amlodipine Norvasc
Effect of prolonged treatment with amlodipine on enhanced vascular contractility in cardiomyopathic hamsters.

Sato A, Hattori Y, Watanabe M, Okamoto H, Tomioka H, Fukao M, Sakuma I, Kitabatake A, Kanno M.

Department of Pharmacology, Hokkaido University School of Medicine, Sapporo, Japan. asato med.hokudai.ac.jp

This study examined the effects of prolonged treatment with amlodipine on the enhanced vascular contractions in dilated cardiomyopathic (CM) hamsters. From the ages of 5 to 20 weeks, CM hamsters (BIO 53.58) orally received amlodipine. Then we compared the contractile responses to vasoconstrictors in aortas and mesenteric arteries from CM hamsters with or without treatment with those in the arteries from controls (F1b). We also investigated the effect of amlodipine treatment on the Ca2+ sensitivity of tension in beta-escin-skinned smooth muscle of mesenteric artery. The contractile responses to phenylephrine, angiotensin II, and high K+ in both aorta and mesenteric artery were greatly enhanced in CM hamsters compared with controls. Amlodipine treatment slightly but significantly inhibited the enhanced responses in aorta but did not alter the responses in mesenteric arteries. The Ca2+ sensitivity of tension was significantly increased in CM hamster preparations, which was unaffected by amlodipine treatment. These data indicate that amlodipine treatment differentially affects the enhanced responses to vasoconstrictors between large and small blood vessels from CM hamsters. The lack of effect of amlodipine treatment on the responsiveness of CM mesenteric artery leads to the suggestion that the preventive effect of amlodipine on focal myocytolytic necrosis of cardiomyocytes, which was previously reported to be the main cause of cardiomyopathy, results from an action on cardiomyocytes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10413078&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Effect of Ca2+ channel blockers on arterial hypertension and heart ischaemic lesions induced by chronic blockade of nitric oxide in the rat.

de Oliveira CF, Nathan LP, Metze K, Moreno H Jr, de Luca IM, Sucupira M, Zatz R, Zappellini A, Antunes E, de Nucci G.

Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas (SP), Brazil.

The effects of the Ca2+ channel blockers diltiazem, nifedipine and amlodipine were investigated on both arterial hypertension and myocardial changes induced by chronic blockade of nitric oxide synthesis. Control male Wistar rats received Nomega-nitro-L-arginine methyl ester (L-NAME; 20 mg rat(-1) day(-1)) in the drinking water for 8 weeks; blood pressure and body weight were monitored weekly. The Ca2+ channel blockers were given concomitantly to L-NAME, as follows: diltiazem (13.5 mg rat(-1) day(-1)) and amlodipine (6.25 mg rat(-1) day(-1)) were administered in the drinking water whereas nifedipine (6.25 mg rat(-1) day(-1)) was given in the chow. Nomega-nitro-L-arginine methyl ester induced a time-dependent increase in blood pressure which was significantly attenuated by diltiazem (154+/-1.6 vs. 139+/-1.6 mm Hg, p < 0.05), nifedipine (166+/-2.7 vs. 150+/-2.1 mm Hg, p < 0.05) and amlodipine (208+/-5.8 vs. 158+/-1.8 mm Hg, p < 0.05) at the last week of the treatment. Rats treated with the L-NAME also developed myocardial ischaemia, as indicated by the increased percentage of fibrous tissue found in the left ventricles of these animals (10.9+/-0.1%, p < 0.01) when compared to control ones (6.3+/-0.1%). Neither diltiazem (14.9+/-1.2%) nor nifedipine (11.1+/-1.5%) prevented this effect whereas amlodipine (6.9+/-1.1%, p < 0.01) virtually abolished the increase in fibrous tissue induced by L-NAME. The plasma concentration of the Ca2+ channel blockers was measured by liquid chromatography coupled to mass spectrometry at two different time points (morning and afternoon). Only amlodipine treatment was able to maintain constant levels (186+/-46 ng ml(-1) in the morning and 110+/-19 ng ml(-1) in the evening) compared to nifedipine (3003+/-578 ng ml(-1) in the morning and 436+/-100 ng ml(-1) in the evening) and diltiazem (77+/-51 ng ml(-1) in the morning and not detectable in the evening). In conclusion, our results indicate that amlodipine (but not diltiazem and nifedipine) can efficiently control myocardial ischaemia in nitric oxide deficient rats, probably due to its intrinsically long half-life.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10414439&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Different effects of mibefradil and amlodipine on coronary vessels and during beta-adrenergic stimulation in conscious dogs.

