Vol. 281, Issue 1, 180-187, 1997

Cardiovascular Effects of Cholecystokinin-4 Are Mediated By the Cholecystokinin-B Receptor Subtype In the Conscious Guinea Pig and Dog

Anthony A. Fossa, Michael J. Depasquale, Jean Morrone, Stevin H. Zorn, Dianne Bryce, John A. Lowe and Stafford McLean

Departments of General Pharmacology and Neurosciences, Pfizer Central Research, Groton, Connecticut

Panicogenic effects in humans of the selective cholecystokinin (CCK_B) receptor agonist, cholecystokinin tetrapeptide (CCK₄), have been reported to correlate with increases in heart rate (HR) and mean arterial pressure (MAP). Previous investigators have demonstrated that the nonselective CCK_A and CCK_B receptor agonist, sulfated cholecystokinin octapeptide, also produces increases in HR and mean arterial pressure. The purpose of our study is to determine if the cardiovascular changes induced by CCK₄ are mediated by the CCK_A or CCK_B receptor subtype using selective CCK antagonists for both receptor subtypes. The rank order of potency of the CCK receptor antagonists affecting CCK₄-induced HR and mean arterial pressure changes in the guinea pig corresponded to the rank order of potency for blockade of the CCK_B receptor binding in rat cortex, phosphatidyl inositol turnover in AR 4-2J rat pancreatoma cells and inhibition of pentagastrin-induced acid secretion in the rat. The changes induced by CCK₄ on HR, but not mean arterial pressure, appear to be species dependent as reflected by a decrease in the HR in the guinea pig and an increase in the dog. Nonetheless, the results from the antagonist studies indicate that the cardiovascular responses to CCK₄ in both the guinea pig and dog are mediated by the CCK_B receptor subtype.