Differential responsiveness of conduit and resistance coronary arteries to endothelin A and B receptor stimulation in anesthetized dogs.
The effects of endothelin-1 (ET-1), an ET(A)/ETB-receptor agonist, and IRL 1620, a potent and selective ETB-receptor agonist, were assessed on left circumflex coronary artery diameter (sonomicrometry) and flow (electromagnetic flow probe) in pentobarbital-anesthetized dogs. Intracoronary (i.c.) bolus injections of ET-1 (80 pmol/dose) caused large, sustained coronary diameter decreases (281 +/- 39 microns) and transient flow increases (5.6 +/- 2.6 ml/min), followed by transient (10.0 +/- 1.9 ml/min) and then sustained flow reductions (6.6 +/- 2.5 ml/min) before terminating in ventricular fibrillation after two to five doses (max delta s; n = 4 dogs). IRL 1620 boluses (5-2,000 pmol/dose i.c.; max delta s; n = 3) also dose-dependently and transiently increased (16.8 +/- 1.4 ml/min; 200 pmol), then transiently decreased (12.8 +/- 1.5 ml/min; 1,600 pmol) flow but had minimal effects on diameter (delta = -23 +/- 4 microns; 2,000 pmol). Doses of IRL 1620 beyond 400 pmol were accompanied by a slowly responding, sustained decrease in baseline flow (-9.2 +/- 2.7 ml/min) and baseline diameter (232 +/- 150 microns). In a separate group of dogs (n = 5), IRL 1620 (400 pmol i.c.) was evaluated before and after sequential inhibition of cyclooxygenase (indomethacin; 10 mg/kg i.v.) and then nitric oxide synthase (N omega-nitro-L-arginine methyl ester, L-NAME; 50 mg/kg i.v.). Indomethacin alone did not affect the flow increase to IRL 1620 (11.0 +/- 2.0 versus 11.8 +/- 1.8 ml/min) but blunted the flow decrease by 30 +/- 6% (10.6 +/- 1.4 versus 7.1 +/- 0.7 ml/min).(ABSTRACT TRUNCATED AT 250 WORDS)
Rigel
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Research Department, Ciba-Geigy Corporation, Summit, NJ 07901.
Lappe
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D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors; D000758:Anesthesia; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000494:pharmacology; D019001:Nitric Oxide Synthase; D010446:Peptide Fragments / Q000494:pharmacology; D011453:Prostaglandins / Q000494:pharmacology; D017466:Receptors, Endothelin / Q000187:drug effects*; D013268:Stimulation, Chemical
D016861:Cyclooxygenase Inhibitors; D016232:Endothelins; D010446:Peptide Fragments; D011453:Prostaglandins; D017466:Receptors, Endothelin; C074308:sovateltide; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D019331:NG-Nitroarginine Methyl Ester