BARBITURATE ATTENUATION OF AGONIST AFFINITY IN CEREBRAL-ARTERIES CORRELATES WITH ANESTHETIC POTENCY AND LIPID SOLUBILITY

Barbiturates are known to reduce agonist sensitivity (EC(50)) in vascu lar smooth muscle; we provide evidence that the reduced agonist sensit ivity can be correlated with a reduction in agonist affinity for its r eceptor. The histamine receptor was chosen since this agonist caused a consistent and maximum contraction of the cerebral artery used in thi s study. Segments of the basilar artery of white New Zealand male rabb its were set up in a small-vessel myograph in physiological salt solut ion, kept at 37 degrees C, pH 7.4, and bubbled with a 95% oxygen and 5 % carbon dioxide gas mixture. The equilibrium dissociation constant (K -A) of histamine for its receptor was calculated according to Furchgot t's method by making three concentration-response curves to histamine: control, in the presence of phenoxybenzamine (0.02 mu M), and after a ddition 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 af finity. There is a significant correlation between histamine sensitivi ty and receptor affinity for histamine in a series of arterial segment s from different animals. The attenuation of both pharmacological prop erties 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 sensi tivity was due to a change in agonist affinity. We suggest that barbit urates alter agonist receptor affinity by causing a perturbation in th e membrane lipid environment of the receptor, leading to a conformatio nal change, although alterations in intracellular mechanisms cannot be excluded.