Abstract 399: Whole-Body Deletion of PPAR? in Mice Increases Sympathetic Nerve Activity

Abstract

PPARγ and sympathetic nerve activity (SNA) antagonistically regulate energy metabolism and cardiovascular function with the former promoting anabolism and vasorelaxation and the later favoring catabolism and vasoconstriction. However, the precise relationship between these two factors is not known. The present study examined the influence of PPARγ deletion on SNA. Systemic inactivation of PPARγ was generated constitutively by using Mox2-Cre mice (MoxCre/flox) or inducibly by using the tamoxifen system (EsrCre/flox/TM). Radiotelemetry demonstrates consistent increases in resting daytime heart rate (HR) in both strains of null mice; this was associated a more than 10-fold increase in urinary epinephrine and norepinephrine levels. Subsequently, more detailed analysis of SNA was performed in Esr/flox/TM mice. In response to a bolus ip injection of the gangalion blocker pentolinium at 7.5 mg/kg, the decreases in HR and MAP were greater in the null mice than in the flox controls (delta HR:-254.2 vs. 92.3 beat/min; delta MAP: -67.8 vs. 33.4 mmHg). The HR decrease in response to the beta-blocker metaprolol (12 mg/kg, ip) was greater in the null mice than in the flox controls so was the MAP decease in response to the alpha1-blocker prazosin (1 mg/kg, ip). Baroreflex sensitivity (BRS) was assessed by the measurement of the HR responses to bolus injections of sodium nitroprusside (NP-BRS) or phenylephrine (PE-BRS). EsrCre/flox/TM mice displayed normal PE-BRS but blunted NP-BRS. Echocardiography under anesthesia demonstrated that the ejection fraction (EF) was 11% lower after administration of metaprolol contrasting to a drop of only 1.5% for the flox controls, in parallel with a greater reduction of HR in the KO mice. In contrast, the increase in HR following administration of the beta1 agonist dobutamine (0.8 mg/kg, ip) was less in the KO mice than in the flox controls. Together, we conclude: 1) PPARγ deletion causes the activation of SNA, 2) the parasympathetic nervous system may be unaffected, 3) the blunted response to dobutamine suggest suppressed beta1 receptor activity possibly as a result of compensatory response to sympathoactivation.