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Sildenafil versus nitric oxide for acute vasodilator testing in pulmonary arterial hypertension.

ABSTRACT: Vasoreactivity testing with inhaled NO is recommended for pulmonary arterial hypertension (PAH) because of its therapeutic and prognostic value. Sildenafil has acute pulmonary vasodilating properties, but its diagnostic and prognostic impact in PAH is unknown. Our objective was to compare acute vasodilating responses to sildenafil and those to NO during right heart catheterization and also their prognostic values in patients with PAH. Ninety-nine patients with idiopathic PAH and 99 with associated PAH underwent vasoreactivity testing with NO and sildenafil. Only mild adverse effects of sildenafil, in the form of hypotension, were observed, at a rate of 4.5%. The acute responder rate was 8.1% for NO and 11.6% for sildenafil. The NO-induced response in mean pulmonary arterial pressure and cardiac output correlated with the response to sildenafil. Thirteen patients were long-term responders to calcium channel blockers (CCBs), and 3 of them were correctly identified by acute vasoreactivity test with both drugs. The specificity of the vasoreactivity test for identifying long-term CCB responders was 88.9% for NO and 85.1% for sildenafil testing. A trend toward better survival was found in sildenafil and NO responders, compared with nonresponders. Use of sildenafil for vasoreactivity testing is safe. Sildenafil may be useful as alternative vasoreactivity-testing agent, identifying the same number of long-term CCB responders as NO. However, NO seems to be a more ideal testing drug because of its pharmacologic properties. Moreover, sildenafil vasoreactivity testing might contribute to an improved estimate of prognosis among patients with PAH.

SUBMITTER: Milger K

PROVIDER: S-EPMC4449241 | biostudies-other | 2015 Jun

REPOSITORIES: biostudies-other

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Project description:BackgroundDapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), can reduce cardiovascular events and mortality in patients with heart failure. A number of mechanisms have been proposed to explain the beneficial effects of SGLT2 inhibitors. The purpose of this study was to determine whether dapagliflozin can improve pulmonary vascular remodelling and the efficacy of dapagliflozin as an add-on therapy to sildenafil in rats with pulmonary arterial hypertension (PAH).MethodsA monocrotaline (MCT)-induced PAH rat model was used in our study. MCT-injected rats were randomly divided into four groups and treated for 3 weeks with daily per os treatment with vehicle, dapagliflozin (1 mg/kg/day), sildenafil (25 mg/kg/day), or a combination of dapagliflozin (1 mg/kg/day) and sildenafil (25 mg/kg/day). Haemodynamic measurements, histological analysis, enzyme-linked immunosorbent assay and western blotting analysis were employed to detect the changes in PAH rats after treatments.ResultsDapagliflozin significantly attenuated MCT-induced increases in right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) in PAH rats. Dapagliflozin effectively decreased the thickening of pulmonary artery media and decreased the muscularization of pulmonary arterioles in PAH rats. Moreover, dapagliflozin attenuated nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome activation in lung tissues and the levels of interleukin-1β (IL-1β) and interleukin-18 (IL-18) in plasma. However, dapagliflozin as an add-on therapy to sildenafil in rats with PAH did not show a more pronounced beneficial effect on right ventricular systolic pressure and pulmonary vascular remodelling in MCT rats than sildenafil alone.ConclusionsDapagliflozin reduces right ventricular systolic pressure and pulmonary vascular remodelling in a rat model of PAH. However, combination therapy with dapagliflozin and sildenafil was not more effective than monotherapy with sildenafil in PAH rats.

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Sildenafil versus nitric oxide for acute vasodilator testing in pulmonary arterial hypertension.

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