substance-p--phe(5)-trp(7-9)-leu(11)- and Hypertension

Excess weight gain contributes up to 65% of the risk of primary hypertension, and the increase in blood pressure in response to high-fat diet (HFD) is preceded by significant increases in renal tubular sodium (Na(+)) reabsorption. In normal rats, intrarenal ghrelin infusion increases distal nephron-dependent Na(+) reabsorption via activation of the intrarenal ghrelin receptor (GHSR). This study focusses on the role of intrarenal GHSR-mediated Na(+) reabsorption in HFD-induced hypertension. Dahl salt-sensitive rats received standard diet or HFD for 6 weeks. Rats underwent uninephrectomy and osmotic minipump implantation for chronic intrarenal delivery of vehicle (0.25 μL/h × 28 d), selective GHSR antagonist [D-Lys-3]-growth hormone releasing peptide-6 (0.2μM/d), or GHSR inverse agonist [D-Arg(1), D-Phe(5), D-Trp(7,9), Leu(11)]-substance P (SUB-P) (3.6μM/d). HFD rats with vehicle pumps had significantly increased renal GHSR expression compared with standard diet (0.092 ± 0.005 vs 0.065 ± 0.004 arbitrary units; P < .05), whereas acyl ghrelin levels were similar (16.3±6.2 vs 15.7±8.7 pg/g tissue). HFD rats with vehicle pumps became hypertensive after 2 weeks (P < .05) and showed a significant reduction in 24-hour urine Na(+) before hypertension. At this time, these rats showed an increase in collecting duct α-epithelial Na(+) channel, thereby providing a potential mechanism for the excess Na(+) reabsorption. In contrast, HFD rats with [D-Lys-3]-growth hormone releasing peptide-6 or SUB-P pumps never became hypertensive and did not show the reduction in urine Na(+). Because SUB-P blocks the constitutive, but not ghrelin-dependent, activity of the GHSR, and HFD-induced α-epithelial Na(+) channel up-regulation was abolished during GHSR antagonism, these data suggest that HFD increases the constitutive activity of renal GHSR to increase Na(+) reabsorption and induce hypertension in rats.

Topics: Animals; Blotting, Western; Body Weight; Diet, High-Fat; Eating; Ghrelin; Hypertension; Kidney; Male; Nephrectomy; Oligopeptides; Rats; Rats, Inbred Dahl; Rats, Sprague-Dawley; Receptors, Ghrelin; Sodium; Substance P; Time Factors