amlodipine Norvasc
Amlodipine monotherapy, angiotensin-converting enzyme inhibition, and combination therapy with pacing-induced heart failure.

Kribbs SB, Merritt WM, Clair MJ, Krombach RS, Houck WV, Dodd MG, Mukherjee R, Spinale FG.

Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston 29425-2279, USA.

In patients with congestive heart failure (CHF) receiving therapy with angiotensin-converting enzyme (ACE) inhibition, institution of calcium channel antagonism with amlodipine provided favorable effects. The goal of the present study was to define potential mechanisms for these effects by measuring left ventricular function, hemodynamics, and neurohormonal system activity in a model of CHF in which amlodipine treatment had been instituted either as a monotherapy or in combination with ACE inhibition. Thirty-two pigs were instrumented to allow measurement of cardiac index, total systemic resistance index, and neurohormonal activity in the conscious state and assigned to one of four groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n = 8), (2) amlodipine (1.5 mg x kg(-1) x d[-1]) and pacing (n = 8), (3) ACE inhibition (fosinopril 1.0 mg/kg BID) and pacing (n = 8), and (4) amlodipine and ACE inhibition (1.0 mg x kg(-1) x d(-1) and 1.0 mg/kg BID, respectively) and pacing (n = 8). Measurements were obtained in the normal control state and after the completion of the treatment protocols. With rapid pacing, basal resting cardiac index was reduced compared with control values (2.7+/-0.2 versus 4.7+/-0.1 L x min(-1) x m(-2), respectively, P<.05) and increased from rapid pacing-only values with either amlodipine or combination therapy (3.7+/-0.3 and 4.4+/-0.5 L x min(-1) x m(-2), respectively, P<.05). Basal resting total systemic resistance index was higher in the rapid pacing-only group compared with control values (2731+/-263 versus 1721+/-53 dyne x s x cm(-5) x m2, respectively, P<.05), was reduced with either amlodipine treatment or ACE inhibition (2125+/-226 and 2379+/-222 dyne x s x cm(-5) x m2, respectively, P<.05), and was normalized with combination therapy. Plasma catecholamines, renin activity, and endothelin levels were increased threefold with rapid pacing. Amlodipine, either as a monotherapy or in combination with ACE inhibition, did not result in increased plasma catecholamines and renin activity compared with the rapid pacing-only group. Furthermore, combination therapy reduced steady state norepinephrine and normalized epinephrine levels. The results of the present study demonstrated that monotherapy with either amlodipine or ACE inhibition provides beneficial effects in this pacing model of CHF. Combined amlodipine and ACE inhibition provided greater benefit with respect to vascular resistance properties and neurohormonal system activity compared with either monotherapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9495258&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Regional differences in the vasorelaxant effects of nicorandil and amlodipine on isolated porcine coronary arteries.

Tanko LB, Mikkelsen EO, Frobert O, Bagger JP.

Institute of Pharmacology, University of Aarhus, United Kingdom.

The vasorelaxant effects of nicorandil, a K(+)-channel opener, and amlodipine, a dihydropyridine-type Ca(2+)-channel blocker, were investigated on partially and maximally K(+)-depolarized ring preparations from the porcine left anterior descending coronary artery. By comparing vascular responses in the proximal and distal parts of the epicardial segment, the scope of the study was to evaluate regional differences in the action of nicorandil and amlodipine. Nicorandil (10(-7)-10(-4) M) shifted the K+ concentration-response curves to the right and depressed the maximal contractile responses in a concentration-dependent manner, consistent with K(+)-channel opening and secondary non-K(+)-channel opening mechanisms of action. Nicorandil had a significantly more potent relaxant effect in the proximal compared to the distal arterial rings contracted with 85 mM K+. Pretreatment with methylene blue (10(-5) M) did not significantly influence the regional difference in the action of nicorandil. Amlodipine (10(-9)-10(-6) M) had a significantly more potent and effective inhibitory and relaxant effect than nicorandil under the same conditions. In contrast to nicorandil, the effect of amlodipine was more prominent in the distal compared to the proximal vessel rings. The cumulative addition of extracellular Ca2+ exhibited a more potent contractile response in the distal rather than in the proximal rings. Nicorandil totally and amlodipine partly eliminated the contractile responses to the lowest concentration of Ca2+. The inhibitory effect of amlodipine on the contractile responses to higher Ca2+ concentrations was more pronounced than that of nicorandil. The results show that there are regional differences in the responsiveness of porcine coronary arteries to Ca2+, nicorandil and amlodipine. Our findings indicate that the regional difference in nicorandil-induced vasodilation was caused neither by the K(+)-channel opening nor by the nitrate-like mechanism of action, but could be due to a direct Ca(2+)-influx blocking effect of the drug.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9523184&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
The effects of antihypertensive agents on atherosclerosis-related parameters of human aorta intimal cells.

