Characterization of the receptors and mechanisms involved in the cardiovascular actions of sCCK-8 in the pithed rat.
1. The cardiovascular actions of cholecystokinin and related peptides were investigated in the pithed rat. The receptors and the mechanisms involved in these experiments were characterized. 2. Sulphated cholecystokinin octapeptide (sCCK-8, 0.1-100 nmol kg-1, i.v.) elicited a dose-dependent bradycardia and increase in mean arterial blood pressure. Neither gastrin-17 nor pentagastrin had any effect at concentrations up to 100 nmol kg-1. 3. Both the pressor response and bradycardia elicited by sCCK-8 were reduced by the selective CCKA receptor antagonists, devazepide (0.5-50 nmol kg-1) and lorglumide (1-7 mumol kg-1). The selective CCKB receptor antagonists, CI-988 (1 mumol kg-1) and L-365,260 (15 mumol kg-1) did not inhibit the effects of sCCK-8. 4. The pressor response induced with sCCK-8 was reduced by treatment with either phentolamine (3 mumol kg-1) or guanethidine (2 mumol kg-1) and was unaffected by treatment with propranolol, atropine or hexamethonium. The pressor response also persisted following bilateral adrenalectomy. 5. The bradycardia induced with sCCK-8 was unaffected by treatment with phentolamine, propranolol, guanethidine, atropine, hexamethonium or bilateral adrenalectomy. 6. The tetrapeptide of cholecystokinin (CCK-4) elicited a dose-dependent pressor response but did not induce bradycardia. The pressor response was unaffected by devazepide (50 nmol kg-1), L-365260 (15 mumol kg-1) or phentolamine (3 mumol kg-1). 7. In the pithed rat, sCCK-8 acted via CCKA receptors to increase arterial blood pressure indirectly, at least in part, through activation of alpha-adrenoceptors. The observed bradycardia was also mediated byCCKA receptors but possibly through a direct action on the heart.
Gaw
A J
AJ
Peptic Ulceration Group, Pharmacology I, Glaxo Research and Development Ltd, Ware, Herts.
Hills
D M
DM
Spraggs
C F
CF
D000315:Adrenalectomy; D018663:Adrenergic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001570:Benzodiazepinones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D001919:Bradycardia / Q000139:chemically induced; D002766:Cholecystokinin / Q000633:toxicity*; D003655:Decerebrate State; D020109:Devazepide; D004305:Dose-Response Relationship, Drug; D005755:Gastrins / Q000008:administration & dosage / Q000633:toxicity; D006145:Guanethidine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D006339:Heart Rate / Q000187:drug effects; D006727:Hormone Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D006728:Hormones / Q000008:administration & dosage / Q000633:toxicity; D006973:Hypertension / Q000139:chemically induced; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008536:Meglumine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D010418:Pentagastrin / Q000008:administration & dosage / Q000494:pharmacology; D010646:Phentolamine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011377:Proglumide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011949:Receptors, Cholecystokinin / Q000187:drug effects* / Q000378:metabolism; D012844:Sincalide / Q000633:toxicity*; D013758:Tetragastrin / Q000008:administration & dosage / Q000633:toxicity
D018663:Adrenergic Agents; D001570:Benzodiazepinones; D005755:Gastrins; D006727:Hormone Antagonists; D006728:Hormones; D007211:Indoles; D011949:Receptors, Cholecystokinin; D013758:Tetragastrin; C065599:PD 134308; C013550:gastrin 17; D008536:Meglumine; D002766:Cholecystokinin; D010418:Pentagastrin; D011377:Proglumide; D020109:Devazepide; C048181:lorglumide; D012844:Sincalide; D010646:Phentolamine; D006145:Guanethidine