OR-15: Vascular protective effects of selective sodium transport inhibition in stroke-prone hypertensive rats

Abstract

We previously reported that mineralocorticoid receptor antagonists and amiloride markedly reduced proteinuria and vascular injury in saline-drinking stroke-prone spontaneously hypertensive rats (SHRSP). By inhibiting epithelial sodium channels (ENaC) and sodium-hydrogen exchange (NHE), these agents interfere with sodium transport in the kidney and at extrarenal sites. Presently, we examined whether benzamil (BENZ), an ENaC inhibitor with little NHE inhibitory activity, and dimethylamiloride (DMA), an NHE inhibitor with no ENaC activity, would also protect against the development of pathology in these rats. Saline-drinking SHRSP were infused with either propanediol (vehicle, n=7), DMA (0.7 mg/Kg/day, n=8) or BENZ (0.7 mg/Kg/day, n=8) via subcutaneous osmotic minipumps starting at 8.3 weeks of age. New minipumps were implanted every two weeks. Systolic blood pressure (SBP) was 228±5, 231±4 and 226±3 mm Hg in vehicle-, DMA- and BENZ-treated SHRSP, respectively, at 10 weeks of age and remained severely elevated with no differences among the groups throughout the study. Five of seven vehicle-treated SHRSP showed signs of stroke and all died by 12.7±0.2 weeks of age. In contrast, DMA-treated SHRSP survived until 14.8±0.6 weeks of age (P<.005 vs vehicle) and BENZ-treated SHRSP lived longer still (16.1±0.2 weeks of age; P<.0001 vs vehicle, P<.05 vs DMA). At 11 weeks of age, urinary protein excretion in DMA-treated (14±1 mg/d) and BENZ-treated (14±2 mg/d) SHRSP was significantly lower (P<.02) than in control SHRSP (41±13 mg/d) which is consistent with a delayed onset of kidney damage. Plasma potassium levels measured in a separate series of saline-loaded SHRSP were significantly (P<.05) elevated at 4h after acute subcutaneous injections of 1 mg/Kg of DMA (3.4±0.1 mEq/L, n=8) or BENZ (3.3±0.1 mEq/L, n=8) relative to vehicle alone (3.0±0.1 mEq/L, n=8) but not at 24h after dosing. These findings support a role for both NHE- and ENaC-mediated sodium transport processes in the evolution of vascular injury in saline-drinking SHRSP. The vascular protection achieved at the low doses of inhibitors employed in this study does not appear to be related to major or sustained alterations in SBP or plasma potassium.

Stroke-Prone Hypertensive Rats, Epithelial Sodium Channel Inhibition, Sodium Hydrogen Exchange Inhibition