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