Dihydropyridine calcium antagonists: beneficial or adverse effects in the setting of myocardial ischaemia/reperfusion?
Dihydropyridine (DHP) calcium antagonists are established drugs in the management of hypertension and chronic stable angina. However, recently a dose-related increase in the mortality of patients with coronary artery disease with nifedipine has been suggested. The conclusions of this study were seriously contradicted. Therefore, in our laboratory, the effect of the DHP calcium antagonist nisoldipine on ischaemic myocardial blood flow and function, infarct size, and the functional recovery of reversibly injured, reperfused myocardium was once more investigated in controlled in vivo models. In anaesthetized dogs, in the presence of a severe coronary artery stenosis, intravenous nisoldipine decreased poststenotic subendocardial blood flow and contractile function when arterial pressure was decreased. In contrast, when hypotension was prevented by inflation of an intra-aortic balloon, no aggravation of myocardial ischaemia was seen. During exercise, when aortic pressure is raised by catecholamines, nisoldipine may therefore not exert a pro-ischaemic effect, but may rather improve regional myocardial blood flow and function in the ischaemic region. As has been shown for nifedipine, the functional antagonism of alpha-adrenergic coronary vasomotor tone contributes to the improvement of myocardial blood flow and function of the ischaemic region, in particular during exercise. In anaesthetized pigs, intracoronary administration of nisoldipine prior to a 90-min low-flow ischaemia tended to decrease infarct size. Infarct size resulting from prolonged and severe myocardial ischaemia is reduced by one or more preceding short episodes of ischaemia and reperfusion, a phenomenon called ischaemic preconditioning. A transient exposure to exogenous calcium has been shown to mimic ischaemic preconditioning. Thus, a blockade of calcium channels may interfere with this reduction of infarct size. However, in anaesthetized pigs, nisoldipine did not prevent the reduction of infarct size by ischaemic preconditioning. Reperfused myocardium after short periods of myocardial ischaemia is characterized by a reversible, prolonged depression of myocardial function, a phenomenon called myocardial stunning. In anaesthetized dogs, pre-ischaemic intravenous administration of nisoldipine improved the functional recovery of stunned myocardium following a 15-min complete occlusion of the left circumflex coronary artery. Since myocardial blood flow during myocardial ischaemia and reperfusion was not altered and afterload was kept constant by an intra-aortic balloon, the beneficial effect of nisoldipine appears to be related to an attenuated calcium overload during early myocardial ischaemia. In conclusion, pro-ischaemic effects of calcium antagonists can be avoided when the dosage or mode of administration are adjusted to prevent significant decreases in arterial pressure. Patients in such a way under treatment with calcium antagonists will experience an increase in exercise tolerance and also a better recovery of contractile function after the termination of ischaemia.
Ehring
T
T
Department of Pathophysiology, University School of Medicine, Essen, Germany.
Heusch
G
G
D000818:Animals; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000009:adverse effects; D003326:Coronary Circulation; D003331:Coronary Vessels / Q000187:drug effects; D004095:Dihydropyridines / Q000008:administration & dosage / Q000009:adverse effects; D004285:Dogs; D006801:Humans; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy*; D017682:Myocardial Stunning / Q000188:drug therapy; D015737:Nisoldipine / Q000008:administration & dosage / Q000009:adverse effects; D014661:Vasoconstriction / Q000187:drug effects
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D015737:Nisoldipine; C038806:1,4-dihydropyridine