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Stimulation of soluble guanylate cyclase attenuates acute pulmonary hypertension and augments the pulmonary vasodilator response to inhaled nitric oxide



Stimulation of soluble guanylate cyclase attenuates acute pulmonary hypertension and augments the pulmonary vasodilator response to inhaled nitric oxide



FASEB Journal 18(4-5): Abst 688 14



Continuous inhalation of nitric oxide (NO) produces potent and selective pulmonary vasodilation via a cGMP-dependent mechanism. However, this effect terminates after NO is discontinued. We tested the hypotheses that direct pharmacological sensitization of soluble guanylate cyclase (sGC) can augment and prolong the pulmonary vasodilator response to inhaled NO. In awake lambs instrumented with vascular catheters and a tracheostomy tube, U-46619 (a stable analog of thromboxane A2) was infused i.v. to increase mean pulmonary arterial pressure (PAP) to 35 mmHg. In seven animals, the novel potent sGC activator BAY 41-2272, infused i.v. at 0.03, 0.1 and 0.3 mg/kg/h, produced dose-dependent reductions in PAP and pulmonary vascular resistance. The two higher doses reduced systemic arterial pressure and vascular resistance and increased cardiac output. In another eight animals, 2, 10, and 20 ppm of inhaled NO were administered before and during an i.v. infusion of BAY 41-2272 at 0.1 mg/kg/h. BAY 41-2272 both enhanced and prolonged the pulmonary vasodilator response to NO by two-to-three fold. In an additional eighth lambs, administration of L-NAME did not alter the pulmonary vasodilator effect of either BAY 41-2272 or inhaled NO. Our results suggest that direct activation of sGC, either alone or in combination with inhaled NO, may provide an effective treatment option for pulmonary hypertension.Supported by HL042397.

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