Sildenafil (Viagra®) Prevents Cox-1/ TXA2 Pathway-Mediated Vascular Hypercontractility in ApoE-/- Mice

Abstract

Background/Aims: The atherosclerotic apolipoprotein E-deficient (apoE^-/-) mouse exhibits impaired vasodilation and enhanced vasoconstriction responsiveness. The objectives of this study were: a) to determine the relative contribution of cyclooxygenases (Cox-1 and Cox-2), thromboxane A2 (TXA2) and endothelin-1 (ET-1) to enhancing vascular hyperresponsiveness in this model of atherosclerosis and b) to investigate the beneficial effects of the phosphodiesterase 5 inhibitor sildenafil on this endothelial dysfunction. Methods: Adult male apoE^-/- mice were treated with sildenafil (40 mg/kg/day, for 3 weeks) and compared with non-treated ApoE^-/- and wild-type mice. The beneficial effects of sildenafil on vascular contractile response to phenylephrine (PE) in aortic rings were evaluated before and after incubation with Cox-1 (SC-560) or Cox-2 (NS-398) inhibitors or the TP antagonist SQ-29548, and on contractile responsiveness to ET-1. Results: ApoE^-/- mice exhibited enhanced vasoconstriction to PE (R_max ∼35%, p<0.01), which was prevented by treatment with sildenafil. The enhanced PE-induced contractions were abolished by both Cox-1 inhibition and TP antagonist, but were not modified by Cox-2 inhibition. Aortic rings from ApoE^-/- mice also exhibited enhanced contractions to ET-1 (R_max ∼30%, p<0.01), which were attenuated in sildenafil-treated ApoE^-/- mice. In addition, we observed augmented levels of vascular proinflammatory cytokines in ApoE^-/- mice, which were partially corrected by treatment with sildenafil (IL-6, IL-10/IL-6 ratio and MCP-1). Conclusion: The present data show that the Cox-1/TXA2 pathway prevails over the Cox-2 isoform in the mediation of vascular hypercontractility observed in apoE^-/-mice. The results also show a beneficial effect of sildenafil on this endothelial dysfunction and on the proinflammatory cytokines in atherosclerotic animals, opening new perspectives for the treatment of other endothelium-related cardiovascular abnormalities.

Altered cyclooxygenase-1 and enhanced thromboxane receptor activities underlie attenuated endothelial dilatory capacity of omental arteries in obesity

“…The data is also consistent with COX-1 being the primary isoform related to endothelium-dependent contractions [9,17,33,34] and enhanced thromboxane A2 TP receptor-dependent vascular contractions being associated with metabolic diseases [32,35]. Together, COX-1/TXA2 pathway has been shown to mediate vascular hypercontractility linked to endothelial dysfunction in obesity [32] and experimental model of hyperlipidemia [36]. Thromboxane A2 TP receptor is coupled to guanine nucleotide-binding protein Gq in vascular smooth muscle (VSM) [37].…”

Sildenafil attenuates nonsteroidal anti‐inflammatory‐induced gastric ulceration in mice via antioxidant and antigenotoxic mechanisms

“…The novelty of the present study is the demonstration of the impact of SIL on oxidative stress, through complementary assays. While traditional techniques only quantify cumulative oxidation of target molecules (lipids, proteins or DNA) without distinguishing among the direct contributors to oxidative stress, our data demonstrate that SIL reduces oxidative damage due to a direct reduction in •O 2 ‐ , H 2 O 2 and particularly, in •OH/OONO ‐ species, also contributing to an increase in NO bioavailability, as recently observed by our group and others in distinct experimental models 31‐33 . The sum of this evidence may help to explain the potential benefits of SIL as an interesting candidate for gastroprotective therapies.…”

Arachidonic Acid Metabolites in Cardiovascular and Metabolic Diseases

“…The anti-inflammatory and anti-thrombotic features of aspirin, the only known irreversible inhibitor of platelet COX1, are primarily related to the suppression of PG and TXA2 synthesis [ 241 ]. In this context, a recent study demonstrated that the COX1/TXA2 pathway is a relevant contributor to vascular hypercontractility in atherosclerotic apoE deficient mice, and its pharmacological inhibition improves endothelial function [ 242 ]. Despite being a well-established therapy in cardiovascular disease, some aspects of aspirin treatment warrant further investigation, as reflected by a recent analysis demonstrating an interaction of body weight with the effectiveness of aspirin to prevent cardiovascular events [ 243 ].…”