K+ channel pulmonary vasodilation in fetal lambs: role of endothelium-derived nitric oxide.
To define the role and mechanism of action of K+ channels in regulating fetal pulmonary vascular tone, we studied the hemodynamic effects of pinacidil (a K+ channel activator) and glibenclamide (a K+ channel blocker). The effects of pinacidil were compared with those of acetylcholine [an endothelium-derived relaxing factor- (EDRF) dependent pulmonary vasodilator] and 8-bromoguanosine 3',5'-cyclic monophosphate (8-bromo-cGMP, an EDRF-independent pulmonary vasodilator) before and after treatment with N omega-nitro-L-arginine [a competitive inhibitor of an EDRF, endothelium-derived nitric oxide (EDNO), synthesis], or L-arginine (the substrate for the formation of EDNO). In 14 unanesthetized fetal lambs in utero, catheters were inserted into the fetal pulmonary artery, descending aorta, left atrium, and superior vena cava to measure pressures and administer drugs. An ultrasonic flow transducer was placed around the left pulmonary artery to measure flow (QP) continuously. In eight animals, pinacidil, acetylcholine, and 8-bromo-cGMP caused similar acute maximal increases in QP of 128, 137, and 155 ml/min, respectively. After a 60-min infusion of N omega-nitro-L-arginine (2.07 +/- 0.27 mg.kg-1.min-1), the increase in QP caused by acetylcholine and pinacidil was significantly attenuated, by 84 and 68%, respectively, with only a 10% attenuation of the increase in QP caused by 8-bromo-cGMP. In six additional N omega-nitro-L-arginine-pretreated fetal lambs, infusion of L-arginine (32.2 +/- 4.3 mg.kg-1.min-1) restored the vasodilatory effects of acetylcholine and pinacidil. A 20-min infusion of glibenclamide (n = 6; 0.64 +/- 0.07 mg.kg-1.min-1) blocked the vasodilation by pinacidil but not acetylcholine.(ABSTRACT TRUNCATED AT 250 WORDS)
Chang
J K
JK
Department of Pediatrics, University of California, San Francisco 94143.
Moore
P
P
Fineman
J R
JR
Soifer
S J
SJ
Heymann
M A
MA
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D005333:Fetus / Q000502:physiology*; D005905:Glyburide / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019335:Nitroarginine; D020110:Pinacidil; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011247:Pregnancy; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology*; D012756:Sheep; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
D006146:Guanidines; D015221:Potassium Channels; D014665:Vasodilator Agents; D019335:Nitroarginine; D015124:8-Bromo Cyclic Adenosine Monophosphate; D009569:Nitric Oxide; D020110:Pinacidil; D001120:Arginine; D000109:Acetylcholine; D005905:Glyburide