PY 108-068: a calcium antagonist with an unusual pattern of cardiovascular activity.

PY 108-068 (PY) is a potent dihydropyridine derived calcium antagonist, which is light-stable enough to allow experiments in vitro to be done under normal daylight. It potently antagonized depolarization-induced contraction of rabbit aorta (EC50: 4 X 10(-9) M) but not receptor-stimulated contraction (EC50 much greater than 10(-5) M). It also decreased the rate of spontaneously beating guinea-pig and rabbit atria very potently (EC25 2.9 and 4.3 X 10(-9) M respectively) but considerably higher concentrations were needed for negative inotropic effects on guinea-pig left atria or rabbit papillary muscles (EC25 1.5 and 1 X 10(-7) M respectively). In open chest dogs PY (10 micrograms/kg i.v.) increased coronary flow and cardiac output, lowered blood pressure, and tended to decrease heart rate while myocardial contractile force was unchanged. Myocardial oxygen consumption, however, was decreased despite the absence of cardiodepression. Similar results with respect to the systemic circulation were observed in cats. The effects of PY on the vascular beds of a large number of organs were investigated using tracer microspheres. PY effected regional vasodilatation in the heart, brain and skeletal muscle. Antivasoconstrictor effects of PY were investigated in similar cat experiments by pretreating the animals with angiotension II infusions. The vasoconstrictor effects of angiotensin II on the vessels of the kidney, stomach and small intestine were antagonized, even though no vasodilatation had been seen in these regions in the previous experiments without the vasoconstrictor pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)