Orekhov AN, Tertov VV, Pivovarova EM.

Institute of Experimental Cardiology, Cardiology Research Center, Moscow, Russia.

Four antihypertensive agents - amlodipine, verapamil, propranolol and perindoprilat - were studied in human cell cultures. Antiatherogenic activity was investigated using uninvolved human aortic smooth muscle intima cells and atherogenic serum obtained from patients with coronary atherosclerosis. Amlodipine and verapamil significantly inhibited serum-induced increases in cholesterol content, cell-proliferative activity and protein synthesis in the cultured cells. Propranolol increased all three parameters, while perindoprilat had no effects. In addition, amlodipine and verapamil significantly lowered the intracellular cholesterol content of smooth muscle cells derived from atherosclerotic plaque and inhibited cell proliferation and protein synthesis. Propranolol increased all of these parameters, while perindoprilat produced no effects. The antiatherogenic and antiatherosclerotic actions of verapamil and amlodipine were confirmed in an ex vivo model. These studies demonstrated a beneficial antiatherosclerotic effect of amlodipine that was greater than that of verapamil. Perindoprilat had a neutral effect on atherosclerotic parameters, while the action of propranolol appeared to be potentially detrimental.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9524011&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
A therapeutic dosage of amlodipine prevents vascular hyporeactivity induced in rats by lipopolysaccharide.

Salomone S, Morel N, Godfraind T.

Laboratoire de Pharmacologie, Universite Catholique de Louvain, Bruxelles, Belgium.

The aim of this work was to investigate whether treatment with the 1,4-dihydropyridine Ca2+ antagonist amlodipine could affect the vascular hyporesponsiveness induced by cytokines. Endotoxemia was induced by Salmonella typhosa lipopolysaccharide (LPS) injection (4 mg kg(-1), i.p.). In endothelium-denuded rings of thoracic aorta from untreated rats, contractile response to noradrenaline was decreased after LPS injection, this effect was partially overcome by the addition of N(omega)-nitro-L-arginine (L-NNA, 100 microM) into the bathing solution. In amlodipine-pretreated rats (15 mg kg(-1) day(-1), orally, for one week), the effect of LPS was lower than in untreated ones and it was completely reversed by L-NNA. The relaxation of the noradrenaline-induced tone evoked by L-arginine (10 microM) in aortae of LPS-injected rats was reduced in amlodipine-pretreated rats. Amlodipine-treatment reduced both the LPS-induced Ca2+-independent NOS activity in homogenates of heart and the expression of iNOS mRNA in aortae of LPS-injected rats. However, the vascular hyporeactivity induced by exposing aortae to interleukin-1beta in vitro was not influenced by amlodipine (10 nM). Amlodipine (10 microM) also did not affect the production of nitrite in primary aortic smooth muscle cell culture challenged by LPS although nitrite production in macrophage culture challenged with LPS was significantly inhibited. The results show that rat pretreatment with amlodipine prevented the decrease of vascular responsiveness induced by LPS, an effect that may be at least partly related to reduction of in vivo NOS induction. The weak effect of amlodipine on the in vitro NOS induction indicates that the protective action in endotoxemia did not result from a short term interaction with L-type Ca2+ channels in vascular smooth muscle. Alternative mechanisms are discussed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9550296&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Different effects of calcium antagonists on fluid filtration of large arteries and albumin permeability in spontaneously hypertensive rats.

Lacolley P, Poitevin P, Koen R, Levy BI.

