β1- and β2-adrenoceptor binding and functional response in right and left atria of rat heart

Eric N. Juberg, Kenneth P. Minneman, Peter W. Abel

Research output: Contribution to journalArticle

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Abstract

The properties of β1- and β2-adrenoceptors in right and left atria of rat heart, and their roles in mediating chronotropic and inotropic responses to β-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 6.5×109 l/mol-min and 2.3×109 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 specific125IPIN binding. Inhibition of125IPIN binding by β-adrenoceptor antagonists was stereoselective and the order of potency was timolol > 1-propranolol > d-propranolol > sotalol. Inhibition by β1- and β2-adrenoceptor subtype selective antagonists yielded flat displacement curves with low Hill coefficients. Nonlinear regression analysis of displacement by β1-selective (practolol, atenolol and metoprolol) and β2-selective (ICI 118,551) antagonists gave estimates of the proportion of β1- and β2-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 by β-adrenoceptor agonists were also measured. pA2 values for non-subtype selective β-adrenoceptor antagonists in inhibiting isoprenaline-induced increases in rate and force were highly correlated with KD values determined for specific125IPIN binding. pA2 values for β1- and β2-selective antagonists in inhibiting isoprenaline-induced increases in rate and force correlated well with the p KD values of these drugs in binding to β1-adrenoceptors, but not with the p KD values in binding to β2-adrenoceptors. Dose-response curves for stimulation of both rate and force by the β2-selective agonists procaterol and zinterol were shifted to a much greater extent by selective blockade of β1-adrenoceptors with metoprolol than by selective blockade of β2-adrenoceptors with ICI 118,551, suggesting that these compounds caused their effects by activating β1-adrenoceptors. These results suggest that β1- and β2-adrenoceptors coexist in both left and right atria of rat heart in approximately a 2:1 ratio, however only β1-adrenoceptors mediate the chronotropic and inotropic effects of β-adrenoceptor agonists.

Original languageEnglish
Pages (from-to)193-202
Number of pages10
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume330
Issue number3
DOIs
StatePublished - Sep 1985
Externally publishedYes

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Heart Atria
Adrenergic Receptors
Metoprolol
Isoproterenol
Propranolol
Procaterol
Practolol
Sotalol
Pindolol
Timolol
Atenolol

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

β1- and β2-adrenoceptor binding and functional response in right and left atria of rat heart. / Juberg, Eric N.; Minneman, Kenneth P.; Abel, Peter W.

In: Naunyn-Schmiedeberg's Archives of Pharmacology, Vol. 330, No. 3, 09.1985, p. 193-202.

Research output: Contribution to journalArticle

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N2 - The properties of β1- and β2-adrenoceptors in right and left atria of rat heart, and their roles in mediating chronotropic and inotropic responses to β-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 6.5×109 l/mol-min and 2.3×109 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 specific125IPIN binding. Inhibition of125IPIN binding by β-adrenoceptor antagonists was stereoselective and the order of potency was timolol > 1-propranolol > d-propranolol > sotalol. Inhibition by β1- and β2-adrenoceptor subtype selective antagonists yielded flat displacement curves with low Hill coefficients. Nonlinear regression analysis of displacement by β1-selective (practolol, atenolol and metoprolol) and β2-selective (ICI 118,551) antagonists gave estimates of the proportion of β1- and β2-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 by β-adrenoceptor agonists were also measured. pA2 values for non-subtype selective β-adrenoceptor antagonists in inhibiting isoprenaline-induced increases in rate and force were highly correlated with KD values determined for specific125IPIN binding. pA2 values for β1- and β2-selective antagonists in inhibiting isoprenaline-induced increases in rate and force correlated well with the p KD values of these drugs in binding to β1-adrenoceptors, but not with the p KD values in binding to β2-adrenoceptors. Dose-response curves for stimulation of both rate and force by the β2-selective agonists procaterol and zinterol were shifted to a much greater extent by selective blockade of β1-adrenoceptors with metoprolol than by selective blockade of β2-adrenoceptors with ICI 118,551, suggesting that these compounds caused their effects by activating β1-adrenoceptors. These results suggest that β1- and β2-adrenoceptors coexist in both left and right atria of rat heart in approximately a 2:1 ratio, however only β1-adrenoceptors mediate the chronotropic and inotropic effects of β-adrenoceptor agonists.

AB - The properties of β1- and β2-adrenoceptors in right and left atria of rat heart, and their roles in mediating chronotropic and inotropic responses to β-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 6.5×109 l/mol-min and 2.3×109 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 specific125IPIN binding. Inhibition of125IPIN binding by β-adrenoceptor antagonists was stereoselective and the order of potency was timolol > 1-propranolol > d-propranolol > sotalol. Inhibition by β1- and β2-adrenoceptor subtype selective antagonists yielded flat displacement curves with low Hill coefficients. Nonlinear regression analysis of displacement by β1-selective (practolol, atenolol and metoprolol) and β2-selective (ICI 118,551) antagonists gave estimates of the proportion of β1- and β2-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 by β-adrenoceptor agonists were also measured. pA2 values for non-subtype selective β-adrenoceptor antagonists in inhibiting isoprenaline-induced increases in rate and force were highly correlated with KD values determined for specific125IPIN binding. pA2 values for β1- and β2-selective antagonists in inhibiting isoprenaline-induced increases in rate and force correlated well with the p KD values of these drugs in binding to β1-adrenoceptors, but not with the p KD values in binding to β2-adrenoceptors. Dose-response curves for stimulation of both rate and force by the β2-selective agonists procaterol and zinterol were shifted to a much greater extent by selective blockade of β1-adrenoceptors with metoprolol than by selective blockade of β2-adrenoceptors with ICI 118,551, suggesting that these compounds caused their effects by activating β1-adrenoceptors. These results suggest that β1- and β2-adrenoceptors coexist in both left and right atria of rat heart in approximately a 2:1 ratio, however only β1-adrenoceptors mediate the chronotropic and inotropic effects of β-adrenoceptor agonists.

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