Inhibition of pentagastrin-induced pressor response in conscious rats by the CCK-B receptor antagonist CI-988 and chlordiazepoxide.
Elevation of blood pressure is a characteristic feature of spontaneous and pharmacologically induced panic attacks in man. We examined whether this symptom could be reproduced in conscious rats and, if so, whether the cardiovascular changes induced by anxiogenic agents could be employed as a functional in vivo screen for CCK-B receptor antagonists which might be predictive of anxiolytic activity. Bolus i.v. administration of pentagastrin (0.1-100 micrograms/kg) or the beta-carboline FG-7142 (0.001-3 mg/kg) caused transient ( < or = 5 min) dose-dependent increases in arterial blood pressure of up to 41 mmHg. The benzodiazepine receptor agonist chlordiazepoxide (10 mg/kg i.v, 15 min previously) attenuated the pressor response induced by either pentagastrin (1 microgram/kg i.v.) or FG-7142 (0.3 mg/kg i.v.). In contrast, the CCK-B receptor antagonist CI-988 (3 mg/kg i.v., 15 min previously) inhibited the pressor response induced by pentagastrin, but not FG-7142. Antagonism of the pressor response elicited by pentagastrin in animals provides a simple method to establish the active dose range for CCK-B receptor antagonists in vivo. Since cardiovascular parameters can be readily monitored in man, this approach may assist in guiding clinical dose ranging studies to establish therapeutically beneficial effect of these compounds in panic disorder.
Webb
J K
JK
Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK.
Rupniak
N M
NM
Boyce
S
S
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002243:Carbolines / Q000494:pharmacology*; D002707:Chlordiazepoxide / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008536:Meglumine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010418:Pentagastrin / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*
D002243:Carbolines; D006727:Hormone Antagonists; D007211:Indoles; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; C065599:PD 134308; C035874:FG 7142; D008536:Meglumine; D002707:Chlordiazepoxide; D010418:Pentagastrin