Analysis of pulmonary and systemic vascular responses to cromakalim, an activator of K+ATP channels.
Cardiovascular and pulmonary responses to cromakalim, a member of a novel class of antihypertensive agents that open ATP-sensitive K+ (K+ATP) channels, were investigated in the anesthetized cat. Intravenous injections of cromakalim in doses of 30-300 micrograms/kg decreased arterial pressure (AP), pulmonary arterial pressure (PAP), and increased cardiac output (CO), while producing small changes in right and left atrial pressures. Pulmonary and systemic vascular resistances were decreased and vasodilator responses to cromakalim were blocked by glybenclamide, a K+ATP channel-blocking agent. The low dose of cromakalim caused a reflex increase in heart rate (HR) and right ventricular contractile force (RVCF), whereas the high dose decreased HR and RVCF. Under constant-flow conditions the K+ATP channel opener caused dose-dependent decreases in hindquarters perfusion pressure, and when tone was elevated in the pulmonary vascular bed, dose-dependent decreases in pulmonary lobar arterial perfusion pressure. Hindquarters and pulmonary lobar vasodilator responses to cromakalim were inhibited in a specific manner by glybenclamide. The present data show that cromakalim has significant vasodilator activity in both the systemic and pulmonary vascular beds and suggest that responses to this agent result from activation of glybenclamide-sensitive K+ATP channels. These data show that cromakalim can cause substantial decreases in systemic and pulmonary vascular resistance in a dose that has little effect on RVCF.
Minkes
R K
RK
Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana 70112.
Kvamme
P
P
Higuera
T R
TR
Nossaman
B D
BD
Kadowitz
P J
PJ
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology*; D001775:Blood Circulation / Q000187:drug effects*; D002415:Cats; D019806:Cromakalim; D016232:Endothelins / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006614:Hindlimb / Q000098:blood supply; D009200:Myocardial Contraction / Q000187:drug effects; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D020108:Nicorandil; D020110:Pinacidil; D015221:Potassium Channels / Q000187:drug effects*; D011652:Pulmonary Circulation / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D016278:Ventricular Function, Right
D000959:Antihypertensive Agents; D001578:Benzopyrans; D016232:Endothelins; D006146:Guanidines; D015221:Potassium Channels; D011758:Pyrroles; D014665:Vasodilator Agents; D019806:Cromakalim; D009536:Niacinamide; D020108:Nicorandil; D020110:Pinacidil; D000255:Adenosine Triphosphate; D005905:Glyburide