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

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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 determinedKD's were 75 pmol/l in right and 30 pmol/l in left atria and were similar to the equilibriumKD'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 withKD values determined for specific125IPIN binding. pA2 values forβ1- andβ2-selective antagonists in inhibiting isoprenaline-induced increases in rate and force correlated well with the pKD values of these drugs in binding toβ1-adrenoceptors, but not with the pKD 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.