Dopaminergic receptors linked to adenylate cyclase in human cerebromicrovascular endothelium.
Cultured endothelium derived from three fractions of human cerebral microvessels was used to characterize dopamine (DA) receptors linked to adenylate cyclase activity. DA or D1 agonist, (+/-)-SKF-82958 hydrobromide, stimulated endothelial cyclic AMP formation in a dose-dependent manner. The selective D1 antagonist, (+/-)SCH-23390, inhibited in a dose-dependent manner the production of cyclic AMP induced by DA. The affinity for the D1 receptor appeared to be greater in endothelium derived from large and small microvessels than from capillaries. Cholera toxin ADP-ribosylation of Gs proteins abolished the DA stimulatory effect on endothelial adenylate cyclase, whereas pertussis toxin ADP-ribosylation enhanced the DA-inducible formation, indicating the presence of both D1 and D2 receptors. Agonists of alpha 1-adrenergic receptors (phenylephrine, 6-fluoronorepinephrine) or serotonin (5-HT), which stimulated the production of cyclic AMP, had no additive effect on DA-stimulated cyclic AMP formation. Incubation of these agents with DA produced the same or lower levels of cyclic AMP as compared to that formed by DA alone. The effect of alpha 1-adrenergic agonists or 5-HT on DA production of cyclic AMP was partially prevented by the D2 antagonist, S(-)-sulpiride, or ketanserin (5-HT2 greater than alpha 1 greater than H1 antagonists), respectively. These findings represent the first demonstration of D1- (stimulatory) and D2- (inhibitory) receptors linked to adenylate cyclase in microvascular endothelium derived from human brain. The data also indicate that dopaminergic receptors can interact with either alpha 1-adrenergic or or 5-HT receptors in endothelium on the adenylate cyclase level.(ABSTRACT TRUNCATED AT 250 WORDS)
Bacic
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Laboratory of Neuropathology and Neuroanatomical Sciences, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
Uematsu
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S
McCarron
R M
RM
Spatz
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M
D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism*; D001552:Benzazepines / Q000494:pharmacology*; D002196:Capillaries; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation; D002772:Cholera Toxin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007700:Kinetics; D008833:Microcirculation; D009638:Norepinephrine / Q000031:analogs & derivatives / Q000494:pharmacology; D037342:Pertussis Toxin; D010656:Phenylephrine / Q000494:pharmacology; D011954:Receptors, Dopamine / Q000187:drug effects / Q000502:physiology*; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D012701:Serotonin / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D001552:Benzazepines; D015259:Dopamine Agents; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D010566:Virulence Factors, Bordetella; D010656:Phenylephrine; D012701:Serotonin; C071262:SK&F 82958; C024884:6-fluoronorepinephrine; D002772:Cholera Toxin; D000242:Cyclic AMP; D037342:Pertussis Toxin; D000262:Adenylyl Cyclases; D009638:Norepinephrine