Effects of the CCK(A) receptor antagonists SR 27897B and PD140548 on baroreflex function in conscious rats.
Since the cardiovascular effects of cholecystokinin (CCK) seem to particularly involve the A ('peripheral') subtype of CCK (CCK[A]) receptor, we examined the actions of two novel, highly selective CCK(A) receptor antagonists, PD140548 (N-alpha-methyl-N[(tricyclo[3.3.1.1(3,7)]dec-2-yloxy)carbony l]-L-tryptophyl]-D-3-(phenylmethyl)-beta-alanine) and SR 27897B (1-[[2-(4-(2-chlorophenyl)thiazol-2-yl)aminocarbonyl]acetic acid) on CCK-induced alterations in blood pressure and heart rate, and on the baroreceptor reflex in the conscious, instrumented rat. CCK (2 microg, i.v.) produced a pressor response and biphasic effects on heart rate involving an initial bradycardia followed by a pronounced tachycardia. Administration of PD140548 (10 mg/kg, i.v.) and SR 27897B (0.6 mg/kg, i.v.) significantly inhibited the pressor effects of CCK (35 and 47%, respectively), whilst reversing the bradycardic responses to a tachycardia. The CCK(A) receptor antagonists had different effects on the baroreceptor heart rate reflex since only PD140548 caused a significant increase in the gain or sensitivity of the reflex. This effect of PD140548 on gain is likely to occur via a central mechanism and may reflect the increased lipophilicity of PD140548 relative to SR 27897B. Overall, these investigations provide new evidence for the involvement of the CCK(A) receptor in cardiovascular regulation.
Bunting
M W
MW
Department of Pharmacology, Monash University, Clayton, Vic., Australia.
Beart
P M
PM
Widdop
R E
RE
D000818:Animals; D017704:Baroreflex / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006727:Hormone Antagonists / Q000494:pharmacology*; D007210:Indoleacetic Acids / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000494:pharmacology*
D006727:Hormone Antagonists; D007210:Indoleacetic Acids; D007211:Indoles; C102662:PD 140548; D011949:Receptors, Cholecystokinin; D013844:Thiazoles; C080460:SR 27897