Heloire F, Hittinger L, Champagne S, Suto Y, Houel R, Ennezat PV, Sambin L, Crozatier B, Su JB.

INSERUM U400, Faculte de Medecine, 94010 Creteil, France.

Coronary effects of Ca -channel blockers mibefradil and amlodipine were compared in conscious dogs. Ten dogs were instrumented for measurement of aortic and left ventricular pressures, circumflex coronary blood flow velocity (CBFv), and coronary diameter (CD). A permanent catheter was implanted in the circumflex coronary artery. At doses having no systemic effects (7.5-150 micro g/kg), mibefradil and amlodipine increased CBFv and CD dose dependently. At the same dose, mibefradil increased less CBFv than amlodipine. However, for a similar increase in CBFv induced by amlodipine, mibefradil increased CD more. BAY K8644, an L-type Ca -channel agonist, prevented the CBFv and CD responses to amlodipine, but minimally affected the coronary responses to mibefradil. Intracoronary isoproterenol (6 ng/kg) increased LV dP/dt max, CBFv, and CD. Amlodipine markedly altered these responses, while mibefradil did not affect LV inotropic response and slightly altered CBFv response to isoproterenol. Thus, in conscious dogs, both mibefradil and amlodipine exert coronary vasodilation, with different patterns on coronary conductance and resistance vessels and during beta-adrenergic stimulation. These differences could be related to their actions on different Ca channels.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12451323&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Effects of amlodipine on nitric oxide synthase mRNA expression and coronary microcirculation in prolonged nitric oxide blockade-induced hypertensive rats.

Kobayashi N, Yanaka H, Tojo A, Kobayashi K, Matsuoka H.

Department of Medicine, Dokkyo University School of Medicine, Mibu, Tochigi, Japan.

We evaluated the effects of long-term treatment with amlodipine, a calcium antagonist, on nitric oxide synthase (NOS) activity and NOS messenger RNA (mRNA) expression in the left ventricle (LV) and its relation to coronary reserve, and microvascular remodeling in Nomega-nitro-L-arginine methyl ester (L-NAME)-induced hypertensive rats. Seventeen male Sprague-Dawley rats were given L-NAME (60 mg/kg/day) in drinking water for 6 weeks to induce hypertension, and then treated with amlodipine (L-NAME + A, 5 mg/kg/day, n = 9), or a vehicle (L-NAME + V, n = 8) for 4 weeks. Age-matched rats (C, n = 8) served as the control group. An increased blood pressure in L-NAME + V was significantly decreased in L-NAME + A. Nitrite production and endothelial cell (e) NOS mRNA in the LV were significantly decreased in L-NAME + V compared with C, and were significantly increased in L-NAME + A compared with C and L-NAME + V. L-NAME + V had a significantly decreased coronary reserve and capillary density, and a significantly increased type I collagen mRNA expression, wall-to-lumen ratio, perivascular fibrosis, myocardial fibrosis, and myocyte cross-sectional area. These parameters in the microvasculature were significantly improved by amlodipine. We concluded that NOS activity and eNOS mRNA were significantly increased by amlodipine in the LV of L-NAME-induced hypertensive rats, and that these increase NOS activity and eNOS mRNA expression may play a role in the amelioration of coronary reserve and microvascular remodeling.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10445667&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Vascular-selective effect of lercanidipine and other 1,4-dihydropyridines in isolated rabbit tissues.

Angelico P, Guarneri L, Leonardi A, Testa R.

Pharmaceutical R & D Division, Recordati S.p.A., Milano, Italy.

