Myogenic tone is coupled to phospholipase C and G protein activation in small cerebral arteries.
The cellular transduction mechanisms underlying the response of blood vessels to mechanical forces such as pressure or stretch are largely unknown. In this report we test the hypothesis that myogenic tone in the cerebral circulation is coupled to activation of phospholipase C (PLC) and G proteins. Rat posterior cerebral arteries (luminal diam 189 +/- 4 microns) were cannulated in an arteriograph and allowed to develop myogenic tone at 75 mmHg (122 +/- 6 microns; P < 0.01). Exposure to U-73122, an inhibitor of PLC, produced concentration-dependent vasodilation, with near-maximal (> 90%) inhibition at concentrations > 3 microM (50% inhibitory concentration = 0.8 +/- 0.04 microM). The action of U-73122 was confirmed by demonstrating that constrictor responses to serotonin (PLC mediated) could be significantly attenuated or abolished at concentrations (0.5-1 microM) that were ineffective in antagonizing potassium depolarization or indolactam-induced constrictions (both PLC independent). Incubation in pertussis toxin (100 ng/ml, 2-2.5 h), an inhibitor of some G protein subtypes, reduced myogenic tone by 74 +/- 12%, with luminal diameters increasing from 129 +/- 7 to 160 +/- 7 microns. Conversely, nonspecific G protein activation using AlF-4 (NaF+AlCl3, 0.5-5 mM) significantly increased myogenic tone by 86 +/- 9%, reducing luminal diameters from 132 +/- 6 to 88 +/- 8 microns (P < 0.01). Together, these findings suggest that 1) PLC is activated in arteries that possess myogenic tone, 2) pharmacological inhibition of PLC results in a virtual loss of pressure-induced constriction, and 3) G proteins may modulate mechanotransduction through pathways superimposed on basal myogenic tone.
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Department of Obstetrics and Gynecology, University of Vermont College of Medicine, Burlington 05405.
Laher
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Kelley
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D000818:Animals; D002536:Cerebral Arteries / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology*; D004789:Enzyme Activation; D004963:Estrenes / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000502:physiology*; D008297:Male; D037342:Pertussis Toxin; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D012969:Sodium Fluoride / Q000494:pharmacology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014661:Vasoconstriction; D014666:Vasomotor System / Q000187:drug effects / Q000502:physiology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D004963:Estrenes; D011760:Pyrrolidinones; D010566:Virulence Factors, Bordetella; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D012969:Sodium Fluoride; D037342:Pertussis Toxin; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins