Ischaemia enhances the role of Ca2+-activated K+ channels in endothelium-dependent and nitric oxide-mediated dilatation of the rat hindquarters vasculature.
1. We compared the effects of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine (L-NOARG) and tetraethylammonium (TEA), a blocker of large conductance Ca(2+)-activated K(+) (BK(Ca)) channels, on vasodilator responses to endothelium-dependent (acetylcholine; ACh) and -independent (sodium nitroprusside; SNP) vasodilators. The mechanism of the vasodilator responses was determined in rat hindquarters under normal conditions (sham ischaemia) and after 2 h ischaemia followed by reperfusion with physiological saline. 2. In sham ischaemia, the responses to ACh were significantly reduced by L-NOARG (1 mmol/L) and TEA (1 mmol/L) and there was a further reduction in response the presence of both agents. Dilator responses to SNP were significantly enhanced by L-NOARG, whereas TEA did not alter the SNP-induced vasodilatation when given either alone or in the presence of L-NOARG. 3. After ischaemia, L-NOARG caused a similar inhibition of ACh-induced dilatation to that observed in sham ischaemia. However, TEA alone or combined with L-NOARG caused a significantly greater inhibition of the ACh-induced vasodilatation after ischaemia than observed in the sham ischaemia group. Tetraethylammonium alone did not affect the responses to SNP, but it did attenuate the enhanced dilatation observed in the presence of L-NOARG. 4. In the rat hindquarters vasculature, both nitric oxide and the opening of TEA-sensitive K(+) channels contribute to ACh-induced endothelium-dependent dilatation. In addition, a TEA-sensitive mechanism was not involved in the SNP-induced dilatation under normal conditions but, after ischaemia, if there is a further inhibition of endogenous nitric oxide by L-NOARG, exogenous nitric oxide causes dilatation that is sensitive, in part, to TEA. Thus, the contribution of the opening of BK(Ca) channels to endothelium-dependent vasodilatation assumes greater importance after ischaemia and reperfusion. This may reflect an increased ability of nitric oxide or cGMP to open BK(Ca) channels after ischaemia.
Woodman
Owen L
OL
Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia. owenlw@unimelb.edu.au
Wongsawatkul
Orapin
O
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology*; D005260:Female; D006614:Hindlimb / Q000098:blood supply*; D007511:Ischemia / Q000378:metabolism* / Q000503:physiopathology; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D019335:Nitroarginine / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism / Q000502:physiology*; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D002121:Calcium Channel Blockers; C494842:Kcnma1 protein, rat; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D019335:Nitroarginine; D009569:Nitric Oxide