The aim of this study was to characterize the in-vitro vasoselectivity of lercanidipine (in comparison with lacidipine, amlodipine, nitrendipine and felodipine) by evaluating its functional calcium antagonistic activity on rabbit vascular (aorta) and cardiac tissues (heart ventricle). Although incubation with all the compounds tested elicited a concentration-dependent relaxant effect on vascular tissue precontracted with KCl (80 mM), 50% relaxation was reached at different times for each concentration and drug tested. At 10 nM concentration 50% relaxation was reached after 210 min with lercanidipine, 278 min with amlodipine, 135 min with lacidipine, 75 min with nitrendipine and 70 min with felodipine. The onset of the effect was, therefore, similar for lercanidipine, amlodipine and lacidipine, but faster for nitrendipine and felodipine. Similarly, all the compounds tested concentration-dependently reduced the force of cardiac contraction (negative inotropic activity). In this model, the time needed to reach 50% reduction in contractile force was also concentration-dependent, and the ranking order of the speed of onset of the effect (evaluated as the ratio of the IC50 values (the concentrations inhibiting contraction by 50%) calculated after 1 and 4 h incubation) was lacidipine (3.8) > amlodipine (9.6) > felodipine (39) > lercanidipine (68) = nitrendipine (89). The vasoselectivity, expressed as the ratio of the IC50 values obtained on cardiac and vascular tissue, were (for 4 h incubation) 730, 193, 95, 6 and 3 for lercanidipine, lacidipine, amlodipine, felodipine and nitrendipine, respectively, showing that lercanidipine is the most vasoselective of the calcium-antagonists tested. The results show that lercanidipine reduces the inotropic force of the rabbit heart to a lesser extent than do other calcium antagonists, and that this drug had the best heart/vessel selectivity index among the compounds tested at all the times tested.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10454048&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Differential effects of T- and L-type calcium antagonists on glomerular dynamics in spontaneously hypertensive rats.

Nakamura Y, Ono H, Frohlich ED.

Hypertension Research Laboratories, Alton Ochsner Medical Foundation, New Orleans, LA, USA.

To determine whether there is a difference in the effects of T- and L-type calcium antagonists on systemic, renal, and glomerular hemodynamics, the pathological changes of N(G)-nitro-L-arginine methyl ester (L-NAME)-exacerbated nephrosclerosis and clinical alterations were investigated in spontaneously hypertensive rats (SHR). Seven groups of 17-week-old male SHRs were studied: Group 1, control; Group 2, mibefradil, 50 mg. kg(-1). d(-1); Group 3, L-NAME in drinking water, 50 mg/L; Group 4, L-NAME (50 mg/L) plus mibefradil (50 mg. kg(-1). d(-1)); Group 5, L-NAME (50 mg/L) plus amlodipine (10 mg. kg(-1). d(-1)); Group 6 and 7, L-NAME (50 mg/L) for 3 weeks followed by mibefradil (50 mg. kg(-1). d(-1)) or amlodipine (10 mg. kg(-1). d(-1)), respectively, for the subsequent 3 weeks. Both the T- and L-channel calcium antagonists similarly reduced mean arterial pressure and total peripheral resistance index. These changes were associated with significant decreases in afferent and efferent glomerular arteriolar resistances and the ultrafiltration coefficient (P<0.01). Furthermore, the histopathological glomerular and arterial injury scores and urinary protein excretion were also significantly improved (P<0.01), and left ventricular and aortic masses were significantly diminished in all treated groups. Both drugs, mibefradil and amlodipine, had effects of increasing the single-nephron glomerular filtration ratio (SNGFR), and single-nephron plasma flow (SNPF), and of reducing glomerular afferent arteriolar resistance and urinary protein excretion. Thus, the T-type (mibefradil) and L-type (amlodipine) calcium antagonists each prevented and reversed the pathophysiological alterations of L-NAME-exacerbated hypertensive nephrosclerosis in SHR. The T-type calcium antagonist (mibefradil) seemed to have been more effective than the L-type amlodipine antagonist and it produced a greater reduction in afferent arteriolar resistance while preserving SNGFR.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10454453&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
[Effects of benidipine hydrochloride (Coniel) on blood pressure, heart rate and plasma norepinephrine concentration in spontaneously hypertensive rats]

[Article in Japanese]

Karasawa A, Nomura H, Nito M, Sonoda R, Tanaka H, Kosaka N, Yamaguchi K, Kobayashi S.

Pharmaceutical Research Institute, Kyowa Hakko Kogyo, Co., Ltd., Shizuoka, Japan.

We investigated the effects of benidipine hydrochloride (benidipine, Coniel) on blood pressure, heart rate and plasma norepinephrine (NE) concentration in spontaneously hypertensive rats and compared them with those of other calcium channel blockers. Benidipine (2 mg/kg, p.o.) was compared with the equihypotensive doses of nifedipine (5 mg/kg), cilnidipine (6 mg/kg) and amlodipine (3 mg/kg). All the 4 calcium channel blockers exhibited significant antihypertensive effects. Nifedipine and cilinidipine significantly increased heart rate, as compared with that in the control group, whereas benidipine or amlodipine did not significantly affect it. The area under the curves for hypotensive effect and tachycardic effect for 10 hr after the drug administration were compared among the 4 compounds. As a result, the tachycardic effect of benidipine was significantly lower than those of nifedipine, cilnidipine and amlodipine, while the hypotensive effects were similar among the 4 compounds. Nifedipine and amlodipine, significantly increased plasma NE concentration, cilnidipine tended to increase it. In contrast, benidipine did not significantly affect plasma NE concentration. These results suggest that the effects of benidipine on plasma NE concentration and heart rate are less prominent than those of the other calcium channel blockers.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10480159&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Amlodipine therapy in congestive heart failure: hemodynamic and neurohormonal effects at rest and after treadmill exercise.

Krombach RS, Clair MJ, Hendrick JW, Mukherjee R, Houck WV, Hebbar L, Kribbs SB, Dodd MG, Spinale FG.

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

This study examined the acute effects of amlodipine treatment on left ventricular pump function, systemic hemodynamics, neurohormonal status, and regional blood flow distribution in an animal model of congestive heart failure (CHF), both at rest and with treadmill exercise. A total of 14 pigs were studied under control conditions and after the development of pacing-induced CHF (240 beats per minute, 3 weeks, n = 7) or with CHF and acute amlodipine treatment for the last 3 days of pacing (1.5 mg/kg per day, n = 7). Under resting conditions, left ventricular stroke volume (mL) was reduced with CHF compared with the normal state (15+/-2 vs. 31+/-1, p<0.05) and increased with amlodipine treatment (23+/-4, p<0.05). At rest, systemic vascular resistance increased with CHF compared with the normal state (3,078+/-295 vs. 2,131+/-120 dyne x s cm(-5), p<0.05) and was reduced after amlodipine treatment (2,472+/-355 dyne x s cm(-5), p<0.05). With exercise, left ventricular stroke volume remained lower and systemic vascular resistance higher in the CHF group, but was normalized with amlodipine treatment. With exercise, left ventricular myocardial blood flow increased from resting values, but was reduced from the normal state with CHF (normal: 1.69+/-0.12 to 7.62+/-0.74 mL/min per gram vs. CHF: 1.26+/-0.12 to 4.77+/-0.45 mL/min per gram, both p<0.05) and was normalized with acute amlodipine treatment (1.99+/-0.35 to 6.29+/-1.23 mL/min per gram). Resting plasma norepinephrine was increased by >5-fold in the CHF group at rest and was not affected by amlodipine treatment. However, with exercise, amlodipine treatment blunted the increase in plasma norepinephrine by >50% when compared with untreated CHF values. Resting plasma endothelin levels increased with CHF compared with the normal state (10.9+/-0.9 vs. 2.8+/-0.4 fmol/mL, p<0.05) and was reduced with amlodipine treatment (7.5+/-1.5 fmol/mL, p<0.5). In other vascular beds, acute amlodipine treatment with CHF improved pulmonary and renal blood flow both at rest and with exercise; however, there were no effects observed on skeletal muscle blood flow. With the development of CHF, acute amlodipine treatment does not negatively influence left ventricular pump function, but rather may provide favorable hemodynamic and neurohormonal effects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10480440&dopt=Abstract amlodipine Norvasc