Beta 1- and beta 2-adrenoceptor binding and functional response in right and left atria of rat heart.
The properties of beta 1- and beta 2-adrenoceptors in right and left atria of rat heart, and their roles in mediating chronotropic and inotropic responses to beta-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. The k1's for association in right and left atria were 6.5 X 10(9) l/mol-min and 2.3 X 10(9) l/mol-min respectively, while the k-1's for dissociation were 0.20 min-1 and 0.17 min-1. The kinetically determined KD's were 75 pmol/l in right and 30 pmol/l in left atria and were similar to the equilibrium KD's determined from Scatchard analysis of saturation isotherms of specific 125IPIN binding. Inhibition of 125IPIN binding by beta-adrenoceptor antagonists was stereoselective and the order of potency was timolol greater than l-propranolol greater than d-propranolol greater than sotalol. Inhibition by beta 1- and beta 2-adrenoceptor subtype selective antagonists yielded flat displacement curves with low Hill coefficients. Nonlinear regression analysis of displacement by beta 1-selective (practolol, atenolol and metoprolol) and beta 2-selective (ICI 118,551) antagonists gave estimates of the proportion of beta 1- and beta 2-adrenoceptors present in rat atria. Right atria contained 67 +/- 4.2% beta 1- and 33 +/- 4.2% beta 2-adrenoceptors, while left atria contained 67 +/- 2.8% beta 1- and 33 +/- 2.8% beta 2-adrenoceptors. Increases in the rate of spontaneously beating right atria and the force of electrically driven left atria caused by beta-adrenoceptor agonists were also measured. pA2 values for non-subtype selective beta-adrenoceptor antagonists in inhibiting isoprenaline-induced increases in rate and force were highly correlated with KD values determined for specific 125IPIN binding. pA2 values for beta 1- and beta 2-selective antagonists in inhibiting isoprenaline-induced increases in rate and force correlated well with the pKD values of these drugs in binding to beta 1-adrenoceptors, but not with the pKD values in binding to beta 2-adrenoceptors. Dose-response curves for stimulation of both rate and force by the beta 2-selective agonists procaterol and zinterol were shifted to a much greater extent by selective blockade of beta 1-adrenoceptors with metoprolol than by selective blockade of beta 2-adrenoceptors with ICI 118,551, suggesting that these compounds caused their effects by activating beta 1-adrenoceptors.(ABSTRACT TRUNCATED AT 400 WORDS)
Juberg
E N
EN
Minneman
K P
KP
Abel
P W
PW
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D006321:Heart / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D010869:Pindolol; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*
D000319:Adrenergic beta-Antagonists; D007457:Iodine Radioisotopes; D011943:Receptors, Adrenergic, beta; D010869:Pindolol; D007545:Isoproterenol