Max Meier

CGP 28392, a Dihydropyridine Ca2+ Entry Stimulator

Agents termed Ca2+ antagonists or Ca2+ channel blockers (e. g., nifedipine, verapamil, diltiazem) reduce Ca2+ influx through specific channels located in the membranes of vascular smooth muscle and myocardial cells. This action results in vasodilation and decreased myocardial contractility [1-5]. Consequently, this group of agents has clinical value in the therapy of angina pectoris, arrhythmias, and hypertension [6]. Compounds that act to increase Ca2+ influx through specific membrane channels might be expected to possess pharmacological activities opposite to those of the Ca2+ antagonists (e. g., vasoconstriction and increased myocardial contractility) [7]. The first Ca2+ entry stimulator (or Ca2+ agonistic compound) structurally related to nifedipine was YC-170 [8]. Like nifedipine, YC-170 is a 1,4-dihydropyridine derivative, but produced vasopressor effects in anesthetized rats and dogs as well as vasoconstriction in the isolated rabbit aorta. Based on indirect evidence, the authors suggested that these effects were due to an enhanced Ca2+ influx into vascular smooth muscle cells.

Comparison of the cardiovascular effects of phentolamine, sodium nitroprusside and nitroglycerin in anaesthetized cats (Comparison of vasodilators)

SummaryThe effects of phentolamine (PH), sodium nitroprusside (NP) and nitroglycerin (GTN) were compared in experiments on anaesthetized cats.All three agents diminished vascular resistance and lowered blood pressure, although they differed in the intensity of their effects (NP>PH=GTN) and the steepness of their dose-response curves (NP>PH>GTN). NP and GTN did not cause consistent changes in heart rate and dP/dt, whereas PH produced marked, dose-dependent increases in these two variables and in cardiac output, which was augmented to a lesser extent by NP and not affected by GTN.It is concluded that whereas the beneficial therapeutic effects of NP and GTN are presumably due exclusively to the reduction of preload and afterload, PH has an additional cardiostimulant action.ZusammenfassungAn narkotisierten Katzen wurden die hämodynamischen Wirkungen von Phentolamin (PH), Nitroprussid-Natrium (NP) und Nitroglycerin (GTN) verglichen.Alle drei Präparate wirkten widerstands- und drucksenkend, wenn auch unterschiedlich in Ausmaß (NP>PH=GTN) und Dosisabhängigkeit (NP>PH>GTN). Während aber NP und GTN keine eindeutigen Änderungen von Herzfrequenz und dP/dt bewirkten, führte PH zu signifikanten und dosisabhängigen Steigerungen dieser zwei Variablen sowie des Herzminutenvolumens, das seinerseits von NP weniger und von GTN gar nicht beeinflußt wurde.Während NP und GTN ihre günstige therapeutische Wirkung vermutlich ausschließlich über eine Reduktion von pre- und afterload entfalten, besitzt PH eine zusätzliche kardiostimulierende Wirkungskomponente.

Importance of cardiac and vascular beta-receptors in the action of phentolamine

To determine to what extent the effects of phentolamine (PHE) are mediated by the cardiac and vascular beta-receptors, the action of the drug was studied in anaesthetized cats pretreated with beta-blockers.Blockade of the cardiac beta-receptors with either propranolol or metoprolol entirely prevented the increases in heart rate,dP/dt and cardiac output caused by PHE. In animals pretreated with propranolol (in a dose blocking the vascular beta-receptors) or metoprolol (in a purely cardioselective dose) PHE significantly lowered blood pressure to the same extent as in untreated controls.The effects of PHE on the heart are thus conditional on the integrity of cardiac beta-receptors, whereas it seems improbable that vascular beta-receptors have any part in its vasodilative action. Evidence presented in the literature rather suggests a predominantly central mode of action.