Possible role for K+ in endothelium-derived hyperpolarizing factor-linked dilatation in rat middle cerebral artery.
OBJECTIVE
Endothelium-derived hyperpolarizing factor (EDHF) and K+ are vasodilators in the cerebral circulation. Recently, K+ has been suggested to contribute to EDHF-mediated responses in peripheral vessels. The EDHF response to the protease-activated receptor 2 ligand SLIGRL was characterized in cerebral arteries and used to assess whether K+ contributes as an EDHF.


METHODS
Rat middle cerebral arteries were mounted in either a wire or pressure myograph. Concentration-response curves to SLIGRL and K+ were constructed in the presence and absence of a variety of blocking agents. In some experiments, changes in tension and smooth muscle cell membrane potential were recorded simultaneously.


RESULTS
SLIGRL (0.02 to 20 micromol/L) stimulated concentration and endothelium-dependent relaxation. In the presence of NG-nitro-L-arginine methyl ester, relaxation to SLIGRL was associated with hyperpolarization and sensitivity to a specific inhibitor of IKCa, 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (1 micromol/L), reflecting activation of EDHF. Combined inhibition of KIR with Ba2+ (30 micromol/L) and Na+/K+-ATPase with ouabain (1 micromol/L) markedly attenuated the relaxation to EDHF. Raising extracellular [K+] to 15 mmol/L also stimulated smooth muscle relaxation and hyperpolarization, which was also attenuated by combined application of Ba2+ and ouabain.


CONCLUSIONS
SLIGRL evokes EDHF-mediated relaxation in the rat middle cerebral artery, underpinned by hyperpolarization of the smooth muscle. The profile of blockade of EDHF-mediated hyperpolarization and relaxation supports a pivotal role for IKCa channels. Furthermore, similar inhibition of responses to EDHF and exogenous K+ with Ba2+ and ouabain suggests that K+ may contribute as an EDHF in the middle cerebral artery.
McNeish
Alister J
AJ
Department of Pharmacy and Pharmacology, The University of Bath, Claverton Down, Bath, BA2 7AY, UK.
Dora
Kim A
KA
Garland
Christopher J
CJ
D000818:Animals; D001464:Barium / Q000494:pharmacology; D001685:Biological Factors / Q000378:metabolism / Q000502:physiology*; D001920:Bradykinin / Q000494:pharmacology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007249:Inflammation; D008297:Male; D020768:Middle Cerebral Artery / Q000378:metabolism / Q000473:pathology*; D009213:Myography / Q000379:methods; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009842:Oligopeptides / Q000378:metabolism; D010042:Ouabain / Q000494:pharmacology; D011188:Potassium / Q000737:chemistry / Q000502:physiology*; D015221:Potassium Channels / Q000378:metabolism; D011312:Pressure; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044464:Receptor, PAR-2 / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
D001685:Biological Factors; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D015221:Potassium Channels; D011720:Pyrazoles; D044464:Receptor, PAR-2; C411671:TRAM 34; C067410:endothelium-dependent hyperpolarization factor; C099570:seryl-leucyl-isoleucyl-glycyl-arginyl-leucine; D001464:Barium; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase; D011188:Potassium; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester