Endothelium-dependent vasorelaxation to the AMPK activator AICAR is enhanced in aorta from hypertensive rats and is NO and EDCF dependent.
Activation of AMP-activated protein kinase (AMPK) induces vasorelaxation in arteries from healthy animals, but the mechanisms coordinating this effect are unclear and the integrity of this response has not been investigated in dysfunctional arteries of hypertensive animals. Here we investigate the mechanisms of relaxation to the AMPK activator 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR) in isolated thoracic aorta rings from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Although AICAR generated dose-dependent (10(-6)-10(-2) M) relaxation in precontracted WKY and SHR aortic rings with (E(+)) or without (E(-)) endothelium, relaxation was enhanced in E(+) rings. Relaxation in SHR E(+) rings was also enhanced at low [AICAR] (10(-6) M) compared with that of WKY (57 ± 8% vs. 3 ± 2% relaxation in SHR vs. WKY E(+)), but was similar and near 100% in both groups at high [AICAR]. Pharmacological dissection showed that the mechanisms responsible for the endothelium-dependent component of relaxation across the dose range of AICAR are exclusively nitric oxide (NO) mediated in WKY rings, but partly NO dependent and partly cyclooxygenase (COX) dependent in SHR vessels. Further investigation revealed that ACh-stimulated COX-endothelium-derived contracting factors (EDCF)-mediated contractions were suppressed by AICAR, and this effect was reversed in the presence of the AMPK inhibitor Compound C in quiescent E(+) SHR aortic rings. Western blots demonstrated that P(Thr(172))-AMPK and P(Ser(79))-acetyl-CoA carboxylase (indexes of AMPK activation) were elevated in SHR versus WKY E(+) rings at low AICAR (∼2-fold). Together these findings suggest that AMPK-mediated inhibition of EDCF-dependent contraction and elevated AMPK activation may contribute to the enhanced sensitivity of SHR E(+) rings to AICAR. These results demonstrate AMPK-mediated vasorelaxation is present and enhanced in arteries of SHR and suggest that activation of AMPK may be a potential strategy to improve vasomotor dysfunction by suppressing enhanced endoperoxide-mediated contraction and enhancing NO-mediated relaxation.
Ford
Rebecca J
RJ
Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada.
Rush
James W E
JW
D000263:Adenylate Kinase / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012265:Ribonucleotides / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D016232:Endothelins; D012265:Ribonucleotides; D009569:Nitric Oxide; D000620:Aminoimidazole Carboxamide; D000263:Adenylate Kinase; C031143:AICA ribonucleotide