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Treatment of Hypertensive Obese Zucker Rats with Metformin Enhances Phenylephrine‐Induced Bradycardia and c‐Fos Expression in the NTS
Author(s) -
Chaudhary Parul,
Schreihofer Ann
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1004.5
Subject(s) - phenylephrine , endocrinology , medicine , baroreflex , baroreceptor , microinjection , metformin , blood pressure , chemistry , insulin , heart rate
With the progression of metabolic syndrome adult obese Zucker rats (OZR) develop impaired baroreflexes that coincide with a reduced ability to activate the nucleus tractus solitarius (NTS). The NTS, which receives baroreceptor afferent inputs, appears to respond less to acute rises in mean arterial pressure (MAP) as suggested by less phenylephrine (PE)‐induced c‐Fos expression compared to age‐matched lean Zucker rats (LZR). In addition microinjection of glutamate into the NTS produces smaller reductions in splanchnic sympathetic nerve activity and MAP in adult OZR versus LZR. We have recently observed that prevention of hypertension improves baroreflexes in OZR, but they are still impaired compared to like‐treated LZR. Because hyperglycemia impairs NTS function and baroreflexes in type I diabetic rats, we hypothesized that improvement of glycemia in OZR would also enhance baroreflexes and the ability to activate the NTS. OZR and LZR were treated with metformin (MET; 300 mg/kg/day in drinking water) for 3 weeks (began at 13 weeks of age) and compared to untreated age‐matched rats. Blood samples were taken in conscious, unfasted rats at 9–10 am. Compared to untreated OZR, MET‐treated OZR had lower blood glucose levels (179±19 vs. 120±8 mg/dl, P <0.05) with no difference between untreated and treated LZR (119±6 vs. 122±6 mg/dl). In contrast, MET did not alter plasma insulin levels (in ng/ml) in either LZR or OZR (5.5±2.1 vs. 2.3±0.7 in LZR and 23±0.1 vs. 19.0±4.7 in OZR). In conscious rats fitted with indwelling femoral catheters and tethers with swivels, MAP was elevated in OZR compared to LZR (136±4 vs. 120±2 mmHg, P <0.05), and these differences persisted in OZR and LZR treated with MET (140±2 vs. 118±4 mmHg, P <0.05). Infusion of PE (iv) to raise MAP by 40 mmHg evoked a smaller bradycardia in untreated OZR vs. LZR (−52±7 vs. −120±7 bpm, P <0.05). Treatment with MET enhanced PE‐induced bradycardia in OZR (−84±12 bpm, P <0.05) but not LZR (−135±12 bpm), and MET‐treated OZR were still impaired compared to MET‐treated LZR ( P <0.05). Likewise, PE‐induced c‐Fos expression in the intermediate NTS (total bilateral counts at bregma −14.2 and −13.8 mm) was reduced in OZR compared to LZR (70±8 vs. 117±9, P <0.05), and MET treatment increased PE‐induced c‐Fos expression in OZR (170±18, P <0.05) but not LZR (154±23). These data suggest treatment with MET improves glycemia in OZR without significantly altering plasma insulin or MAP levels in either OZR or LZR. Further, these data suggest that improved glycemia in OZR partially restores baroreflex‐mediated changes in heart rate coincident with an enhanced response of the NTS to an acute rise in MAP. Further study is needed to determine whether combined treatment to prevent hypertension and improve glycemic control in OZR will normalize baroreflexes and NTS function. Support or Funding Information AHA GRNT18880005.