Relaxant effect of all-trans-retinoic acid via NO-sGC-cGMP pathway and calcium-activated potassium channels in rat mesenteric artery

Abstract

effect of all-trans-retinoic acid via NO-sGC-cGMP pathway and calciumactivated potassium channels in rat mesenteric artery. Am J Physiol Heart Circ Physiol 304: H51-H57, 2013. First published November 2, 2012; doi:10.1152/ajpheart.00240.2012.-Intraperitoneal injection of all-trans-retinoic acid (ATRA) results in a reduction of blood pressure in spontaneously hypertensive rats. However, the mechanisms involved in this effect are not clear. We hypothesized that ATRA may relax resistance arteries. In this study, we found that ATRA relaxed phenylephrine-preconstricted mesenteric arterial rings, which were abrogated by the removal of the endothelium. Pretreatment of endothelium-intact arterial rings with an inhibitor of endothelial nitric oxide (NO) synthase, N G -nitro-L-arginine methyl ester (L-NAME), or soluble guanylyl cyclase, 1H-[1,2,4]-oxadiazole-[4,3-␣]-quinoxaline-1-one, reduced the vasorelaxant effect of ATRA. Incubation of mesenteric arterial rings with ATRA increased the production of NO and cGMP, which were blocked by N G -nitro-L-arginine methyl ester. The vasorelaxant effect of ATRA was markedly attenuated in the presence of an inhibitor of big conductance calcium-activated potassium channels (charybdotoxin), but not with an inhibitor of voltage-dependent potassium channel (4-aminopyridine) or ATP-sensitive potassium channel (glibenclamide). Activation of retinoic acid receptors (RARs) with CH55 or retinoic X receptors (RXRs) with LGD1069 induced the vasorelaxation of phenylephrine-preconstricted mesenteric arterial rings. The RAR (BMS493) and RXR (UVI3003) antagonists blocked the ATRA-induced vasorelaxation. The vasorelaxant effect ATRA is physiologically relevant because the intravenous infusion of ATRA decreased blood pressure in normotensive rats. We conclude that ATRA relaxes resistance vessels via both RARs and RXRs receptors that are mediated by the endothelium-dependent NO-cGMP pathway, which may participate in the control of blood pressure.all-trans-retinoic acid; mesenteric artery; vasorelaxation; nitric oxide synthase; blood pressure A BIOLOGICALLY ACTIVE metabolite of vitamin A, all-transretinoic acid (ATRA) has anti-inflammatory, anticancer, and immunomodulatory actions (20,24,31). ATRA exerts its biological effects by modulating gene transcription through distinct intracellular proteins, including the retinoic acid receptor (RAR) and retinoic X receptor (RXR) (2, 18), and activating some key transcription factors, such as nuclear factor-B (20).Recently, the role of ATRA in the development of cardiovascular dysfunctions has gained attention. It has also been shown that ATRA has potent antiproliferative and antioxidant actions (21, 23). A previous study showed that ATRA, given as daily intraperitoneal infusion, lowers blood pressure in spontaneously hypertensive rats (SHRs) (33). However, the mechanisms by which ATRA decreases blood pressure are not clear. To test the hypothesis that ATRA may relax resistance arteries, we studied the vasorelaxant effect of ATRA on phenylephrine (Phe)-precon...

A Retinoic Acidβ2-Receptor Agonist Exerts Cardioprotective Effects

“…5). Furthermore, although RAR and retinoid X receptor activation has been shown to relax resistance vessels via the endothelium-dependent NO-cGMP pathway (Wang et al, 2013), AC261066-induced cardioprotection was not associated with an increase in coronary flow, since treatment with AC261066 did not modify coronary flow in hearts from ApoE 2/2 and HFD-fed mice.…”

Farnesoid X receptor agonist CDCA reduces blood pressure and regulates vascular tone in spontaneously hypertensive rats

“…15 We applied a normalized circumference (L 0 ) ¼ 0.9 L100 resulting in maximal active force development. The vessels were studied at L 0 in all subsequent protocols.…”

Genetic Variants Associated With Uncontrolled Blood Pressure on Thiazide Diuretic/β‐Blocker Combination Therapy in the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) and INVEST (International Verapamil‐SR Trandolapril Study) Trials

“…This may be of significance given that peroxisome‐proliferator‐activated receptor‐γ has well‐established roles in many cardiovascular and metabolic syndrome phenotypes, including hypertension . Other mechanisms through which retinoic acid may modulate BP include epigenetic alterations and endothelium‐dependent NO‐cGMP signaling . Retinoic acid may also inhibit the development of atherosclerosis and reduce the risk of cardiovascular mortality …”

“…42 Other mechanisms through which retinoic acid may modulate BP include epigenetic alterations 43 and endothelium-dependent NO-cGMP signaling. 44 Retinoic acid may also inhibit the development of atherosclerosis 45,46 and reduce the risk of cardiovascular mortality. 47 The region surrounding the top variant also includes the genes LIPC and AQP9.…”