Based on results obtained during the current project period, I propose to test the hypothesis that hyperinsulinemia contributes importantly to cardiovascular and baroreflex dysfunction during dietary-induced obesity in rats. Obese rats will be produced by programming pups to overeat and then maintaining them on a high-fat diet immediately after weaning. Blood pressure will be monitored routinely by tail-cuff measurement and any changes thereby detected will be verified by direct intra-arterial recording in the same rats. Initial experiments will determine whether the cardiovascular and baroreflex alterations associated with obesity can be reversed or alleviated by dietary restriction or exercise training. Other experiments will attempt to replicate the cardiovascular and baroreflex impairment in obese rats by chronic intravenous infusion of exogenous insulin in normotensive non-obese rats. Similar measurements will be done during intracerebroventricular infusions to determine whether insulin affects cardiovascular and baroreflex function by acting centrally. Assuming that obesity predisposes rats to hypertension, the additive effects of aortic coarctation or DOCA-salt hypertension in obese rats, or of combining dietary-induced obesity with other predisposing factors will also be studied.
My specific aims will be to: (1) establish whether rats with dietary-induced obesity are reasonable models for obesity-hypertension in man by finding out if dietary restriction and/or exercise will restore normal cardiovascular and baroreflex function, (2) record cardiovascular and baroreflex effects of chronic intravenous or intracerebroventricular infusions of insulin in normotensive non-obese rats, and (3) quantify cardiovascular and baroreflex function in before and after induction of aortic-coarctation or DOCA-salt hypertension. By using rats with dietary-induced obesity as models for obesity-hypertension in man, underlying mechanisms can be explored and identified to improve our understanding of how obesity predisposes to hypertension.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular and Renal Study Section (CVB)
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University of Kansas
Schools of Medicine
Kansas City
United States
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Bunag, R; Mellick, J; Allen, B (1999) Abated cardiovascular responses to chronic oral lisinopril treatment in conscious elderly rats. Am J Physiol 276:R1408-15
Bunag, R D; Davidow, L W (1996) Aging impairs heart rate reflexes earlier in female than in male Sprague-Dawley rats. Neurobiol Aging 17:87-93
Bunag, R D; Meyer, M; Vansell, N et al. (1996) Conscious obese rats have impaired reflex bradycardia and enhanced norepinephrine sensitivity. Am J Physiol 271:R654-60
Okada, M; Bunag, R D (1994) Insulin acts centrally to enhance reflex tachycardia in conscious rats. Am J Physiol 266:R481-6
Davidow, L W; Schmitz, T M; Bunag, R D (1994) Aging enhances serotonergic cardiovascular blockade by ketanserin in conscious rats. Aging (Milano) 6:239-48
Okada, M; Bunag, R D (1994) Selective enhancement in SHR of hypotension and bradycardia caused by NTS-injected serotonin. Am J Physiol 266:R599-605
Bunag, R D; Krizsan-Agbas, D; Itoh, H (1991) Sympathetic activation by chronic insulin treatment in conscious rats. J Pharmacol Exp Ther 259:131-8
Barringer, D L; Bunag, R D (1991) Autonomic regulation of reflex bradycardia in rats declines with age. Exp Gerontol 26:65-75
Eriksson, L; Kerecsen, L; Bunag, R D (1991) Strain differences in baroreflex inhibition by centrally infused enalapril in old rats. J Gerontol 46:B65-71
Bunag, R D; Teravainen, T L (1991) Waning cardiovascular responses to adrenergic drugs in conscious ageing rats. Mech Ageing Dev 61:313-26

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