noninduced (56 and 73% inhibition) and pyridine-induced (30 and 51% inhibition) rats. Amlodipine reduced pentoxyresorufin O-deethylase activity (a marker for CYP2B) to 15% of control in incubations utilizing microsomes from phenobarbital-treated rats, but had no effect on this enzyme reaction in noninduced microsomes. The para-nitrophenol hydroxylase, erythromycin N-demethylase, and lauric acid omega and omega-1 hydroxylase activities were significantly inhibited by 1 mM amlodipine in both noninduced and induced microsomes. These results suggest that amlodipine inhibits a number of different P450 forms and therefore has the potential to inhibit the metabolism of a large number of drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9423169&dopt=Abstract amlodipine Norvasc