Abstract
Background: Glyceryl trinitrate (GTN) is a commonly prescribed treatment for acute heart failure patients. However, prolonged GTN treatment induces tolerance, largely due to increased oxidative stress and reduced aldehyde dehydrogenase-2 (ALDH-2) expression. Serelaxin has several vasoprotective properties, which include reducing oxidative stress and augmenting endothelial function. We therefore tested the hypothesis in rodents that serelaxin treatment could attenuate low-dose GTN-induced tolerance.Methods and Results: Co-incubation of mouse aortic rings ex vivo with GTN (10 μM) and serelaxin (10 nM) for 1 h, restored GTN responses, suggesting that serelaxin prevented the development of GTN tolerance. Male Wistar rats were subcutaneously infused with ethanol (control), low-dose GTN+placebo or low-dose GTN+serelaxin via osmotic minipumps for 3 days. Aortic vascular function and superoxide levels were assessed using wire myography and lucigenin-enhanced chemiluminescence assay respectively. Changes in aortic ALDH-2 expression were measured by qPCR and Western blot respectively. GTN+placebo infusion significantly increased superoxide levels, decreased ALDH-2 and attenuated GTN-mediated vascular relaxation. Serelaxin co-treatment with GTN significantly enhanced GTN-mediated vascular relaxation, reduced superoxide levels and increased ALDH-2 expression compared to GTN+placebo-treated rats.Conclusion: Our data demonstrate that a combination of serelaxin treatment with low dose GTN attenuates the development of GTN-induced tolerance by reducing superoxide production and increasing ALDH-2 expression in the rat aorta. We suggest that serelaxin may improve nitrate efficacy in a clinical setting.
Highlights
Organic nitrates such as nitroglycerin (GTN) are widely used for the acute treatment of heart diseases including chronic congestive heart failure, coronary artery disease and acute heart failure (AHF) (Daiber and Münzel, 2015)
Serelaxin Attenuates Development of Tolerance to Glyceryl trinitrate (GTN) in the Mouse Aorta Ex vivo Incubation of mouse aortic rings with 10, 30, and 100 μM, but not 1 μM, of GTN for 1 h followed by a 1 h washout period caused a significant (P < 0.01) decrease in the sensitivity and maximum relaxation to GTN in a concentration-dependent manner (Figure 1A), indicating the development of tolerance to GTN ex vivo
The aims of the present study were to investigate whether or not serelaxin attenuates low-dose GTN tolerance using
Summary
Organic nitrates such as nitroglycerin (GTN) are widely used for the acute treatment of heart diseases including chronic congestive heart failure, coronary artery disease and acute heart failure (AHF) (Daiber and Münzel, 2015). The beneficial effects of nitrates are mainly associated with their ability to dilate venous capacitance vessels, coronary arteries and the aorta, thereby improving left ventricular function and reducing myocardial workload (Abrams, 1995) The mechanisms underlying this vasodilation involve release of NO (and the metabolite 1,2 glyceryl dinitrite) in response to intracellular biotransformation of GTN by the ALDH-2 enzyme (Chen et al, 2002). Serelaxin co-treatment with GTN significantly enhanced GTNmediated vascular relaxation, reduced superoxide levels and increased ALDH-2 expression compared to GTN+placebo-treated rats. Conclusion: Our data demonstrate that a combination of serelaxin treatment with low dose GTN attenuates the development of GTN-induced tolerance by reducing superoxide production and increasing ALDH-2 expression in the rat aorta. We suggest that serelaxin may improve nitrate efficacy in a clinical setting
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