Abstract 236: Reduced Epigastric Artery Reactivity in a Non-Modulator Phenotype of Human Hypertension

Abstract

In normal and modulator hypertensive individuals sodium intake modifies plasma levels and target tissue response to ANG II. This sodium-mediated modulation is defective in 25-30% of the hypertensive population, termed non-modulators. Non-modulators have insulin resistance (IR), abnormal renal function, polymorphisms in the renin-angiotensin-aldosterone system (RAAS) genes, increased tissue levels of ANG II particularly during liberal dietary sodium intake, and increased risk of cardiovascular (CV) damage. We hypothesized that the increased risk of CV damage in non-modulators reflects abnormalities in vascular function. Male hypertensive subjects were placed on restricted salt diet 10 mmol/day for 7 days and phenotyped as modulators (PRA 8.7 ng/ml/hr, HOMA-IR 1.0, ALDO 18.85 ng/dl, n=4, age ≈48) and non-modulators (PRA 8.8 ng/ml/hr, HOMA-IR 1.7, ALDO 8.52 ng/dl, n=3, age ≈60). The subjects were then placed on liberal salt diet (HS, 200 mmol/day for 7 days), BP was measured, then underwent subcutaneous surgery to isolate the superficial inferior epigastric artery for ex vivo vascular function studies. Systolic BP was 144.8 in modulators and 142.0 mmHg in non-modulators. Diastolic BP was 88.5 in modulators and 87.3 mmHg in non-modulators. In epigastric arteries, contraction to ANG II, phenylephrine (Phe), and KCl was less in non-modulators (0.24, 0.56, and 0.53) than in modulators (0.8, 1.43, and 1.1 g/mg tissue). Endothelium-dependent relaxation to acetylcholine (ACh) was not different between non-modulators (22.1) and modulators (22.6%). Bradykinin caused larger endothelium-dependent relaxation than ACh, but was still not different in non-modulators (57.8) vs. modulators (46.3%). In contrast, endothelium-independent relaxation to the nitric oxide (NO) donor sodium nitroprusside was reduced in non-modulators (64.2) vs. modulators (92.5%). The reduced vascular responsiveness to ANG II in non-modulators is consistent with increased vascular tissue RAAS activity, and desensitization to ANG II. The reduced vascular reactivity to the vasoconstrictors Phe and KCl and the vasodilator NO donors is consistent with vascular smooth muscle dysfunction and may explain the increased risk of CV damage in non-modulators during HS dietary intake.