Junichiro Aono

Evaluation of drug effects in a new experimental model of angina pectoris in the intact anesthetized rat

Abstract A simple experimental model of angina pectoris was developed in order to study the electrocardiographic alterations assumed to occur in angina pectoris and to examine the effects of nitroglycerin, dipyridamole, Ca2+-antagonists (nifedipine, verapamil, and diltiazem), and atropine on these changes. In intact anesthetized rats, the right carotid artery was exposed and the tip of a special cannula, through which vasoactive drugs were injected more selectively into the coronary vascular bed, was inserted closely near the right and the left coronary ostium. Single intraaortic injections of 4 to 8 μg methacholine or 100 μg acetylcholine (ACh) (in the presence of physostigmine) developed a reproducible elevation of the ST segment and T wave of the electrocardiogram (ECC). Nitroglycerin, the Ca2+-antagonists, and atropine administered iv prevented these changes in ECG, whereas dipyridamole failed to do so. In the isolated, donor-perfused rat heart, methacholine and ACh administered into the coronary perfusion system caused predominant vasoconstriction. Diltiazem inhibited the vasoconstriction, but dipyridamole failed to prevent it. In intact anesthetized rats, methacholine-induced elevation of the ST segment and T wave is ascribed to coronary vasoconstriction, leading to a transient tissue anoxia or ischemia. Since the ECC changes are fully reversible and readily reproducible, this model seems to be useful for the screening of antianginal drugs.

Species differences in renal vascular effects of dipyridamole and in the potentiation of adenosine action by dipyridamole.

Summary The effects of dipyridamole and adenosine on the renal vasculature and on the enhancement by dipyridamole of the action of adenosine were studied in pigs, dogs, rabbits, and rats. Intravenous adenosine in doses of 10–300 μg/kg produced dose-dependent decreases in heart rate and blood pressure of rabbits and rats. Potentiation of adenosine action by intravenous infusion of dipyridamole occurred only in rabbits. When administered into the renal artery of pigs, dogs, raboits, and rats, adenosine caused dose-dependent vasoconstriction in all species, whereas dipyridamole produced vasoconstriction in rabbits and vasodilation in pigs and rats. In dogs, the renal vascular response to dipyridamole depended on the perfusion method used. In kidneys perfused at a fixed flow rate with a pump, intrarenal dipyridamole elicited vasoconstriction, but in kidneys perfused by their own systemic blood pressure without the use of a pump, it caused vasodilation. The adenosine-induced renal vasoconstriction was enhanced by dipyridamole in pigs, dogs, and rabbits, but not in rats. Species differences and the perfusion method used are important for the renal vascular effects of dipyridamole and for the enhancement of adenosine activity by dipyridamole. Dipyridamole appears to possess not only an indirect action on blood vessels which is related to adenosine, but also a direct vasodilator effect.