Abluminal effects of endothelin in cerebral microvasculature assessed by laser-Doppler flowmetry.
Laser-Doppler flowmetry was used to assess the intraparenchymal effects of endothelin 1 (ET-1) on cortical microvascular perfusion (CP). The initial part of this study examined effects of the intraparenchymal microinjection technique on local cortical microvascular responsivity. In anesthetized rats, the microinjection of vehicle (saline) beneath the cortical surface did not alter CO2 responsivity or autoregulation of the cortical microvasculature. In addition, predictable monophasic changes in local CP were elicited by the intraparenchymal microinjection of known vasodilators and vasoconstrictors, i.e., nitroprusside and prostaglandin F2 alpha, respectively. These experiments demonstrate normal responsivity of the cortical microvasculature after intraparenchymal microinjection. In the second part of this study, intraparenchymal microinjections (100 nl) of ET-1 (1-1,000 fmol) were evaluated. Microinjections of less than 10 fmol of ET-1 did not alter CP. However, doses between 10 and 1,000 fmol of ET-1 elicited monophasic dose-related reductions in CP. At 1,000 fmol, the highest dose studied, ET-1 produced a complex microvascular response consisting of an initial profound reduction in CP followed by alternating cycles of increased perfusion ultimately lapsing back to a prolonged period of hypoperfusion. No significant changes in blood pressure were observed after ET-1 administration, and no significant changes in any of the hemodynamic variables were observed after vehicle microinjection. These results suggest that abluminal microvascular actions of ET-1 mediate cerebral vasoconstriction and hypoperfusion.
Willette
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RN
Department of Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406.
Sauermelch
C F
CF
D000818:Animals; D002245:Carbon Dioxide / Q000097:blood; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000494:pharmacology*; D006706:Homeostasis / Q000187:drug effects; D007834:Lasers; D008833:Microcirculation / Q000187:drug effects; D008845:Microinjections; D010313:Partial Pressure; D051381:Rats; D012709:Serum Albumin / Q000378:metabolism*
D016232:Endothelins; D012709:Serum Albumin; D002245:Carbon Dioxide