Barbiturate attenuation of agonist affinity in cerebral arteries correlates with anesthetic potency and lipid solubility.

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Barbiturates are known to reduce agonist sensitivity (EC50) in vascular smooth muscle; we provide evidence that the reduced agonist sensitivity can be correlated with a reduction in agonist affinity for its receptor. The histamine receptor was chosen since this agonist caused a consistent and maximum contraction of the cerebral artery used in this study. Segments of the basilar artery of white New Zealand male rabbits were set up in a small-vessel myograph in physiological salt solution, kept at 37 degrees C, pH 7.4, and bubbled with a 95% oxygen and 5% carbon dioxide gas mixture. The equilibrium dissociation constant (KA) of histamine for its receptor was calculated according to Furchgott's method by making three concentration-response curves to histamine: control, in the presence of phenoxybenzamine (0.02 microM), and after addition of a barbiturate in concentrations between 0.1 and 1.0 mM. All barbiturates tested, i.e., thiamylal, thiopental, pentobarbital, and phenobarbital, significantly reduced both histamine sensitivity and affinity. There is a significant correlation between histamine sensitivity and receptor affinity for histamine in a series of arterial segments from different animals. The attenuation of both pharmacological properties was consistent with the known rank order of anesthetic potency and with lipophilicity (r = 0.98; p < 0.05). Receptor reserve did not correlate with sensitivity. Thus, most of the change in receptor sensitivity was due to a change in agonist affinity. We suggest that barbiturates alter agonist receptor affinity by causing a perturbation in the membrane lipid environment of the receptor, leading to a conformational change, although alterations in intracellular mechanisms cannot be excluded.