Calcium Channel Blocking Action of Franidipine Hydrochloride (CV-4093-2HCI) In Vitro and In Vivo

Abstract

Abstract-The calcium-channel blocking action of franidipine (CV-4093.2HCI) was investigated in vitro and in vivo. CV-4093.2HCI inhibited the 60 mM K+ induced contraction of rabbit aorta and those of coronary, renal, mesenteric and femoral arteries of dog less potently than nifedipine and nicardipine. In dog portal and femoral veins, CV-4093.2HCI inhibited K+-induced contraction as potently as nifedipine and nicardipine did. The inhibitory effect of this drug was fully developed by pretreatment for 60 min, and it lasted long after washout. The drug inhibited both K+-induced 45Ca-influx and K+-induced contraction at a similar concentration range in rabbit aorta and dog portal vein, but had no effect on 45Ca efflux from either vessel. On the other hand, in the isolated, perfused kidneys and mesenteric vascular beds of SHR, CV-4093.2HCI inhibited K+-induced vasocon striction more effectively than did nifedipine. Moreover, in pithed rats (1.v.) and ganglion-blocked conscious SHR (p.o.), CV-4093.2HCI inhibited more potently a2-adrenergic pressor responses than did nicardipine. These pharmacological properties of CV-4093.2HCI, especially those seen in the isolated, perfused kidney and mesenteric vascular beds, may be responsible for its potent and long-lasting action as an antihypertensive agent.

Effects of CV-4093, a new dihydropyridine calcium channel blocker, on renal hemodynamics and function in strke-prone spontaneously hypertensive rats(SHRSP).

“…In our study, CV-4093 elicited a long-lasting hypotensive action in anesthetized SHRSP and was more potent than nicardipine in this firmly to the site of action, which is considered to be responsible for the long-lasting hy potensive action of the compound (4,12). UF, UNa ,V and FENa after the higher dose of CV-4093 disappeared between 1-1.5 hr after the injection (Table 3), after which the three variables remained at their respective control levels, in contrast to the compound's long lasting hypotensive and renal vasodilating effects.…”

Effects of a new dihydropyridine derivative, CV-40932HCl, on renal hemodynamics in spotaneously hypertensive rats.

“…Moreover, it has been reported that, as compared with nicardipine, the antagonizing effect of CV-4093.2HC1 on potassium-induced vasocontraction was more marked in the isolated kidneys including the arterioles but less in the isolated large renal artery (20). Furthermore, the antagoniz ing effects of CV-4093.2HC1 on potassium induced vasocontraction were less prominent than those of other calcium antagonists in the aorta and coronary artery of dogs and rabbits (20). These findings suggest that CV-4093• 2HCI has a higher affinity for the resistant vessels (arterioles and small arteries) in the kidneys.…”

Prolonged Inhibition of Vascular Contraction and Calcium Influx by the Novel 1,4-Dihydropyridine Calcium Antagonist Cinaldipine (FRC-8653).

“…One is the influx of extracellular cal cium ions through the cell membrane and the other is the release from the intracellular cal cium store (11). Many studies support the view that the vasodilative and calcium antago nistic activities of dihydropyridine calcium antagonists result from blocking the calcium influx through L-channels (8,12). Although movement of calcium ions through L-channels has not been directly measured in the previous studies, continuous suppression of vascular contraction brought about by long-lasting cal cium antagonists is generally assumed to result from prolonged suppression of L-channels.…”

“…In the preparation treated with FRC-8653, inhibition persisted through out the experimental period and approximate ly 70% suppression was still observed 7 hr af ter removal of the drug. Several laboratories have studied the long acting effects of dihy dropyridine calcium antagonists (8)(9)(10) As sources of increased intracellular cal cium, two major mechanisms have become evident. One is the influx of extracellular cal cium ions through the cell membrane and the other is the release from the intracellular cal cium store (11).…”

“…The long-lasting inhibitory effect of calcium antagonists on vascular con traction is generally assumed to result from long-lasting inhibition of L-channels (8)(9)(10), but the direct measurement of calcium influx through L-channels has not been attempted in previous studies. In the present study, we ex amined directly the influx of calcium ions through the cell membrane and confirmed that FRC-8653 inhibited calcium influx for a longer time than nifedipine and nicardipine.…”