title: BW A575C, a chemically novel agent with angiotensin converting enzyme inhibitor and beta-adrenoceptor-blocking properties.
abstract: BW A575C (N-(1-(S)-carboxy-5-[4(3-isopropylamino-2-(R, S)-hydroxypropoxy)indole-2- carboxamido]pentyl)-(R, S)-alanyl-(S)-proline) is a chemically novel agent which exhibits in a single molecule both angiotensin converting enzyme (ACE) inhibition and beta-adrenoceptor-blocking properties. BW A575C produced a competitive blockade of heart rate responses to isoprenaline in a guinea-pig right atrial preparation (pKB 7.18 +/- 0.05, cf. pindolol 8.9 +/- 0.7). BW A575C inhibited a partially purified preparation of ACE obtained from rabbit lung (IC50 10.7 +/- 2.1 nM, cf. enalaprilat, 4.4 +/- 0.8 nM). Intravenous administration of BW A575C (1-100 micrograms kg-1 min-1) to the pithed rat inhibited in a dose-dependent fashion both angiotensin I-induced pressor responses and isoprenaline-induced tachycardia. Dose-ratios obtained from such studies demonstrated that, in this preparation, BW A575C was approximately 100 times more active as an ACE inhibitor than as a beta-adrenoceptor blocking agent. Intravenous administration of BW A575C (1 mg kg-1) to the conscious rat inhibited angiotensin I-induced pressor responses, being approximately equipotent to enalapril and 10 times more potent than captopril. At the same dose, BW A575C had a similar duration of action as an ACE inhibitor to enalapril. Intravenous administration of BW A575C (1 mg kg-1) to either conscious dogs or rats inhibited both angiotensin I-induced pressor responses and isoprenaline-induced heart rate responses. Dose-ratios obtained from such studies demonstrated that in these species, BW A575C was 2-10 times more active as an ACE inhibitor than as a beta-adrenoceptor blocking agent.
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors; D000818:Animals; D003655:Decerebrate State; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008168:Lung / Q000201:enzymology; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D014227:Triazines / Q000494:pharmacology*
chemical_list: D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D014227:Triazines; C049707:palatrigine; D007545:Isoproterenol