title: Effects of two beta3-agonists, CGP 12177A and BRL 37344, on coronary flow and contractility in isolated guinea pig heart.
abstract: The functional role of beta(3)-adrenergic receptors in the heart is still not clear. The actions of two widely used beta(3)-adrenoceptor agonists, such as BRL 37344 and CGP 12177, were studied in the isolated guinea pig heart, perfused at constant pressure according to the Langendorff technique. Heart contractility (dP/dt, first derivative of pressure measured over time) and coronary flow (CF) were assessed simultaneously. BRL 37344 and CGP 12177A at a concentration range of 10-8-10-5 M increased dP/dt and CF. The selective beta(3)-antagonist L-748337 (10-6 M) did not significantly influence either BRL 37344 or CGP 12177A-induced responses. However, both dP/dt and CF responses to BRL 37344 and CGP 12177A at a concentration of 10-7 M were abolished in the presence of the beta(1)/beta(2)-antagonist nadolol (10-5 M). In contrast, cardiovascular responses to CGP 12177A at a higher concentration of 10-5 M were hardly inhibited by nadolol (10-5 M). In addition, BRL 37344 and CGP 12177A at concentrations as low as 10-8 M almost completely abolished an isoprenaline-induced increase in contractility, suggesting that both BRL 37344 and CGP 12177A display beta(1)-antagonistic properties. These data suggest that the stimulatory cardiovascular responses to BRL 37344 at a full range of concentrations, and CGP 12177A at a low concentration of 10-7 M, are not mediated by beta(3)-adrenergic receptors, but rather by activation of beta(1)- or beta(2)-adrenergic receptors. Cardiovascular effects of CGP 12177A at a high concentration of 10-5 M are independent of beta(1)/beta(2)/beta(3)-adrenergic receptors. Summing up, it seems that in the isolated guinea pig heart the functional role of beta(3)-adrenoceptors is not significant. Nonetheless, BRL 37344 and CGP 12177A are not ideal tools for investigation of beta(3)-adrenergic receptor-dependent effects, because these compounds interact with other types of beta-adrenergic receptors.
authors.affiliation: Department of Pharmacology, Jagiellonian University School of Medicine, Krakow, Poland.
authors.forename: Valery I
authors.initials: VI
authors.lastname: Kozlovski
authors.forename: Stefan
authors.initials: S
authors.lastname: Chlopicki
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gryglewski
mesh_terms: D058665:Adrenergic beta-1 Receptor Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D058666:Adrenergic beta-2 Receptor Agonists; D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects* / Q000502:physiology; D004983:Ethanolamines / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D010477:Perfusion; D011412:Propanolamines / Q000494:pharmacology*; D018342:Receptors, Adrenergic, beta-1 / Q000502:physiology; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology; D022702:Receptors, Adrenergic, beta-3 / Q000502:physiology; D013268:Stimulation, Chemical; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D058665:Adrenergic beta-1 Receptor Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D058666:Adrenergic beta-2 Receptor Agonists; D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D004983:Ethanolamines; D011412:Propanolamines; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D022702:Receptors, Adrenergic, beta-3; D014665:Vasodilator Agents; C057368:BRL 37344; C033394:CGP 12177