Antihypertensive Effects of MPC-1304, a Novel Calcium Antagonist, in Experimental Hypertensive Rats and Dogs

Kanda, Atsuhiro; Haruno, Akihiro; Miyake, Hidekazu; Nagasaka, Mitsuaki

doi:10.1097/00005344-199205000-00006

Cited by 16 publications

(8 citation statements)

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“…Nifedipine, also a 1,4-dihydropyridine calcium entry blocker, is reported (17,18) to cause more effective hypotension in hypertensive patients than in normal sub jects. In animal studies using SHR and Wistar Kyoto rats (WKY), calcium entry blocking agents had more potent hypotensive activity in hypertensive rats than normoten sive rats (19,20). Our data in dogs are consistent with these findings in rats.…”

Section: Discussionsupporting

confidence: 87%

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Hypotensive Effects of YM430, a 1,4-Dihydropyridine Derivative, in Spontaneously Hypertensive Rats and Renal Hypertensive Dogs.

Shibasaki¹,

Takizawa²,

Uchida³

et al. 1997

Jpn.J.Pharmacol

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Section: Discussionsupporting

confidence: 87%

“…In SHR, YM430 produced a long-lasting hypotensive effect with a slight increase in HR. However, this eleva tion of HR is not as large as that with other 1,4-dihydro pyridine calcium entry blocking agents (20). In NTD, YM430 produced a long-lasting hypotensive effect but almost had no effect on HR and atrioventricular conduc tion time.…”

Section: Discussionmentioning

confidence: 77%

Hypotensive Effects of YM430, a 1,4-Dihydropyridine Derivative, in Spontaneously Hypertensive Rats and Renal Hypertensive Dogs.

Shibasaki¹,

Takizawa²,

Uchida³

et al. 1997

Jpn.J.Pharmacol

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“…The ratio of the negative chronotropic/negative inotropic potencies of aranidipine was found to be 23 times higher than that of nifedipine in isolated guinea pig myocardia [2]. Also, in anesthetized dogs, the hypotension produced by aranidipine was accompanied by a decrease, rather than an increase in heart rate [2]. Aranidipine has been shown to inhibit the L-type Ca 2+ current in guinea pig ventricular myocytes, with high affinity to the activated as well as the inactivated state of the channel, which may explain its slow kinetics [4].…”

Section: Introductionmentioning

confidence: 79%

“…A remarkable characteristic of aranidipine is its high negative chronotropic potency. The ratio of the negative chronotropic/negative inotropic potencies of aranidipine was found to be 23 times higher than that of nifedipine in isolated guinea pig myocardia [2]. Also, in anesthetized dogs, the hypotension produced by aranidipine was accompanied by a decrease, rather than an increase in heart rate [2].…”

Section: Introductionmentioning

confidence: 87%

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Inhibition of T-Type and L-Type Ca<sup>2+</sup> Currents by Aranidipine, a Novel Dihydropyridine Ca<sup>2+</sup> Antagonist

Masumiya

Tanaka²,

Tanaka³

et al. 2000

Pharmacology

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The effects of aranidipine, a novel dihydropyridine Ca²⁺ channel antagonist, on membrane currents in guinea pig ventricular myocytes and on action potentials in rabbit sinoatrial node tissue were examined. In myocytes, aranidipine (10 nmol/l to 1 μmol/l) concentration-dependently decreased T-type and L-type Ca²⁺ currents. Aranidipine (1 μmol/l) had little effect on K⁺ currents. In the sinoatrial node, 0.1 μmol/l aranidipine increased cycle length, and decreased +v̇_max and the slope of the phase 4 depolarization. Thus, inhibition of both T-type and L-type Ca²⁺ currents by aranidipine may partly explain its potent negative chronotropic activity.

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Contribution of aranidipine metabolites with slow binding kinetics to the vasodilating activity of aranidipine

Miyoshi

Miyake

Ichihara

et al. 1996

Naunyn-Schmiedeberg's Arch Pharmacol

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Aranidipine, a novel dihydropyridine derivative, gives rise to two active metabolites, M-1(alpha) and M-1(beta), which exhibit hypotensive activity comparable to that of nifedipine. The aim of this study was to examine the recovery phase of the vasodilating effect of M-1(alpha) and of M-1(beta), to determine their binding characteristics and to compare the results with those for aranidipine and other dihydropyridine derivatives. During intra-arterial infusion into the femoral vascular beds of anesthetized dogs, M-1(alpha), M-1(beta), and nifedipine, produced increases in femoral blood flow at doses three times higher than the dose of aranidipine required to produce a comparable effect. The onset and recovery of the effects of the metabolites on femoral blood flow were significantly slower than the onset and recovery of the effect of nifedipine. The inhibitory activities of M-1(alpha) and M-1(beta) towards stimulated 45Ca uptake in isolated guinea pig aorta were less than that of aranidipine. In binding studies, using porcine heart membrane preparations, [3H]M-1(alpha) and [3H]M-1(beta) had larger Kd values than [3H]aranidipine and [3H]nitrendipine, but the maximal binding number for each of them was almost the same. The association and dissociation rate constants for [3H]M-1(alpha) and [3H]M-1(beta) binding, as well as those for [3H]aranidipine binding, were significantly smaller than those for [3H]nitrendipine, corresponding to the recovery of the in vivo vasodilating effects of the metabolites. The dissociation rate constants of these radiolabeled ligands were highly positively correlated with the elimination rate constants of their in vivo vasodilating effects. From these results, we conclude that M-1(alpha) and M-1(beta), although their binding affinities and Ca2+ antagonistic actions are less potent, possess slower kinetic binding properties than many other dihydropyridines and that the slow kinetic interaction of these metabolites with the dihydropyridine receptor may contribute to the long-lasting in vivo vasodilating effect of aranidipine.

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Antihypertensive Effects of MPC-1304, a Novel Calcium Antagonist, in Experimental Hypertensive Rats and Dogs

Cited by 16 publications

References 0 publications

Hypotensive Effects of YM430, a 1,4-Dihydropyridine Derivative, in Spontaneously Hypertensive Rats and Renal Hypertensive Dogs.

Hypotensive Effects of YM430, a 1,4-Dihydropyridine Derivative, in Spontaneously Hypertensive Rats and Renal Hypertensive Dogs.

Inhibition of T-Type and L-Type Ca<sup>2+</sup> Currents by Aranidipine, a Novel Dihydropyridine Ca<sup>2+</sup> Antagonist

Contribution of aranidipine metabolites with slow binding kinetics to the vasodilating activity of aranidipine

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