Coexistence of beta 1- and beta 2-adrenoceptors in human right atrium. Direct identification by (+/-)-[125I]iodocyanopindolol binding.

Abstract

The highly specific beta-adrenoceptor radioligand, (+/-)-[125I]iodocyanopindolol, has been used to subclassify beta-adrenoceptors in membranes from human right atrial appendage obtained during open heart surgery. Binding of (+/-)-[125I]iodocyanopindolol was saturable (Bmax = 86.4 +/- 7.4 fmol (+/-)-[125I]iodocyanopindolol bound/mg protein, n = 4), of high affinity (KD = 53 +/- 6 pM, n = 4), rapid, reversible, and stereospecific. The relative potencies of isoprenaline, adrenaline, and noradrenaline for inhibition of (+/-)-[125I]iodocyanopindolol binding and activation of adenylate cyclase were 1:10:10, indicating a population composed mainly of beta 1-adrenoceptors. Inhibition of (+/-)-[125I]iodocyanopindolol binding by beta 1- (practolol, metoprolol, betaxolol) and beta 2- (IPS 339, ICI 118,551, zinterol, procaterol) selective drugs, however, resulted in biphasic displacement curves with slope factors (nH, pseudo Hill coefficients) significantly less than 1.0. Nonlinear regression analysis of these curves revealed a beta 1: beta 2 ratio of 80:20 in human right atrial appendage. Nonselective beta-adrenergic drugs (propranolol, isoprenaline, and adrenaline), on the contrary, inhibited binding with monophasic displacement curves and nH = 1.0. Binding of agonists to the beta-adrenoceptors in human right atrial appendage seems to be regulated by guanyl nucleotides. In the absence of GTP, isoprenaline binds to high and low affinity state of the beta-adrenoceptors. GTP (10(-4) M) converts this heterogeneous binding into a homogeneous one of low affinity. It is concluded that, in human right atria, beta 1- and beta 2-adrenoceptors coexist; however, beta 1-adrenoceptors predominate. The physiological function of beta 2-adrenoceptors in human right atrium remains to be elucidated.

Contribution of β1‐ and β2‐adrenoceptors of human atrium and ventricle to the effects of noradrenaline and adrenaline as assessed with (−)‐atenolol

“…It might be argued that the affinity of (-)-atenolol for P1-and fi2-adrenoceptors was actually overestimated in intact tissues of human heart. However, this is unlikely because from unpublished experiments we have also estimated similar absolute affinities and #1-selectivity of (-)-atenolol for guinea-pig l-(heart) compared to fi2-adrenoceptors (trachea (Stiles et al, 1983;Kaumann & Lemoine, 1987 (Stiles et al, 1983;Brodde et al, 1983). The discrepancies between the data may be related to technical problems with the binding assays.…”

“…Evidence from binding assays increasingly shows that #,-and fl2-adrenoceptors coexist in the human ventricle (Stiles et al, 1983;Gille et al, 1985;Kaumann & Lemoine, 1987) and right atrium (Brodde et al, 1983;Heitz et al, 1983). The adenylate cyclase appears to be coupled preferentially to f2-adrenoceptors in membrane particles obtained from human atrium and ventricle Gille et al, 1985;Kaumann & Lemoine, 1987 (Kaumann & Lemoine, 1987).…”

Treatment of Chronic Heart Failure With β-Adrenergic Receptor Antagonists

“…By the early 1980s, all the pharmacological tools were in place to examine this issue in detail, including highly selective ␤ 1 -and ␤ 2 -AR antagonists and agonists, and computer modeling methods that could resolve mixed populations of receptors from radioligand competition curve data. In 1983, three groups reported evidence of ␤ 2 -AR receptor binding sites in human atrial cardiac tissue, two in right atrial surgical biopsies (estimated to be either 20% 50 or 50% 51 of the total ␤-AR binding) and one from a single organ donor, with a ␤ 2 population of 26%. 12 In the organ donor, LV measurements were also reported, with a ␤ 1 /␤ 2 binding site distribution of 0.86/0.14, similar to results obtained in three autopsy-procured hearts 12 ; in the year after, eight mitral valve surgery patients' papillary muscle ␤ 1 /␤ 2 distribution was reported, at 0.69/0.31.…”

The β1‐ and β2‐adrenoceptor stimulatory effects of alprenolol, oxprenolol and pindolol: a study in the isolated right atrium and uterus of the rat

“…The receptor occupancy (y) was calculated from the equation; y = A/(A + KA) where A is the concentration of agonist which elicits the response and KA is the equilibrium dissociation constant. The dissociation constant for isoprenaline on Pj-and P2-adrenoceptors (3 x 10-7M) was obtained from previous P-adrenoceptor binding studies (Kaumann, 1978;Hedberg & Mattsson, 1981;Brodde et al, 1983). For the partial Pagonist, the equilibrium dissociation constant was obtained from the shift in the concentration-response curve for isoprenaline (see above).…”