EFFECTS OF THE CCKA RECEPTOR ANTAGONISTS SR 27897B AND PD140548 ON BAROREFLEX FUNCTION IN CONSCIOUS RATS

Since the cardiovascular effects of cholecystokinin (CCK) seem to part icularly involve the A ('peripheral') subtype of CCK (CCKA) receptor, we examined the actions of two novel, highly selective CCKA receptor a ntagonists, PD140548 yl]-L-tryptophyl]-D-3-(phenylmethyl)-beta-alanine ) and SR 27897B -(2-chlorophenyl)thiazol-2-yl)aminocarbonyl]acetic aci d) on CCK-induced alterations in blood pressure and heart rate, and on the baroreceptor reflex in the conscious, instrumented rat. CCK (2 mu g, i.v.) produced a presser response and biphasic effects on heart ra te involving an initial bradycardia followed by a pronounced tachycard ia. Administration of PD140548 (10 mg/kg, i.v.) and SR 27897B (0.6 mg/ kg, i.v.) significantly inhibited the presser effects of CCK (35 and 3 7%, respectively), whilst reversing the bradycardic responses to a tac hycardia. The CCK, receptor antagonists had different effects on the b aroreceptor heart rate reflex since only PD140548 caused a significant increase in the gain or sensitivity of the reflex. This effect of PD1 40548 on gain is likely to occur via a central mechanism and may refle ct the increased lipophilicity of PD140548 relative to SR 27897B. Over all, these investigations provide new evidence for the involvement of the CCK, receptor in cardiovascular regulation. (C) 1997 Elsevier Scie nce B.V.