Chronic in vivo or acute in vitro resveratrol attenuates endothelium-dependent cyclooxygenase-mediated contractile signaling in hypertensive rat carotid artery

Exaggerated cyclooxygenase (COX) and thromboxane-prostanoid (TP) receptor-mediated endothelium-dependent contraction can contribute to endothelial dysfunction. This study examined the effect of resveratrol (RSV) on endothelium-dependent contraction and cell-signaling in the common carotid artery (CCA) from spontaneously hypertensive (SHR and Wistar Kyoto rats (WKY). Acetylcholine (Ach)-stimulated endothelium-dependent nitric oxide synthase (NOS)-mediated relaxation in pre-contracted SHR CCA was impaired (max.: 73±6% vs. 87±5% in WKY) (p<0.05) by competitive COX-mediated contraction. Chronic (28d) treatment in vivo (drinking water) with a ~0.075 mg•kg^-1•d^-1 RSV dose neither affected endothelium-dependent relaxation, nor endothelium-dependent contraction and associated prostaglandin (PG) production evaluated in non-precontracted NOS-blocked CCA. In contrast, a chronic ~7.5 mg•kg^-1•d^-1 RSV dose improved endothelium-dependent relaxation (94±6%), and attenuated endothelium-dependent contraction (58±4% vs. 73±5% in No RSV) and PG production (183±43 vs. 519±93 pg•ml^-1), in SHR CCA, while U46619-stimulated TP receptor-mediated contraction was unaffected. In separate acute in vitro experiments, 20µM RSV preincubation attenuated endothelium-dependent contraction (6±4% vs. 62±2% in No Drug) and PG production (121±15 vs. 491±93 pg•ml^-1), and attenuated U46619-stimulated contraction (134±5% vs. 171±4%), in non-precontracted NOS-blocked SHR CCA. Compound C, a known AMP-activated protein kinase (AMPK) inhibitor, did not prevent the RSV attenuating effect on Ach- and U46619-stimulated contraction, but did prevent the RSV attenuating effect on PG production (414±58 pg•ml^-1). These data demonstrate that RSV can attenuate endothelium-dependent contraction both by suppressing arterial wall PG production, which may be partially mediated by AMPK, and by TP receptor hypo-responsiveness, which does not appear to be mediated by AMPK.

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