Effects of sildenafil on hypoxic pulmonary vascular function in dogs.
Sildenafil has been shown to be an effective treatment of pulmonary arterial hypertension and is believed to present with pulmonary selectivity. This study was designed to determine the site of action of sildenafil compared with inhaled nitric oxide (NO) and intravenous sodium nitroprusside (SNP), known as selective and nonselective pulmonary vasodilators, respectively. Inhaled NO (40 ppm), and maximum tolerated doses of intravenous SNP and sildenafil, (5 microg x kg(-1) x min(-1) and 0.1 mg x kg(-1) x h(-1)), respectively, were administered to eight dogs ventilated in hypoxia. Pulmonary vascular resistance (PVR) was evaluated by pulmonary arterial pressure (Ppa) minus left atrial pressure (Pla) vs. flow curves, and partitioned into arterial and venous segments by the occlusion method. Right ventricular hydraulic load was defined by pulmonary arterial characteristic impedance (Zc) and elastance (Ea) calculations. Right ventricular arterial coupling was estimated by the ratio of end-systolic elastance (Ees) to Ea. Decreasing the inspired oxygen fraction from 0.4 to 0.1 increased Ppa - Pla at a standardized flow of 3 l x min(-1) x m(-2) from 6 +/- 1 to 18 +/- 1 mmHg (mean +/- SE). Ppa - Pla was decreased to 9 +/- 1 by inhaled NO, 14 +/- 1 by SNP, and 14 +/- 1 mmHg by sildenafil. The partition of PVR, Zc, Ea, and Ees/Ea was not affected by the three interventions. Inhaled NO did not affect systemic arterial pressure, which was similarly decreased by sildenafil and SNP, from 115 +/- 4 to 101 +/- 4 and 98 +/- 5 mmHg, respectively. We conclude that inhaled NO inhibits hypoxic pulmonary vasoconstriction more effectively than sildenafil or SNP, and sildenafil shows no more selectivity for the pulmonary circulation than SNP.
Fesler
Pierre
P
Department of Internal Medicine, Hôpital Lapeyronie, Montpellier, France.
Pagnamenta
Alberto
A
Rondelet
Benoit
B
Kerbaul
François
F
Naeije
Robert
R
D000280:Administration, Inhalation; D018686:Anesthetics, Intravenous; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002698:Chloralose; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D000860:Hypoxia / Q000503:physiopathology*; D007275:Injections, Intravenous; D009569:Nitric Oxide / Q000008:administration & dosage / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011652:Pulmonary Circulation / Q000187:drug effects* / Q000502:physiology; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones; D014655:Vascular Resistance / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
D018686:Anesthetics, Intravenous; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D009599:Nitroprusside; D002698:Chloralose; D009569:Nitric Oxide; D000068677:Sildenafil Citrate