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Increased salt sensitivity secondary to leptin resistance in SHHF rats is mediated by endothelin
Authors:Radin  M. Judith  Holycross   Bethany J.  Hoepf  Toni M.  McCune  Sylvia A.
Affiliation:(1) Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA;(2) The Dorothy M. DAvis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA;(3) Department of Food Science and Technology, The Ohio State University, Columbus, OH 43210, USA
Abstract:
A link between leptin resistance, obesity, and salt sensitivity has been suggested. SHHF/Mcc-facp rats (SHHF) were used to study the effect of gene dosage of a null mutation of the leptin receptor (cp) on salt sensitivity and response to a combined endothelin A and B receptor antagonist (bosentan). Obese (cp/cp), heterozygous (+/cp), and homozygous lean (+/+) male SHHF were fed a low salt diet (0.3% NaCl) for 7 days, followed by a high salt diet (8.0% NaCl) for 7 days. There were no significant differences in systolic blood pressure between genotypes on low salt. In response to high salt, cp/cp had significantly greater systolic pressure than +/cp and +/+. On high salt diet, cp/cp showed a significant increase in 24 h urinary endothelin excretion and increased renal expression of preproendothelin mRNA. There was no effect of high salt diet on renal excretion of nitric oxide (NOx) or on gene expression of endothelial, neuronal, or cytokine-induced nitric oxide synthase isoforms (eNOS, nNOS, iNOS, respectively). Treatment with bosentan prevented the high salt-induced increment in systolic blood pressure in cp/cp. This was associated with a doubling of renal NOx excretion, but without changes in eNOS, nNOS, or iNOS expression. Endothelin receptor antagonism did not normalize systolic pressure in any of the genotypes. Our studies indicate that obesity secondary to leptin resistance (cp/cp) results in increased salt sensitivity that is mediated by endothelin in the SHHF rat.
Keywords:hypertension  leptin  endothelin  salt sensitivity  SHHF rat  obesity  nitric oxide
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