? 1- and? 2-adrenoceptor binding and functional response in right and left atria of rat heart

Abstract

The properties ofβ₁- andβ₂-adrenoceptors in right and left atria of rat heart, and their roles in mediating chronotropic and inotropic responses toβ-adrenoceptor agonists were examined. [¹²⁵I](-)-pindolol (¹²⁵IPIN) bound saturably and specifically to a single class of high affinity sites in homogenates of both right and left atria. Thek₁'s for association in right and left atria were 6.5×10⁹ l/mol-min and 2.3×10⁹ l/mol-min respectively, while thek₋₁'s for dissociation were 0.20 min⁻¹ and 0.17 min⁻¹. The kinetically determinedK_D's were 75 pmol/l in right and 30 pmol/l in left atria and were similar to the equilibriumK_D's determined from Scatchard analysis of saturation isotherms of specific¹²⁵IPIN binding. Inhibition of¹²⁵IPIN binding byβ-adrenoceptor antagonists was stereoselective and the order of potency was timolol > 1-propranolol > d-propranolol > sotalol. Inhibition byβ₁- andβ₂-adrenoceptor subtype selective antagonists yielded flat displacement curves with low Hill coefficients. Nonlinear regression analysis of displacement byβ₁-selective (practolol, atenolol and metoprolol) andβ₂-selective (ICI 118,551) antagonists gave estimates of the proportion ofβ₁- andβ₂-adrenoceptors present in rat atria. Right atria contained 67±4.2%β₂-adrenoceptors and 33±4.2%β₂-adrenoceptor, while left atria contained 67±2.8%β₁- and 33±2.8%β₂-adrenoceptors. Increases in the rate of spontaneously beating right atria and the force of electrically driven left atria caused byβ-adrenoceptor agonists were also measured. pA₂ values for non-subtype selectiveβ-adrenoceptor antagonists in inhibiting isoprenaline-induced increases in rate and force were highly correlated withK_D values determined for specific¹²⁵IPIN binding. pA₂ values forβ₁- andβ₂-selective antagonists in inhibiting isoprenaline-induced increases in rate and force correlated well with the pK_D values of these drugs in binding toβ₁-adrenoceptors, but not with the pK_D values in binding toβ₂-adrenoceptors. Dose-response curves for stimulation of both rate and force by theβ₂-selective agonists procaterol and zinterol were shifted to a much greater extent by selective blockade ofβ₁-adrenoceptors with metoprolol than by selective blockade ofβ₂-adrenoceptors with ICI 118,551, suggesting that these compounds caused their effects by activatingβ₁-adrenoceptors. These results suggest thatβ₁- andβ₂-adrenoceptors coexist in both left and right atria of rat heart in approximately a 2∶1 ratio, however onlyβ₁-adrenoceptors mediate the chronotropic and inotropic effects ofβ-adrenoceptor agonists.