Studies on the specificity of the inhibitory action of N,N-diisopropyl-N'-isoamyl-N'-diethylaminoethylurea (P-286) on adrenal catecholamine release in the anaesthetized rat.
1. The ability of P-286 (N,N-diisopropyl-N'-isoamyl-N'-diethylaminoethylurea) to reduce selectively the release of catecholamines from the adrenal medulla has been studied in urethane-anaesthetized rats. 2. Pressor responses to acetylcholine (Ach) and the nicotinic receptor-agonist 1,4-dimethylphenylpiperazine (DMPP) in rats treated with atropine, (+/-)-propranolol and guanethidine were used as the index of adrenal catecholamine release. 3. The injection of P-286 (1-10 mg/kg, i.v.) elicited a dose-dependent bradycardia which was associated with hypotension. P-286 reduced pressor responses to Ach and DMPP in a dose-dependent manner with an IC50 of 2.5 mg/kg and, following near complete blockade, pressor responses to DMPP returned to 50% of control after 90 min. 4. In non-atropinized rats, P-286 (30 mg/kg, i.v.) was without effect on the bradycardic responses elicited by stimulation of the right vagus nerve at frequencies of 5-40 Hz while pressor responses to DMPP in bilaterally adrenalectomized, non-guanethidine treated rats were reduced by approximately 50% after P-286 (10 mg/kg, i.v.). 5. The latter effect of P-286 on responses to DMPP in adrenalectomized rats cannot be attributed to ganglionic blockade since in rats with intact adrenals P-286 (10 mg/kg, i.v.) also reduced pressor responses to i.v. adrenaline and i.v. angiotensin II by approximately 50%. Thus the reduction in response to DMPP in adrenalectomized rats and to the non-nicotinic agonists may be a reflection of an action on the mechanism of contraction of vascular smooth muscle; that is, at a post-receptor event. 6. The results of the study show that P-286 selectively reduces adrenal catecholamine release at doses which do not affect autonomic ganglia. Its usefulness as a tool in cardiovascular research, however, may be limited by an action of vascular smooth muscle.
Malta
E
E
School of Pharmacology, Victorian College of Pharmacy, Parkville, Victoria, Australia.
Angus
J A
JA
D000109:Acetylcholine / Q000494:pharmacology; D000313:Adrenal Medulla / Q000378:metabolism*; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002395:Catecholamines / Q000037:antagonists & inhibitors*; D004246:Dimethylphenylpiperazinium Iodide / Q000494:pharmacology; D004837:Epinephrine / Q000494:pharmacology; D005725:Ganglia, Autonomic / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000187:drug effects; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
D002395:Catecholamines; D011976:Receptors, Muscarinic; D000804:Angiotensin II; C001003:N,N-diisopropyl-N'-isoamyl-N'-diethylaminoethylurea; D004246:Dimethylphenylpiperazinium Iodide; D014508:Urea; D000109:Acetylcholine; D004837:Epinephrine