OP.8C.02] NORADRENERGIC RECEPTOR FUNCTION IN HEALTHY AND OBESE PERIVASCULAR ADIPOSE TISSUE

Abstract

Objective: Healthy perivascular adipose tissue (PVAT) exerts an anti-contractile effect which is vital in regulating blood pressure, and evidence suggests that sympathetic nervous stimulation of PVAT triggers the release of anti-contractile factors via activation of beta3-adrenoceptors. In obesity there is sympathetic over-activity, which may result in a loss of PVAT function and subsequent hypertension. Therefore we examined beta3-adrenoceptor function in obesity. Design and method: Electrical field stimulation (EFS) profiles of healthy and obese mouse mesenteric arteries (<200um, +/−PVAT) were characterised using wire myography (0.1–30 Hz, 20 V, 0.2ms pulse duration, 4 s 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. Beta3-adrenoceptor function was investigated using the agonist CL-316,243 (10uM) and antagonist SR59203A (100 nM). The role of the vasodilator nitric oxide (NO) was studied using nitric oxide synthase (NOS) inhibitor L-NMMA (100uM), and NOS activator histamine (100uM). Results: During EFS healthy PVAT elicited an anti-contractile effect; which was lost in obesity. Solution transfer from stimulated healthy exogenous PVAT to a –PVAT vessel significantly reduced contraction, confirming that stimulated PVAT releases a transferable anti-contractile factor. Solution transfer from obese PVAT had no effect on contraction. Inhibition of beta3-adrenoceptors in healthy PVAT using SR59230A significantly reduced the anti-contractile effect, whereas activation of beta3-adrenoceptors in obese PVAT using CL-316,243 did not restore function. Using immunohistochemistry, expression of beta3-adrenoceptors is reduced in obesity. 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 in health PVAT releases an anti-contractile factor via activation of beta3-adrenoreceptors, which downstream triggers the release of NO. In obesity, the anti-contractile effect is lost and cannot be restored by beta3-activation, but is restored by activation of NOS. This reveals that in obesity beta3-adrenoreceptors are downregulated, leading to a loss of anti-contractile function, which may contribute to the development of hypertension. Targeting the NOS pathway may restore anti-contractile function, and treat the vascular complications of obesity.