EXISTENCE OF β₃‐ADRENOCEPTORS IN RAT HEART: FUNCTIONAL IMPLICATIONS

Abstract

1. beta(3)-Adrenoceptors (AR) have been reported to be present in numerous species, where they mediate multiple responses. 2. The aim of the present study was to determine whether beta(3)-AR are present in intact rat heart and the functional implications of beta(3)-AR stimulation. The response to the cardiac beta(3)-AR-selective agonist BRL37344 was expressed as the percentage of values measured at baseline. 3. BRL37344 induced dose-dependent negative inotropic effects at concentrations ranging from 10(-11) to 10(-7) mol/L. BRL37344 (10(-8) mol/L) induced a decrease of left ventricular developed pressure (LVDP) from 127 +/- 5 to 89 +/- 16 mmHg (69 +/- 15%; P < 0.01) and +dP/dt from 2594 +/- 59 to 1885 +/- 50 mmHg/s (72 +/- 8%; P < 0.01). Moreover, a significant reduction of -dP/dt from 2176 +/- 42 to 1458 +/- 43 mmHg/s (67 +/- 8%; P < 0.01) was observed. The BRL37344 dose-response curves were not altered by nadolol (10(-5) mol/L), a potent beta(1)- and beta(2)-AR antagonist, but were completely suppressed by the addition of SR59230A (10(-5) mol/L), a potent beta(3)-AR antagonist. 4. The present study provides functional evidence for the presence of beta(3)-AR in rat hearts and shows, for the first time, that a highly specific beta(3)-AR antagonist can block the attenuation of LVDP caused by the specific beta(3)-AR agonist BRL37344 in rat beating hearts.

The Role of β-adrenergic Receptors in the Cardioprotective Effects of Beta-Preconditioning (βPC)

“…However, in contrast to isoproterenol and formoterol, transient administration of the β3-AR agonist BRL37344 caused a significant reduction in aortic output of the working rat heart and an increase in heart rate (Table 1), confirming the negative inotropic effects reported by others, but the effect on heart rate is controversial [10,31,32]. Preconditioning with a combination of BRL37344 and isoproterenol abolished the isoproterenol-induced reduction in infarct size (Fig.…”

“…Surprisingly, administration of the β3-AR antagonist SR59230A at a concentration of 100 nM (similar to that used by others [32,33]) to non-preconditioned hearts before the onset of sustained ischaemia, caused a significant reduction in infarct size after 35 min coronary artery ligation and improvement in post-ischaemic functional recovery (Fig. 3, Table 4).…”

Beta 3-adrenoreceptor regulation of nitric oxide in the cardiovascular system

“…This decrease in contractility after β3-AR stimulation has been confirmed in a transgenic mouse model with cardiac-specific overexpression of the β3-AR protein 98, in isolated Langendorff perfused rat hearts 99, and in other species such as dog and guinea pig 100, 101. Positive inotropic effects have been seen after β3-AR stimulation as well, best documented in the atrium, though the mechanism is not completely established and could be partly due to non-specific stimulation of β1/β2-AR 35, 102.…”

Beta-3 Adrenoceptors as New Therapeutic Targets for Cardiovascular Pathologies

“…In rat Langendorff-perfused heart, BRL37344 also produced a concentration-dependent negative inotropic effect. This effect was not altered by nadolol, a ß 1 -and ß 2 -AR antagonist, but was completely suppressed by the addition of SR59230A or L-748337 [13,14]. The negative inotropic effect induced by BRL37344 involved an NO-cyclic guanosine monophosphate (cGMP)-dependent pathway [14].…”