cGMP modulates basal and activated microvessel permeability independently of [Ca2+]i.
To investigate the mechanisms whereby guanosine 3',5'-cyclic monophosphate (cGMP) modulates microvessel permeability in vivo, we measured changes in microvessel hydraulic conductivity (Lp) and endothelial cytoplasmic Ca2+ concentration ([Ca2+]i) in response to the cGMP analogs 8-bromo-cGMP (8-BrcGMP) and 8-(p-chlorophenylthio)cGMP (8-pCPT-cGMP) in the presence and absence of inflammatory stimuli in intact individually perfused microvessels in frog and rat mesenteries. The cGMP analog caused a transient increase in Lp and potentiated ATP or bradykinin-induced increases in Lp in frog and rat mesenteric microvessels, respectively. The mean peak value of the test Lp/control Lp after exposure to 8-BrcGMP was 5.3 +/- 0.5 in frog microvessels and 2.8 +/- 0.4 in rat microvessels. The ATP-induced increase in Lp in frog microvessels was further raised by 8-BrcGMP from 7.0 +/- 0.9 to 12.4 +/- 1.9 times the control. In rat mesenteric microvessels, the bradykinin-induced increase in Lp was potentiated by 8-BrcGMP from 4.8 +/- 0.4 to 8.3 +/- 1.3 times the control and was suppressed by the guanylate cyclase inhibitor LY-83583 to 2.6 +/- 0.5 times the control. A similar but larger effect was found when using 8-pCPT-cGMP. In contrast to the actions of increased cGMP on microvessel permeability, cGMP analogs had no effect on basal endothelial [Ca2+]i and did not alter the magnitude and time course of ATP or bradykinin-induced increases in endothelial [Ca2+]i. These results suggested that an elevation of cGMP levels in endothelial cells is a necessary step to increase microvessel permeability in intact microvessels, and this regulatory process occurs downstream from Ca2+ influx, which differs from that reported in large-vessel endothelium in culture and in vascular smooth muscle cells. Experiments carried on microvessels in both frog and rat mesenteries provided a direct comparison of the endothelial cell regulatory mechanisms between species.
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Department of Human Physiology, School of Medicine, University of California, Davis, California 95616, USA.
Zeng
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Curry
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D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D005260:Female; D007552:Isotonic Solutions / Q000494:pharmacology; D008297:Male; D008643:Mesentery / Q000098:blood supply; D011894:Rana pipiens; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077331:Ringer's Solution; D013997:Time Factors; D014699:Venules / Q000187:drug effects* / Q000502:physiology
D000634:Aminoquinolines; D007552:Isotonic Solutions; C016276:8-bromocyclic GMP; D000077331:Ringer's Solution; D000255:Adenosine Triphosphate; C041715:6-anilino-5,8-quinolinedione; D006152:Cyclic GMP; D001920:Bradykinin; D002118:Calcium