[Pharmacological properties of (+/-)-4-[2-hydroxy-3-(3-(2-methoxyphenoxy)-2-propylamino)propoxy]-1(2H) -isoquinolinone (N-1518), a new combined alpha- and beta-adrenoceptor blocking drug].
The alpha, beta-adrenergic blocking, antihypertensive and vasodilating properties of N-1518 were compared with those of labetalol. N-1518 blocked alpha- and beta-adrenoceptors competitively as indicated by parallel rightward displacement of the dose-response curve of each agonist in isolated organs and in anesthetized dogs. As judged by pA2 values and DR10 values, N-1518 was as potent as labetalol in blocking alpha- and beta-adrenoceptors. The beta 1/alpha 1 ratio of N-1518 was 8.3 for pA2 values in isolated organs and 13.6 for DR10 values in anesthetized dogs, respectively. N-1518 inhibited dose-dependently the pressor response to intravenous administration of noradrenaline, but labetalol did not depress the response to noradrenaline in anesthetized dogs. N-1518 is composed of four optical isomers. The SR-isomer was the most potent in blocking beta-receptors, and the RR-isomer was the most potent in blocking alpha-receptors. N-1518 has no intrinsic sympathomimetic activity in reserpinized rats and has no local anesthetic activity in guinea pigs. Single oral administration of N-1518 produced a fall in blood pressure in conscious SHR and renal hypertensive dogs without causing tachycardia. Intra-arterially administered N-1518 in the dog hindlimb resulted in vasodilation as indicated by the increase in blood flow. The magnitude of the responses was approximately 3 times more potent than that of labetalol.
Sugai
T
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Department of Pharmacology, Niigata University School of Medicine, Japan.
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D000779:Anesthetics, Local; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D005260:Female; D005263:Femoral Artery / Q000187:drug effects; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D007741:Labetalol / Q000494:pharmacology; D008297:Male; D050198:Phenoxypropanolamines; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D012039:Regional Blood Flow / Q000187:drug effects; D013237:Stereoisomerism; D014665:Vasodilator Agents
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D000779:Anesthetics, Local; D007546:Isoquinolines; D050198:Phenoxypropanolamines; D014665:Vasodilator Agents; C066919:N 1518; D007741:Labetalol