Hypertensive Young Adult Female Obese Zucker Rats (OZR) do not have the Blunted Baroreflexes and Poor Glycemic control observed in age‐matched Hypertensive Male OZR

Abstract

Obese Zucker rats (OZR) have hyperphagia owing to dysfunctional leptin receptors and gain excess weight compared to lean Zucker rats (LZR) with functional leptin receptors. Young adult male OZR (12–14 wks) develop hypertension and impaired baroreflexes coincident with blunted activation of the nucleus tractus solitarius (NTS), the brain stem site that receives baroreceptor afferent inputs. Male OZR at this age have hyperinsulinemia and chronically elevated fed glucose levels (despite normal fasting glucose) with significant glucose intolerance as measured by telemetry (DSI). Treatment with metformin (300mg/day, 4 wks) restores glycemic control in OZR without eliminating hypertension or hyperinsulinemia, with no effect on these measures in LZR. After treatment with metformin male OZR have improved baroreflexes and activation of the NTS, suggesting hyperglycemia contributes to these deficits in adult male OZR. In contrast to males, at this age female OZR are hypertensive but do not develop impaired baroreflex‐mediated changes in heart rate (HR; Tenorio et al., 2013). The present study examined whether preserved baroreflex‐mediated changes in HR in female OZR extend to sympathetic baroreflexes and diminished activation of the NTS, and whether female OZR maintain glycemic control at this age (13–14 wks). Female OZR had excess weight gain (215±8 g vs. 483±14 g in 9 LZR and 10 OZR, P<0.05), similar to male OZR. Female rats were instrumented with indwelling femoral catheters run through a tether to record MAP and HR and infuse drugs while rats were conscious and undisturbed. As expected, female OZR had higher MAP (135±2 vs. 121±2 mmHg in 10 OZR and 7 LZR, P<0.05). However, infusion of phenylephrine (PE) to raise MAP by 40 mmHg evoked a comparable bradycardia in female OZR and LZR (−111±13 vs. −129±20 bpm in 9 OZR and 7 LZR) and c‐Fos expression in NTS (311±38 and 390±32 counts). A different set of rats was anesthetized with isoflurane for surgical preparation to measure MAP (femoral artery) and splanchnic sympathetic nerve activity (SNA) and to infuse drugs (femoral vein). Then, the rat was anesthetized with urethane (1.5g/kg iv LZR body weight), ventilated, and paralyzed. As seen with PE‐induced bradycardia, iv infusions of PE and nitroprusside to evoke wide range of MAP elicited comparable changes in SNA of female 5 OZR and 5 LZR (range, 90±16% in OZR vs. 94±3% in LZR and slope, −1.96±0.4 in OZR vs. −2.86±0.4 in LZR). As seen in males, adult female OZR were hyperinsulinemic compared to LZR (7.5±2.0 vs. 1.0±0.1 ng/dl, p<0.05). In contrast to hyperglycemia seen in male OZR, 24hr fed glucose measured by telemetry was equivalent in female OZR and LZR (95±3 vs. 89 ±1 mg/dl in 7 LZR and 6 OZR), and when challenged with glucose (1g/kg, ip) the AUC in female OZR and LZR were comparable (275±38 vs. 195±12 in 6 OZR and 6 LZR). These data suggest better maintenance of glycemic control in hypertensive, hyperinsulinemic young adult female OZR may preserve activation of the NTS and baroreflexes. In addition, these data highlight differing mechanisms for the development of hypertension and impaired control of SNA and HR by baroreflexes in the setting of metabolic syndrome.Support or Funding InformationNIHR01HL138109 to AMS AHA GRNT18880005 to AMS PRE27260088 to PCThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.