Is there a third heart β-adrenoceptor?

doi:10.1016/0165-6147(89)90065-5

Trends in Pharmacological Sciences

Volume 10, Issue 8, August 1989, Pages 316-320

https://doi.org/10.1016/0165-6147(89)90065-5 Get rights and content

Abstract

A series of partial agonists with high affinity for myocardial β₁- and β₂-adrenoceptors cause stimulant effects in heart that are resistant to blockade of β₁- and -adrenoceplors. The concentrations of partial agonist that cause stimulant effects greatly exceed those that cause blockade. Alberto Kaumann suggests that such non-conventional partial agonists, often analogues of pindolol, may act through a third heart β₂-adrenoceptor, which resembles the β₃-adrenoceptor of white adipocytes and smooth muscle of airways and ileum

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This in vitro study was designed to investigate whether carteolol, a non-conventional partial agonists of β₁-adrenoceptors, relaxes phenylephrine-constricted rat aorta through activation of the low-affinity state of β₁-adrenoceptors or antagonist effect at α₁-adrenoceptors. Carteolol-induced complete concentration-dependent relaxation of phenylephrine-contracted aorta (pD₂ = 3.65 ± 0.04), this effect not being modified by endothelium removal and not antagonised by NO-synthase inhibitor N^G-nitro-l-arginine methyl ester (100 µM) or cyclo-oxygenase inhibitor indomethacin (10 µM). The effect of carteolol was unaffected by the non-selective β-adrenoceptor antagonist propranolol (1 µM), or the β₂-adrenoceptor selective antagonist (±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol (ICI 118,551, 1 µM). Increasing concentrations of carteolol produced a parallel rightward shift of the concentration–response curves for phenylephrine-induced contraction, exhibiting a pK_B of 4.28 ± 0.07. Carteolol affinity for α₁-adrenoceptors was evaluated by means of competition experiments carried out in BHK-21 cell membranes expressing rat recombinant α_1D-adrenoceptor, the α₁-adrenoceptor subtype mainly present in rat aorta. Carteolol competed monophasically with [³H]prazosin, exhibiting a pK_i value (3.39 ± 0.31) similar to its pD₂ and not very far from its pK_B. In conclusion, this study indicates that carteolol relaxes phenylephrine-contracted aorta through its α₁-adrenoceptor antagonist properties, excluding the possibility that the relaxant effect is due to the activation of β-adrenoceptors, particularly of the low-affinity state of β₁-adrenoceptors, by the drug.
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Citation Excerpt :
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Low blocking potencies of bupranolol and CGP20712. As found on other species (Kaumann, 1989) including man (Kaumann, 1996), CGP12177 also causes cardiostimulation at nanomolar concentrations on rat cardiac tissues (Kaumann & Molenaar, 1996; Malinowska & Schlicker, 1996, 1997; Sarsero et al., 1999) but vascular relaxation at micromolar concentrations (Brawley et al., 2000a 2000b; Koslowska et al., 2003; Mallem et al., 2004, 2005; Briones et al., 2005). The vascular relaxant potency of (±)-cyanopindolol (Brawley et al., 2000a,b; Kozlowska et al., 2003; Mallem et al., 2004, 2005) is also consistently lower than its cardiostimulant potency (Kaumann & Molenaar, 1996; Malinowska & Schlicker, 1996; Sarsero et al., 1999).
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Trends in Pharmacological Sciences

ViewpointIs there a third heart β-adrenoceptor?

Abstract

Life Sci.

J. Biol. Chem.

Life Sci.

Eur. J. Pharmacol.

J. Bioi. Chem.

Naunyn-Schmiedeberg's Arch. Phannacol.

Naunyn-Schmiedeberg's Arch. Pharmacol.

Br. J. Pharmacol.

Br. J. Pharmacol.

Eur. Heart J.

Naunyn-Schmiedeberg's Arch. Pharmacol.

Naunyn-Schmiedeberg's Arch. Pharmacol.

Mol. Pharmacol.

Nauyn-Schmiedeberg's Arch. Pharmacol.

Naunyn-Schmiedeberg's Arch. Pharmacol.

Br. J. Pharmacol.

Naunyn-Schimedcberg's Arch. Pharmacol.

N. Engl. J. Med.

J. Pharmacol. Exp. Ther.

Viewpoint
Is there a third heart β-adrenoceptor?