(Stroke. 1999;30:1125-1133.)
© 1999 American Heart Association, Inc.
Original Contributions |
P2u Receptor–Mediated Release of Endothelium-Derived Relaxing Factor/Nitric Oxide and Endothelium-Derived Hyperpolarizing Factor From Cerebrovascular Endothelium in Rats
From the Departments of Anesthesiology (J.Y., T.D.J., S.P.M., R.M.B.) and Medicine (J-V.M.) and the Graduate Program in Cardiovascular Sciences of the DeBakey Heart Center (S.P.M., R.M.B.), Baylor College of Medicine, Houston, Tex, and the Department of Internal Medicine, University of Lund (J.Y.), Lund, Sweden.
Background and Purpose—Stimulation of P2u purinoceptors by UTP on endothelium dilates the rat middle cerebral artery (MCA) through the release of endothelium-derived relaxing factor/nitric oxide (EDRF/NO) and an unknown relaxing factor. The purpose of this study was to determine whether this unknown relaxing factor is endothelium-derived hyperpolarizing factor (EDHF).
Methods—Rat MCAs were isolated, cannulated, pressurized, and luminally perfused. UTP was added to the luminal perfusate to elicit dilations.
Results—Resting outside diameter of the MCAs in one study was 209±7 µm (n=10). The MCAs showed concentration-dependent dilations with UTP administration. Inhibition of NO synthase with NG-nitro-L-arginine methyl ester (L-NAME) (1 µmol/L to 1 mmol/L) did not diminish the maximum response to UTP but did shift the concentration-response curve to the right. Scavenging NO with hemoglobin (1 or 10 µmol/L) or inhibition of guanylate cyclase with ODQ (1 or 10 µmol/L) had effects on the UTP-mediated dilations similar to those of L-NAME. In the presence of L-NAME, dilations induced by 10 µmol/L UTP were accompanied by 13±2 mV (P<0.009) hyperpolarization of the vascular smooth muscle membrane potential (-28±2 to -41±1 mV). Iberiotoxin (100 nmol/L), blocker of the large-conductance calcium-activated K channels, sometimes blocked the dilation, but its effects were variable. Charybdotoxin (100 nmol/L), also a blocker of the large-conductance calcium-activated K channels, abolished the L-NAME–insensitive component of the dilation to UTP.
Conclusions—Stimulation of P2u purinoceptors on the endothelium of the rat MCA released EDHF, in addition to EDRF/NO, and dilated the rat MCA by opening an atypical calcium-activated K channel.
Editorial Comment
Department of Internal Medicine, Cardiovascular Center, University of Iowa College of Medicine, Iowa City, Iowa
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