Hemodynamic effects of inducible nitric oxide synthase inhibition combined with sildenafil during acute pulmonary embolism

Abstract

While endogenous nitric oxide (NO) may be relevant to the beneficial hemodynamic effects produced by sildenafil during acute pulmonary embolism (APE), huge amounts of inducible NO synthase (iNOS)-derived NO may contribute to lung injury. We hypothesized that iNOS inhibition with S-methylisothiourea could attenuate APE-induced increases in oxidative stress and pulmonary hypertension and, therefore, could improve the beneficial hemodynamic and antioxidant effects produced by sildenafil during APE. Hemodynamic evaluations were performed in non-embolized dogs treated with saline (n=4), S-methylisothiourea (0.01 mg/kg followed by 0.5 mg/kg/h, n=4), sildenafil (0.3 mg/kg, n=4), or S-methylisothiourea followed by sildenafil (n=4), and in dogs that received the same drugs and were embolized with silicon microspheres (n=8 for each group). Plasma nitrite/nitrate (NOx) and thiobarbituric acid reactive substances (TBARS) concentrations were determined by Griess and a fluorometric assay, respectively. APE increased mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance index (PVRI) by 25±1.7 mm Hg and by 941±34 dyn s cm(-5) m(-2), respectively. S-methylisothiourea neither attenuated APE-induced pulmonary hypertension, nor enhanced the beneficial hemodynamic effects produced by sildenafil after APE (>50% reduction in pulmonary vascular resistance). While sildenafil produced no change in plasma NOx concentrations, S-methylisothiourea alone or combined with sildenafil blunted APE-induced increases in NOx concentrations. Both drugs, either alone or combined, produced antioxidant effects. In conclusion, although iNOS-derived NO may play a key role in APE-induced oxidative stress, our results suggest that the iNOS inhibitor S-methylisothiourea neither attenuates APE-induced pulmonary hypertension, nor enhances the beneficial hemodynamic effects produced by sildenafil.

Prevention of the development of heart failure with preserved ejection fraction by the phosphodiesterase‐5A inhibitor vardenafil in rats with type 2 diabetes

“…Vardenafil, however, significantly affected the DM‐associated nitro‐oxidative stress as it prevented an increase of 3‐NT staining and the elevation of catalase and thioredoxin‐1 in the ZDF group myocardium. The protective feature of PDE5A inhibition is probably attributed to its antioxidative effects28 and to the enhancement of cGMP signalling 12. Moreover, vardenafil significantly increased the ratio of PLB/SERCA2a gene expression which might have contributed to the observed improved diastolic function in the ZDF + Vard group.…”

N‐Acetylcysteine potentiates the haemodynamic‐improving effect of sildenafil in a rabbit model of acute pulmonary thromboembolism via the p38 MAPK pathway

“…Endogenous NO biosynthesis has been reported to play a protective role in haemodynamic homeostasis during APT . The activation of the NO‐cGMP pathway attenuates the haemodynamic derangement in APT . Recent studies have shown that haemolysis and the release of arginase I caused by experimental pulmonary embolism contribute to subsequent depletion of L‐arginine which is the substrate for NO synthesis .…”

“…Once the acute mechanical obstruction of the pulmonary arteries happens, vessels of the pulmonary bed constrict with subsequent increase in pulmonary vascular pressure, acute right heart failure and even death. A series of the vasoactive factors including nitric oxide (NO) and other oxidative stress factors is widely accepted to contribute to pulmonary hypertension in APT . Forkhead transcription factors are highly conserved in eukaryotic organisms and include four family members (FoxO1, FoxO3a, FoxO4 and FoxO6) .…”

“…A series of the vasoactive factors including nitric oxide (NO) and other oxidative stress factors is widely accepted to contribute to pulmonary hypertension in APT. [4][5][6] Forkhead transcription factors are highly conserved in eukaryotic organisms and include four family members (FoxO1, FoxO3a, FoxO4 and FoxO6). 7 FoxO1, as one of the targets of PI3K/AKT, has been reported to regulate a series of biological activities.…”

Beneficial effects of inhaled NO on apoptotic pneumocytes in pulmonary thromboembolism model

“…However, this treatment does not work in all patients. Studies examining the inhalation delivery of NO in experimental and clinical applications have shown discrepant results; some show to mitigate LIRI including its antioxidant properties and its cytoprotective abilities including attenuating apopotosis [16-18], whereas others demonstrate detrimental or neutral effects [19,20] and the detailed mechanisms remain to be understood.…”