SELECTIVE REDUCTION OF PVR BY INHALATION OF A CGMP ANALOG IN A PORCINE MODEL OF PULMONARY-HYPERTENSION

Selective reduction of pulmonary vascular resistance (PVR) remains a t herapeutic goal for the treatment of pulmonary hypertension, but curre nt therapeutic options remain limited. Although the gas nitric oxide ( NO) selectively dilates the pulmonary vascular bed, it requires specia l equipment for administration, has a short biologic half-life, and is potentially toxic. We hypothesized that stimulation of the NO pathway at the level of its second messenger, guanosine 3',5'-cyclic monophos phate (cGMP), by targeted pulmonary delivery of a membrane-permeable n onhydrolyzable eGMP analogue would cause selective pulmonary vasodilat ion. Pulmonary hypertension was induced in 21 pigs by the intravenous infusion of a thromboxane A(2) analogue (9,11-dideoxy-9 alpha, 11 alph a-epoxymethanoprostaglandin F-2 alpha). Inhaled 8-bromoguanosine 3',5' -cyclic monophosphate (8-BrcGMP) lowered PVR in a time- and dose-depen dent manner, with maximal effect achieved after 20 min, Compared with physiological saline control, 8-BrcGMP inhalation (3.0 mu g/kg) lowere d PVR by 25 +/- 3% (P < 0.01), whereas there was no significant declin e in systemic vascular resistance (4 +/- 6%); mean pulmonary arterial pressure declined 13 +/- 3% (P < 0.01), whereas there was little chang e in mean arterial pressure; cardiac output increased 10 +/- 4% (P < 0 .05). PVR did not decrease after inhalation of noncyclic 8-bromoguanos ine 5'-monophosphate, indicating that stimulation of the NO-cGMP pathw ay beyond the level of NO results in pulmonary vasodilation independen t of stimulation of purinergic receptors. Inhaled 8-BrcGMP had no dele terious effect on load-independent measures of ventricular contractili ty, as shown by left ventricular pressure-volume loops generated at di fferent preloads. Because selective pulmonary vasodilation was not obs erved after intravenous administration of 8-BrcGMP, these studies demo nstrate that targeted delivery of a cGMP analogue by inhalation can se lectively reduce PVR.