A trial for kinetic evaluation of the antagonistic potency of several .BETA.-antagonists on presynaptic .BETA.-adrenoceptors.

Abstract

Abstract-The antagonistic potency, pA2, of several non-selective i3-antagonists on presynaptic (3-adrenoceptors was evaluated using a parallel line assay and MacKay's equation against isoproterenol-induced increases in 3H release in isolated guinea-pig pulmonary arteries preloaded with 3H-norepinephrine. Cumulatively applied isoproterenol at 10-9 M, 10-8 M and 10-7 M dose-dependently increased 3H release evoked by transmural field stimulation at 1 Hz . 19-Antagonists tested dose-dependently antagonized the isoproterenol-induced increases.The order of pA2 was carteolol (11.23+0.09)>nadolol (9.78±0.05)>pindolol (9.59±0.03) >propranolol (9.26±0.17). Carteolol has the highest pA2 and is a useful tool for clarifying whether or not presynaptic (3-adrenoceptors tonically function.

Carteolol is a weak partial agonist on β3-adrenergic receptors in brown adipocytes

“…As an agonist, carteolol is nearly as potent (i.e., has similar EC 50 values) on the β 3 -receptor (5 µM; Table 1) as it has on β 1 /β 2 -receptors (0.2-3 µM) (Takayanagi et al 1989;Koike et al 1996) and is in all cases only a partial agonist (intrinsic activity 40-60%). However, as an antagonist, carteolol has a very high affinity for β 1 /β 2 -receptors (≤ 1 nM) (Kuwahara et al 1987;Takayanagi et al 1989;Koike et al 1996) but, as shown here, has very low affinity (> 10 µM) for β 3 -receptors. Thus, carteolol antagonist or agonist selectivity is close to unity for β 3 -receptors, in contrast with the ≈1000-fold ratio for β 1 /β 2 -receptors.…”

“…The calculated pK B values for carteolol as an antagonist were 4.6 against norepinephrine, 5.0 against BRL-37344, and 4.8 against CGP-12177; i.e., carteolol is a comparatively weak antagonist on the β 3 -receptor with a pK B ≤ 5 (which is a lower affinity than, for instance, propranolol has on these receptors). This value should be compared with the affinity of carteolol as an antagonist at the β 1 /β 2 -receptor, which is four to six orders of magnitude better (pA 2 of 9-11) (Kuwahara et al 1987;Takayanagi et al 1989;Koike et al 1996).…”

Local cardiac effects of substance P: roles of acetylcholine and noradrenaline

“…We observed that 10-6 M nadolol and phentolamine can produce about a 250 fold blockade of effects of exogenous isoprenaline on guinea-pig right atria (data not shown). Additionally, the antagonistic potency, pA2, of nadolol against effects of isoprenaline has been reported to be 9.78 ± 0.05 (Kuwahara et al, 1987). Thus, this concentration of nadolol and phentolamine (10-6 M) should be high enough to antagonize adequately the effects of NA adrenoceptors.…”