Cholinergic-adrenergic receptor interactions in cerebral microvessels.
Enriched capillary preparations isolated from rat cerebral cortex were used to evaluate cholinergic-adrenergic receptor interactions in cerebral endothelium. Possible receptor interactions were determined by measuring an intracellular mediator, cyclic AMP and alterations in GTP-sensitive agonist binding. Unstimulated microvessel homogenates generate 66 +/- 16 pmol/mg/10 min of cyclic AMP. Adrenergic agonists norepinephrine and isoproterenol increase cyclic AMP to 147 +/- 31 and 149 +/- 23 pmol/mg/10 min, respectively. Addition of the muscarinic agonist carbachol has no effect on basal cyclic AMP but it completely blocks the stimulation elicited by adrenergic agonists. The displacement of quinuclidinyl benzilate (QNB) by carbachol yields an IC50 of 1.5 +/- 0.45 X 10(-4) M and a Hill coefficient of 0.54 +/- 0.07, indicating a heterogeneous population of binding sites. Guanine nucleotides shift the displacement curve to the right (IC50, 4.7 +/- 0.16 X 10(-4) M) and convert the binding site population to greater homogeneity (0.76 +/- 0.18). Isoproterenol prevents both the affinity shift and binding site conversion evoked by guanine nucleotides. These data suggest that cholinergic-adrenergic interactions occur at both the level of receptor binding and the generation of an intracellular messenger. Since cyclic AMP has been purported to play a role in regulation of blood-brain barrier permeability, the existence of adrenergic-cholinergic, i.e., excitatory-inhibitory modulators of adenylate cyclase in cerebral endothelium, suggests that these receptors may mediate physiological and/or pathological alterations of cerebrovascular permeability.
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Wiener
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D000262:Adenylyl Cyclases / Q000032:analysis; D000818:Animals; D001921:Brain / Q000098:blood supply*; D002217:Carbachol / Q000494:pharmacology; D000242:Cyclic AMP / Q000032:analysis; D006150:Guanine Nucleotides / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008833:Microcirculation / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D011941:Receptors, Adrenergic / Q000502:physiology*; D011950:Receptors, Cholinergic / Q000502:physiology*
D006150:Guanine Nucleotides; D011941:Receptors, Adrenergic; D011950:Receptors, Cholinergic; D002217:Carbachol; D000242:Cyclic AMP; D000262:Adenylyl Cyclases