Institut National de la Sante et de la Recherche Medicale, U337, Paris, France.

OBJECTIVE: To compare the effects of chronic administration of two dihydropyridines, nifedipine and amlodipine, and the non-dihydropyridine Ca2+ antagonist mibefradil on fluid filtration of large arteries and extravasation of albumin in spontaneously hypertensive rats. METHODS: Spontaneously hypertensive rats aged 2 months were randomly allocated to oral treatment once a day with 30 mg/kg mibefradil (n=12), 100 mg/kg nifedipine (n=12), 20 mg/kg amlodipine (n=12) or placebo (n=12) for 1 month. Instantaneous blood pressure of rats under pentobarbital anaesthesia was recorded at the end of the treatment Fluid filtration across the carotid arterial wall was determined in situ in the isolated carotid artery. Extravasation of 25 mg/kg Evans Blue dye that had been injected intravenously was used to assess whole vascular permeability to albumin after chronic treatment with mibefradil. RESULTS: Similar reductions in mean arterial pressure were obtained in all Ca2+ antagonist-treated rats. Heart rate was similar in rats in control, nifedipine and amlodipine groups but was significantly lower in mibefradil-treated rats (by 19%, P< 0.001). Fluid filtration across the carotid wall was greater in all Ca2+ antagonist-treated animals. However, fluid filtration was significantly less in mibefradil-treated rats than it was in nifedipine-treated, and amlodipine-treated rats. Furthermore, administration of mibefradil did not significantly modify extravasation of albumin in all tested tissues (pancreas, testis, spleen, lung, kidney, intestine, liver, skeletal muscle) except for cardiac and brain tissues, in which the permeability of albumin was increased by 24 and 33%, respectively, compared with values for the control group (P < 0.05). CONCLUSION: These results indicate that Ca2+ antagonists increase fluid filtration through large arteries from spontaneously hypertensive rats. That the lower fluid filtration in mibefradil-treated rats was associated with no change in extravasation of albumin in most tissues and especially in skeletal muscle suggests that vascular permeability in hypertensive rats was impaired less by mibefradil treatment than it was by dihydropyridine Ca2+ antagonist treatments.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9557928&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Effects of long-acting calcium channel antagonists on neurohumoral factors: comparison of nifedipine coat-core with amlodipine.

Tsutamoto T, Tsutsui T, Maeda K, Hayashi M, Wada A, Ohnishi M, Fujii M, Ishii C.

First Department of Internal Medicine, Shiga University of Medical Science, Seta, Otsu, Japan. tutamoto belle.shiga-med.ac.jp

Calcium channel antagonists can induce sympathetic hyperactivity, leading to a poor prognosis for hypertensive patients. Nifedipine formulations that allow once-daily administration are now available for use in clinical practice. To compare the effects of nifedipine with those of amlodipine, we studied 36 essential hypertensive patients. Those who had been administered nifedipine sustained-release were treated with amlodipine in place of nifedipine sustained-release, and those who had been administered amlodipine were treated with nifedipine coat-core in place of amlodipine. Substitution of nifedipine sustained-release by amlodipine had no significant effect on hypertensive symptoms. However, the plasma levels of norepinephrine, renin, and aldosterone were significantly lower (p < 0.001-0.05) in patients taking amlodipine in place of nifedipine sustained-release. Substitution of amlodipine by nifedipine coat-core again had no significant effect on hypertensive symptoms. However, the plasma levels of norepinephrine, renin, and aldosterone did not change significantly after the substitution. These findings indicate that, at the effective anti-hypertensive concentrations of nifedipine coat-core and amlodipine, nifedipine coat-core may not increase sympathetic nerve activity as is observed with amlodipine. The results also suggest that the duration of action of nifedipine formulations is an important determinant for nifedipine-induced hyperactivity in the reflex sympathetic nerve and the renin-angiotensin systems.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12688402&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Effects of amlodipine once or twice daily on circadian blood pressure profile, myocardial hypertrophy, and beta-adrenergic signaling in transgenic hypertensive TGR(mREN2)27 rats.

Witte K, Schnecko A, Voll C, Schmidt T, Lemmer B.

