Pulmonary vasodilation to endothelin isopeptides in vivo is mediated by potassium channel activation.
The present study was undertaken to investigate the effects of endothelin (ET) isopeptides on the pulmonary vascular bed of the intact spontaneously breathing cat under conditions of constant pulmonary blood flow and left atrial pressure. When pulmonary vasomotor tone was actively increased by intralobar infusion of U-46619, intralobar bolus injections of ET-1 (1 microgram), ET-2 (1 microgram), and ET-3 (3 micrograms) produced marked reductions in pulmonary and systemic vascular resistances. The pulmonary vasodilator response to each ET isopeptide was not altered by atropine (1 mg/kg iv), indomethacin (2.5 mg/kg iv), and ICI 118551 (1 mg/kg iv) but was significantly diminished by glybenclamide (5 mg/kg iv). This dose of glybenclamide significantly diminished the decrease in lobar arterial and systemic arterial pressures in response to intralobar injection of pinacidil (30 and 100 micrograms) and cromakalim (10 and 30 micrograms), whereas pulmonary vasodilator responses to acetylcholine (0.03 and 0.1 microgram), prostaglandin I2 (0.1 and 0.3 microgram), and isoproterenol (0.03 and 0.1 microgram) were not altered. The systemic vasodilator response to each ET isopeptide was not changed by glybenclamide or by the other blocking agents studied. The present data comprise the first publication demonstrating that ET-1, ET-2, and ET-3 dilate the pulmonary vascular bed in vivo. The present data further suggest that the pulmonary vasodilator response to ET isopeptides depends, in part, on activation of potassium channels and is mediated differently from the systemic vasodilator response to these substances. Contrary to earlier work, the present data indicate the pulmonary vascular response to ET isopeptides does depend on the preexisting level of pulmonary vasomotor tone.(ABSTRACT TRUNCATED AT 250 WORDS)
Lippton
H L
HL
Department of Pulmonary Medicine, Louisiana State University Medical School, New Orleans 70112.
Cohen
G A
GA
McMurtry
I F
IF
Hyman
A L
AL
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D002415:Cats; D016232:Endothelins / Q000494:pharmacology*; D005260:Female; D006146:Guanidines / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D020110:Pinacidil; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D011652:Pulmonary Circulation / Q000187:drug effects* / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D001095:Arachidonic Acids; D016232:Endothelins; D006146:Guanidines; D015221:Potassium Channels; D016718:Arachidonic Acid; D020110:Pinacidil; D007545:Isoproterenol; D000109:Acetylcholine