Dopaminergic Receptors Linked to Adenylate Cyclase in Human Cerebromicrovascular Endothelium

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Abstract
: 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 D, 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 α1‐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 α1‐adrenergic agonists or 5‐HT on DA production of cyclic AMP was partially prevented by the D2 antagonist, S(‐)‐sulpiride, or ketanserin (5‐HT2 > α1 > 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 α1adrenergic or 5‐HT receptors in endothelium on the adenylate cyclase level. These results provide strong support for the previously contemplated existence of a central dopaminergic mechanism in cerebral vessels, a notion that is clinically important.