title: NIP-121 is more effective than nifedipine in acutely reversing chronic pulmonary hypertension.
abstract: To determine if NIP-121, a new antihypertensive agent with K+ channel-opening activity, would be an effective vasodilator in pulmonary hypertension, we studied its acute hemodynamic effects under normoxic conditions in conscious chronically hypoxic pulmonary hypertensive rats and in control pulmonary normotensive rats. In contrast to no pulmonary vasodilation by NIP-121 in control rats, the K+ channel activator (10-100 mg/kg i.v.) decreased both mean pulmonary arterial pressure (from 42 +/- 2 to 33 +/- 2 mmHg; P < 0.05) and total pulmonary resistance (from 278 +/- 30 to 213 +/- 32 mmHg.l-1 x min; P < 0.05) in hypertensive rats. NIP-121 produced similar dose-related decreases in mean systemic arterial pressure and total systemic resistance in both groups of rats. Both the pulmonary and the systemic vasodilations to NIP-121 were inhibited by pretreatment with the blocker of ATP-sensitive K+ channels, glibenclamide (20 mg/kg), but not with the inhibitor of endothelium-derived relaxing factor synthesis, nitro-L-arginine (10 mg/kg). The L-type voltage-gated Ca2+ channel blocker, nifedipine (10-1,000 mg/kg i.v.), failed to cause pulmonary vasodilation in normoxic hypertensive rats, although there was dose-related systemic vasodilation. These results show that in contrast to the Ca2+ channel blocker, nifedipine, the K+ channel activator, NIP-121, is a potent vasodilator of chronic hypoxia-induced pulmonary hypertension in the rat. The mechanism of its hypotensive action in the hypertensive pulmonary vasculature might be more than simply membrane hyperpolarization and indirect inhibition of the L-type voltage-gated Ca2+ channel.
authors.affiliation: Department of Medicine, University of Colorado Health Sciences Center, Denver 80262.
authors.forename: M
authors.initials: M
authors.lastname: Oka
authors.forename: K G
authors.initials: KG
authors.lastname: Morris
authors.forename: I F
authors.initials: IF
authors.lastname: McMurtry
mesh_terms: D000531:Altitude; D000818:Animals; D002908:Chronic Disease; D005905:Glyburide / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D000860:Hypoxia / Q000503:physiopathology; D008297:Male; D009543:Nifedipine / Q000627:therapeutic use*; D010069:Oxadiazoles / Q000627:therapeutic use*; D010880:Piperidines / Q000627:therapeutic use*; D011652:Pulmonary Circulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D010069:Oxadiazoles; D010880:Piperidines; C070366:NIP 121; D009543:Nifedipine; D005905:Glyburide