Abstract 183: High Intraluminal Pressure Reduces AT1 Receptor Internalization and Maintains Arteriolar Constrictions to Angiotensin II
Previously we found that high intraluminal pressure upregulates several components of the renin-angiotensin system in the arterial wall. We hypothesized, that exposure of microvessels to high intraluminal pressure interferes with type 1 angiotensin II (AT1) receptor internalization leading to sustained availability of the AT1 receptors and maintained Ang II-induced constrictions. We have found that in isolated rat skeletal muscle arterioles (~ 150 μm) Ang II-induced constrictions decreased significantly by the second applications (from 59 ± 4% to 26 ± 5%, at 10−8 M, p<0.05), if the intraluminal pressure was maintained at a normotensive level (80 mmHg). In contrast, if arterioles were exposed to high intraluminal pressure (160 mmHg, for 30 min) Ang II-induced constrictions remained substantial upon second applications (51 ± 3% at 10−8 M). Responses to norepinephrine (10−7 M) were unaffected by the levels of intraluminal pressure. Furthermore, in pressurized arteries, AT1 receptor internalization was measured by radiolabeled Ang II binding assay. At normal intraluminal pressure acid resistant (i.e. internalized) Ang II (10−8 M) binding was 59 ± 5% of the total binding, which was significantly reduced to 38 ± 5% by high pressure exposure. These findings are the first to show that high intraluminal pressure via reducing AT1 receptor internalization, maintains the Ang II-induced constrictions of resistance arterioles. We propose that in hypertension a sustained availability of AT1 receptors contributes to the enhanced Ang II-induced vascular signaling even in the presence of low levels of circulating Ang II. This mechanism may explain the beneficial effects of angiotensin converting enzyme inhibitors and AT1 receptor blockers in several forms of hypertension.