RT Journal Article
SR Electronic
T1 161 Noradrenergic Receptor Function in Healthy and Obese Perivascular Adipose Tissue
JF Heart
JO Heart
FD BMJ Publishing Group Ltd and British Cardiovascular Society
SP A115
OP A115
DO 10.1136/heartjnl-2016-309890.161
VO 102
IS Suppl 6
A1 Sophie Saxton
A1 Sarah Withers
A1 Jacqueline Ohanian
A1 Anthony Heagerty
YR 2016
UL http://heart.bmj.com/content/102/Suppl_6/A115.1.abstract
AB Perivascular adipose tissue (PVAT) exerts an anti-contractile effect which is vital in regulating blood pressure. Evidence suggests that the sympathetic nervous stimulation of PVAT triggers the release of anti-contractile factors via activation of beta3-adrenoceptors. There is considerable evidence of sympathetic over-activity in obesity, which could result in the loss of PVAT function, and subsequent hypertension. Therefore it was decided to examine beta3-adrenoceptor function in obesity.Electrical field stimulation (EFS) profiles of healthy and obese mouse mesenteric arteries (<200 um, +/-PVAT) were characterised using wire myography (0.1–30 Hz, 20V, 0.2 ms 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. Beta3-adrenoceptor function was investigated using the agonist CL-316,243 (10uM) and antagonist SR59203A (100nM). The role of the vasodilator nitric oxide (NO) was studied using nitric oxide synthase (NOS) inhibitor L-NMMA (100uM), and NOS activator histamine (100uM).During EFS healthy PVAT elicits an anti-contractile effect (n = 8, P < 0.001); however the anti-contractile function of obese PVAT is lost (n = 8, P = 0.35). Inhibition of beta3-adrenoceptors in healthy PVAT using SR59230A significantly reduced the anti-contractile effect (n = 8, P < 0.01), whereas activation of beta3-adrenoceptors in obese PVAT using CL-316,243 did not restore function (n = 7, P = 0.77). Solution transfer from stimulated healthy exogenous PVAT to a -PVAT vessel significantly reduced contraction (n = 8, P < 0.01), confirming that stimulated PVAT releases a transferable anti-contractile factor. The release of this factor could be inhibited using SR59230A (n = 7, P = 0.47). Solution transfer from obese PVAT had no effect on contraction (n = 6, P = 0.41), and again could not be restored using CL-316,243 (n = 6, P = 0.14). In healthy PVAT, inhibition of NOS using L-NMMA abolished the anti-contractile effect (n = 8, P < 0.01). In obese PVAT, activation of NOS using histamine was able to restore the anti-contractile function (n = 4, P < 0.05).These results demonstrate that in health PVAT releases an anti-contractile factor via activation of beta3-adrenoreceptors, which downstream trigger the release of NO. In obesity, the anti-contractile effect is lost and cannot be restored by beta3-adrenoceptor activation, but is restored by activation of NOS. This suggests that in obesity beta3-adrenoreceptors must be downregulated or desensitised, leading to a loss of anti-contractile function, which may contribute to the development of hypertension.