YIA 03-09 NORADRENERGIC RECEPTOR FUNCTION IN HEALTHY AND OBESE PERIVASCULAR ADIPOSE TISSUE

Abstract

Objective: Perivascular adipose tissue (PVAT) exerts an anti-contractile effect vital to regulating blood pressure. Evidence suggests that the sympathetic nervous stimulation of PVAT triggers the release of anti-contractile factors via activation of β3-adrenoceptors. Therefore it was decided to examine β3-adrenoceptor function in obesity. Design and Method: Electrical field stimulation (EFS) of healthy and obese mouse mesenteric arteries (<200 μm, +/-PVAT) were characterised using wire myography (0.1–30 Hz, 20V, 0.2ms pulse duration, 4s train duration). To demonstrate the release of an anti-contractile factor in health, the solution surrounding stimulated exogenous PVAT was transferred to a PVAT denuded vessel. β3-adrenoceptor function was investigated using the agonist CL-316,243 (10 μM) and antagonist SR59203A (100nM). The role of the vasodilator nitric oxide (NO) was studied using nitric oxide synthase (NOS) inhibitor L-NMMA (100 μM), and NOS activator histamine (100 μM). Results: Healthy PVAT elicits an anti-contractile effect which was lost in obesity. Inhibition of β3-adrenoceptors significantly reduced the anti-contractile effect, whereas activation of β3-adrenoceptors in obese PVAT using CL-316,243 did not restore function. Solution transfer from stimulated healthy exogenous PVAT to a –PVAT vessel significantly reduced contraction, confirming the release of a transferable factor. The release of this factor could be inhibited using SR59230A. Solution transfer from obese PVAT had no effect on contraction, and again could not be restored using CL-316,243. In healthy PVAT, inhibition of NOS using L-NMMA abolished the anti-contractile effect. In obese PVAT, activation of NOS using histamine was able to restore the anti-contractile function. Conclusions: These results demonstrate that healthy PVAT releases an anti-contractile factor via activation of β3-adrenoreceptors, which downstream triggers the release of NO. In obesity, the anti-contractile effect is lost and cannot be restored by β3-activation, but is restored by activation of NOS. This suggests that in obesity β3-adrenoreceptors must be downregulated or desensitised, leading to a loss of anti-contractile function.