Institute of Pharmacology & Toxicology, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Germany.

The effects of amlodipine on blood pressure profiles, cardiac hypertrophy, and beta-adrenergic signal transduction were studied in transgenic hypertensive TGR(mREN2)27 rats (TGRs), which are characterized by an inverse circadian blood pressure rhythm. Cardiovascular parameters were monitored by radiotelemetry; beta-adrenoceptor density and function were measured by radioligand binding and by determination of beta-adrenergic stimulation of adenylyl cyclase. Ventricular weight and the activity of cardiac sarcolemmal 5-nucleotidase were used as measures of hypertrophy. Acute i.p. injection of amlodipine (1, 3, 10 mg/kg body weight) either at 8:00 or at 20:00 h dose-dependently reduced blood pressure irrespective of the dosing time. For long-term treatment, TGRs were divided into three groups: untreated; amlodipine, once-daily, 5 mg/kg; and amlodipine, twice daily, 2.5 mg/kg. Both treatment schedules resulted in decreased 24 h means in systolic and diastolic blood pressure and a reduction in ventricular hypertrophy but had no effects on cardiac beta-adrenergic signaling. Once-daily dose of amlodipine at 8:00 h decreased blood pressure predominantly during the daily resting period of the rats, whereas twice-daily dosing induced a bimodal blood pressure pattern. However, even after 5 weeks of treatment, typical circadian profiles could not be observed with either treatment, indicating a short duration of action of amlodipine in rats. Thus it remains an open question whether pharmacologic normalization of the circadian blood pressure pattern in TGRs will more effectively reduce myocardial hypertrophy and restore beta-adrenergic signaling than a reduction in 24-h blood pressure per se.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9593064&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Amlodipine inhibition of serum-, thrombin-, or fibroblast growth factor-induced vascular smooth-muscle cell proliferation.

Stepien O, Gogusev J, Zhu DL, Iouzalen L, Herembert T, Drueke TB, Marche P.

Universite Rene Descartes & Department of Pharmacology, CNRS URA 1482, CHU Necker, Paris, France.

Atherosclerosis, like several other vascular diseases, exhibits structural and functional abnormalities resulting partially from an exaggerated proliferation of vascular smooth-muscle cells (VSMCs). Ca2+ channel blockers, such as amlodipine, have been suggested to retard or even prevent the progression of atherosclerosis. To determine the mechanisms involved in these effects, we investigated the influence of amlodipine on VSMC proliferation by using rat aortic VSMCs in culture. Amlodipine (0.1-10 microM) inhibited serum-, basic fibroblast growth factor (bFGF)-, and thrombin-induced VSMC proliferation and DNA synthesis in a concentration-dependent manner, as demonstrated by cell count and bromodeoxyuridine (BrdU)-incorporation measurements, respectively. Delayed addition of amlodipine after VSMC stimulation showed that the drug exerted its effect early in G1 phase of the cell cycle. This observation was confirmed by the finding that amlodipine did not influence DNA synthesis in VSMCs arrested to the G1/S boundary by hydroxyurea treatment. Consistent with its effects on VSMC growth/proliferation, amlodipine also decreased c-myc, c-fos, and c-jun protooncogene expression induced by serum, thrombin, or bFGF within 1 h after cell activation, as assessed by semiquantitative reverse transcriptase (RT)-polymerase chain reaction (PCR) analysis. The calcium channel agonist Bay K 8644, which counteracted the inhibition by nifedipine of bFGF-, thrombin- or serum-induced DNA synthesis, was ineffective to antagonize the inhibitory effect of amlodipine. The aforementioned effects of amlodipine were of similar amplitude, irrespective of the growth-enhancing agent used. This strongly indicates that amlodipine acts downstream of receptor activation to exert its antiproliferative action, probably early in the G1 phase of the cell cycle. Moreover, the lack of antagonistic effect between amlodipine and Bay K 8644 suggests that, in addition to its L-type Ca2+ channel inhibitory effect, amlodipine inhibits other intracellular signaling pathways. Such an interference of amlodipine with mitogenic signaling pathways might contribute to confer a blood vessel-protecting potential on amlodipine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9593080&dopt=Abstract amlodipine Norvasc