Influence of β-adrenoceptor agonists on the pulmonary circulation. Effects of a β3-adrenoceptor antagonist, SR 59230A

https://doi.org/10.1016/S0014-2999(98)00146-0Get rights and content

Abstract

The aims of this study were (a) to compare in the rat isolated perfused lung preparation, the effects of isoprenaline and of three β3-adrenoceptors agonists, SR 59104A, (N-[(6hydroxy-1,2,3,4-tetrahydronaphtalen-(2R)-2yl)methyl]-(2R)-2-hydroxy-2-(3-chlorophenyl)ethanamine hydrochloride), SR 59119A (N[(7-methoxy-1,2,3,4-tetrahydronaphtalen-(2R)-2yl)methyl]-(2R)-2-hydroxy-2-(3-chlorophenyl)ethanamine hydrochloride) and SR 58611A (ethyl{(7S)-7-[(2R)-2-(3-chlorophenyl)-2-hydroxyethylamino]-5,6,7,8-tetrahydronaphtalen-2-yloxy}acetate hydrochloride) on hypoxia-induced pulmonary vasoconstriction, and (b) to investigate the potential existence of atypical β-adrenoceptors in these effects. Propranolol (0.1 μM) was used to antagonize β1- and β2-adrenoceptors whereas SR 59230A, 3-(2-ethylphenoxy)-1-[(1S)-1,2,3,4-tetrahydronapht-1-ylamino]-(2S)-2-propanol oxalate) (0.3 μM) was used to block β3-adrenoceptors. Isoprenaline and the three β3-adrenoceptors agonists caused concentration-dependent relaxations during the pulmonary pressure response. Propranolol and SR 59230A inhibited the relaxant effects of isoprenaline. SR 59230A but not propranolol inhibited those of SR 59104A. Finally, propranolol and SR 59230A failed to oppose SR 59119A- and SR 58611A-induced relaxant effects. In concentrations ≥1 μM, SR 59230A caused per se a relaxation of the hypoxic vasoconstricted lung. These results suggest the existence of atypical β-adrenoceptors in the rat pulmonary vessels.

Introduction

In 1984, for the first time, studies using novel thermogenic β-adrenoceptor agonists suggested that catecholamines-induced stimulation of lipolysis in rodent brown and white adipose tissues was mediated by an atypical β-adrenoceptor, designed as the β3-adrenoceptor (Arch et al., 1984). More recently, biological effects mediated by β3-adrenoceptors have also been identified in the gastrointestinal tract, especially in the rat and human colon (Manara et al., 1996; De Ponti et al., 1996). There are indications that atypical β-adrenoceptors, which are sensitive to preferential pharmacological agonists that have little effects on β1- and β2-adrenoceptors (e.g., BRL 37344 and SR 58611A), but relatively insensitive to the conventional β-adrenoceptor antagonists, are also present in the myocardium (Kaumann and Molenaar, 1996), and in the vascular smooth muscle including the rat carotid artery (Oriowo, 1994), the rat thoracic aorta (Oriowo, 1995) and the canine cutaneous vessels (Berlan et al., 1994). Nevertheless, the similarity of these receptors with the β3-adrenoceptor present in the rat adipose tissue remains to be demonstrated (Kaumann and Molenaar, 1996). The recent introduction of the first β3-selective adrenoceptor antagonist, SR 59230A (Manara et al., 1995, Manara et al., 1996) prompted us to determine whether functionally relevant atypical β-adrenoceptors would also be present in the pulmonary vasculature. We therefore investigated the vasodilator profiles of three selective β3-adrenoceptor agonists: SR 59104A, SR 59119A and SR 58611A on the hypoxic vasoconstriction in the rat isolated perfused lung preparation and compared them to that of the well known β-adrenoceptor agonist, isoprenaline.

Section snippets

Animal surgery and perfusion

Twenty two groups (n=5 to 9 per group) of male Wistar rats (Dépré, St Doulchard, France) weighing 280–340 g, were anaesthetized with sodium pentobarbitone (100 mg kg−1) and the lungs were removed for extracorporeal perfusion as previously described (Dumas et al., 1994). Mean perfusion pressure which was measured from a side-arm of the arterial line (Harvard transducer, −50 to 300 mmHg, South Natick, MA, USA), was recorded continuously (Ankersmit WR 3701 recorder, Graphtec, Tokyo, Japan) and

Results

In lung preparations, the mean baseline inflation pressure was 10.40±0.11 cm H2O (n=136) and was not significantly modified by hypoxic ventilation or addition of the various drugs. After equilibration of the preparation, the baseline perfusion pressure in normoxic ventilation was similar in all series of rats (4.93±0.08 mmHg, n=136).

In a 1st control series, ventilation with the hypoxic gas mixture produced a significant increase of the perfusion pressure (+3.81±0.05 mmHg, n=136, +77% from

Discussion

The rat isolated perfused lung preparation allows the exploration of the vasomotor tone in all pulmonary vessels and particularly in the small arteries and veins which are known to account for the greatest part of pulmonary vasculature resistances (Madden et al., 1985; Zhao et al., 1993). We investigated the effects of three phenylethanolaminotetralines reported to exert atypical β-adrenoceptor agonist properties (Bianchetti and Manara, 1990; Croci et al., 1995), SR 59104A, SR 59119A and SR

References (22)

  • T Kenakin

    Agonist-receptor efficacy: II. Agonist trafficking of receptor signals

    Trends Pharmacol. Sci.

    (1995)
  • A.M Lands et al.

    Differentiation of receptors responsive to isoproterenol

    Life Sci.

    (1967)
  • A.D Strosberg et al.

    The β3-adrenoceptor constitutes indeed a versatile receptor

    Trends Pharmacol. Sci.

    (1997)
  • J.R.S Arch et al.

    Atypical β-adrenoceptor on brown adipocytes as target for anti-obesity drugs

    Nature

    (1984)
  • M Berlan et al.

    β3-adrenoceptor-mediated increase in cutaneous blood flow in the dog

    J. Pharmacol. Exp. Ther.

    (1994)
  • A Bianchetti et al.

    In vitro inhibition of intestinal motility by phenylethanolaminotetralines: evidence of atypical β-adrenoceptors in rat colon

    Br. J. Pharmacol.

    (1990)
  • J.W Black et al.

    Activation and blockade of β-adrenoceptors in common cardiac disorders

    Br. Med. J.

    (1973)
  • N Blin et al.

    Mediation of most atypical effects by species homologues of the β3-adrenoceptor

    Br. J. Pharmacol.

    (1994)
  • T Croci et al.

    The novel β3-adrenoceptor agonists SR 59119A and SR 59104A are stereospecifically antagonized by SR 59230A

    Br. J. Pharmacol.

    (1995)
  • F De Ponti et al.

    Functional evidence of atypical β3-adrenoceptors in the human colon using the β3-selective adrenoceptor antagonist SR 59230A

    Br. J. Pharmacol.

    (1996)
  • M Dumas et al.

    Effects of two K+ channel openers, aprikalim and pinacidil, on hypoxic pulmonary vasoconstriction

    Eur. J. Pharmacol.

    (1994)
  • Cited by (0)

    View full text