Mechanisms of relaxant action of nicardipine, a new Ca++-antagonist, on isolated dog cerebral and mesenteric arteries.

Abstract

SUMMARY In helically-cut strips of cerebral and mesenteric arteries contracted with prostaglandin (PG) F^, carbocyclic thromboxane A 2 (cTxA 2 ) or K + , the addition of nicardipine caused a dose-related relaxation. Nicardipine-induced relaxation was greater in cerebral than in mesenteric arteries when contracted with PGF 2a and cTxA 2 , but did not appreciably differ in the arteries contracted with K + . Cerebral arteries contracted with hemolysate and PGF 2a relaxed in response to nicardipine to a similar extent. The contractile response to PGF 2a was attenuated by pretreatment with nicardipine, the attenuation being greater in cerebral than in mesenteric arteries. Ca ++ -induced contractions in cerebral and mesenteric arteries previously exposed to Ca + + -free media and depolarized by excess K + were attenuated by nicardipine to a similar extent. PGF 2a -induced contractions of cerebral arteries exposed to Ca + + -free media were attenuated by nicardipine, whereas those of mesenteric arteries were unaffected. Attenuations by nicardipine of the Ca + + -induced contraction in PGF 2a -treated cerebral arteries were greater than those seen in mesenteric arteries. It may be concluded that nicardipine produces a greater relaxation of cerebral arteries than mesenteric arteries, possibly due to a greater inhibition of the Ca + + -influx and to a decrease in the release of Ca + + from intracellular storage sites in cerebral arteries. As far as the concentrations used are concerned, nicardipine appears to attenuate the inward movement of Ca + + across cell membrane in mesenteric arterial smooth muscle, but not the release of intracellular^ stored Ca + + .Stroke Vol 14, No 2, 1983 CHEMICAL FACTORS OF THE PATHOGENESIS of cerebral vasospasm following subarachnoid hemorrhage include serotonin, 1-3 catecholamines 4 " 6 and prostaglandins 7-9 that are released from the subarachnoid hematoma 10 " and cerebral vessel. 7,812 These substances produce contractions of cerebral and extracerebral vessels by increasing the release of Ca + + from intracellular storage sites and the transmembrane influx of Ca + + . 1314 Ca ++ -antagonists which preferentially interfere with the Ca ++ -influx relax cerebral arterial smooth muscle previously contracted with these vasoconstrictors to a greater extent than extracerebral arteries, 15 ' 16 and the ability of the antagonists to effectively relieve the experimentally-induced cerebral vasospasm has been demonstrated. 17 Nicardipine has recently been reported to interfere with the uptake of 45 Ca ++ by rabbit aortae, 18 to increase the cerebral blood flow in dogs, monkeys and human patients, 19 and to relieve the experimentallyinduced cerebrovascular spasm in cats.20 At vasodilatory concentrations, this drug produces less bradycardia, A-V conduction block and decreased cardiac contractility. 21The present study was undertaken to clarify the action and the mechanism of action of nicardipine on isolated dog cerebral and mesenteric arteries stimulated by PGF 2a , cTxA 2 , hemolysate and K + , ...

Intrathecal administration of nicardipine hydrochloride to prevent vasospasm in patients with subarachnoid hemorrhage

“…Therefore, the rate of VS found in this study may be considered extremely low. The mean concentration of nicardipine in the CSF 12 h after the intrathecal administration was 231.44 ng/ml, which matches the effective concentration revealed by in vitro study at 10 -9 -10 -5 M (molecular weight of nicardipine is 515.99) [36]. In this study, nicardipine was administered every 12 h, so the effective concentration was likely maintained during the interval between each administration, and the fewer incidences of VS in this study may be partly due to the nicardipine in the CSF.…”

Efficacy and mechanism of action of a calcium channel blocker after global cerebral ischemia in rats.

“…43 " 45 NC and its dihydropyridine relatives block calcium uptake by membrane fractions from cerebral arteries 46 resulting in relaxation of smooth muscle in the walls of cerebral arteries and arterioles. 47 " 49 Dihydropyridine binding sites are also present in cerebral tissue 50 - 51 and a dihydropyridine-sensitive calcium channel has been identified in neuronal soma, 51 suggesting that these drugs might be effective in modifying calcium entry into neurons. In previous studies we have demonstrated substantial extraction of unchanged NC into normal and ischemic rat brain 21 and have demonstrated improved neuronal function after subcutaneous infusion.…”

Comparative effects of nicardipine, a new calcium antagonist, on size of myocardial infarction after coronary artery occlusion in dogs.

“…3 Calcium antagonists that inhibit transmembrane calcium influx in cardiac and vascular smooth calcium antagonist synthesized by Takenaka and his colleagues, is a dihydropyridine derivative and a potent coronary and cerebral vasodilator (figure 1). [25][26][27][28][29][30][31][32][33] Nicardipine has been shown to relax the isolated canine coronary arterial strip twice as much as nifedipine, six times as much as nitroglycerin, 10 times as much as verapamil, and 80 times as much as diltiazem. 27 In anesthetized dogs nicardipine increases coronary blood flow to the same extent as nifedipine and three times as much as nitroglycerin, while it has much less effect on atrioventricular conduction and cardiac contractility when compared with verapamil and diltiazem.27…”