Vasorelaxation by pinacidil in isolated perfused lungs is enhanced in rats with hypoxic pulmonary hypertension but is dependent on the constrictor.
The potassium channel opening drug, pinacidil, has been examined in isolated perfused lungs taken from rats with hypoxic pulmonary hypertension (housed in 10% oxygen for 7 days) and control rats. Inhibition by pinacidil (1 to 30 microM) of noradrenaline (NA)-induced vasoconstriction (NA infusions; beta-adrenoceptors blocked) and of hypoxic pulmonary vasoconstriction (HPV; ventilation for 3.5-4.5 min with 0-1% oxygen) were compared. The vasoconstrictor responses in preparations from control and hypoxic rats, respectively, were (mm Hg) NA 6.6 +/- 0.68 (6); 8.2 +/- 1.45 (9); HPV 7.8 +/- 1.03 (12); 8.8 +/- 0.93 (13). These responses were reversibly inhibited by pinacidil. In lungs from control rats pinacidil was 10-fold less potent against NA than against HPV, but in lungs from hypoxic rats it was equipotent against NA and HPV. When tested against NA, but not HPV, pinacidil was significantly more potent in lungs from hypoxic rats than control rats. It is postulated that NA-induced vasoconstriction in lungs from hypoxic rats, and HPV in both groups of rats, involve calcium influx through voltage-operated calcium channels. Consequently, these responses are readily inhibited by drugs such as pinacidil which open potassium channels and hyperpolarise the cell membrane. In contrast in lungs from control rats, NA-induced constriction may involve mainly intracellular calcium release and thus be less readily inhibited by the hyperpolarising effect of pinacidil.
Wanstall
J C
JC
Department of Physiology and Pharmacology, University of Queensland, Brisbane, Australia.
D000818:Animals; D006146:Guanidines / Q000627:therapeutic use*; D006976:Hypertension, Pulmonary / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D000860:Hypoxia / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D010477:Perfusion; D020110:Pinacidil; D051381:Rats; D017208:Rats, Wistar; D014661:Vasoconstriction / Q000187:drug effects*; D014665:Vasodilator Agents / Q000627:therapeutic use*
D006146:Guanidines; D014665:Vasodilator Agents; D020110:Pinacidil