Calcium antagonists represent a new class of drugs, which were suggested to act by a selective inhibition of Ca2+ influx through cell membranes. We studied the mechanism of action of three calcium antagonists, diltiazem, nifedipine, and verapamil, by investigating the effect on 45Ca uptake and efflux in rat heart and aorta and in rabbit vessels. The uptake of La3+-resistant 45Ca was not decreased by nifedipine or verapamil either in the heart or in the vessels and was increased by diltiazem in rabbit vessels. The efflux of 45Ca from the mesenteric vein of rabbit, originating presumably from intracellular and membrane-boudn fractions, was enhanced by nifedipine. These effects were observed with drug concentrations inhibiting contractions in isolated atria and the spontaneous and norepinephrine-, potassium-, or barium-induced contractions in the portal vein of rats. Thus, our results suggest that calcium antagonistic drugs act by other mechanisms than the inhibition of transmembranous Ca flux, probably on the release and binding of Ca2+ in intracellular pools. The relatively greater inhibition of norepinephrine- than K+-induced contractions in vessels by the calcium antagonistic drugs and the abolition of the inotropic effect of norepinephrine in rat atrium exposed to 0-Ca Krebs solution for a short period are other effects suggesting an intracellular action for these drugs.
The responses to 5‐hydroxytryptamine (5‐HT) of rabbit isolated mesenteric artery and vein and longitudinal smooth muscle of guinea‐pig ileum were examined in Krebs solution containing 0, 1.2 or 2.4 mm Mg2+. When the concentration of Mg2+ was raised the spontaneous contractile activity of rabbit mesenteric vein was depressed. The responses to 5‐HT in rabbit mesenteric artery and vein and guinea‐pig ileum were greater in the absence of Mg2+. The initial fast component of 5‐HT‐induced contractions in rabbit mesenteric vein was reduced more consistently than the subsequent slow component by increasing the Mg2+ concentration. Exposure of mesenteric vein to Ca‐free solution containing ethyleneglycoltetra‐acetic acid (EGTA) promptly abolished 5‐HT contraction in normal‐Mg but not in low‐Mg Krebs solution. In mesenteric veins, no difference was observed in either the ‘lanthanum‐resistant’ uptake of 45Ca or total tissue Ca, measured by atomic absorption spectrophotometry, after 60 min exposure to either low‐Mg or normal‐Mg Krebs solution. On the other hand, after 5 min exposure, the ‘lanthanum‐resistant’ uptake of 45Ca was greater in the absence of Mg2+ than in the presence of higher Mg2+ concentrations. It is suggested that Mg2+ depressed the 5‐HT response at least partly by reducing the availability of Ca2+ from a rapidly equilibrating intracellular pool.
Calcium antagonistic drugs (also called slow channel or calcium channel inhibitors or calcium entry blockers) represent a major development in cardiovascular pharmacology. Their main site of action is at the slow channels where they inhibit Ca2+ influx into the cells. This characteristic distinguishes them from other drugs such as sodium nitroprusside, papaverine, hydralazine and diazoxide which interfere with the availability of calcium ions for their physiological functions by acting at sites other than the 'calcium channels'. There is considerable evidence, however, that calcium antagonistic drugs act at an intracellular site(s) as well as the 'calcium channels'. At present, verapamil, nifedipine and diltiazem are the most important representatives of this new class of drugs. Their chemical structures are quite different but their pharmacological characteristics are similar. The action of these drugs is primarily confined to the cardiovascular system. In the heart they depress cardiac contractions and heart rate and protect the ischaemic myocardium from calcium injury. Furthermore, verapamil and diltiazem (but not nifedipine) prolong AV conduction and refractoriness, which is important for their use as antiarrhythmic agents. All 3 drugs are powerful dilators of the coronary and peripheral arteries. These in vitro effects can be substantially altered by activation of baroreceptor reflexes in vivo, as is expected with vasodilators that cause little or no inhibition of noradrenaline release from sympathetic nerve endings. The combination of coronary dilatation with decreased oxygen demand of the myocardium and with decreased preload explains their value in the treatment of vasospastic and effort angina.
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