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.