Endothelial dysfunction in the aorta of transgenic rats harboring the mouse Ren-2 gene

The renin-angiotensin system plays an important role in the pathophysiology of hypertension. We studied vascular function in the aorta of mouse Ren-2 transgenic rats (TGR(mRen2)27), Changes in isometric tension of isolated ao rta of TGR(mRen2)27 and Sprague-Dawley rats (SD) were recorded in organ cha mbers. Contractions to angiotensin II (AII), big-endothelin and endothelin- l (ET-1), but not KCI were decreased in TGR. Blockade of nitric oxide (NO)- synthase by L-NAME or removal of the endothelium did not alter these decrea sed contractions to ET-I and AU in TGR, suggesting that receptors or signal ing pathways of these two agonists are downregulated during hypertension. C ontractions to norepinephrine (NE) were also lower in TGR, however blockade of NO-synthase by L-NAME or removal of the endothelium evoked similar cont ractions to NE in both strains, suggesting that basal release of NO reduces contractions to NE to a greater extent in transgenic than control rats. In the presence of L-NAME, acetylcholine evoked endothelium-dependent contr actions (EDCF) in TGR, which were blocked by the thromboxane/prostaglandin H-2 receptor antagonists SQ 30741, and partially by the thromboxane synthas e inhibitor CGS 13080, suggesting that prostaglandin H-2 is the mediator, Endothelium-dependent relaxation to acetylcholine was decreased in TGR, whi le endothelium-independent relaxations to sodium nitroprusside were similar in both strains. SQ 30741 did not improve relaxations to acetylcholine in TGR indicating that impaired relaxations to acetylcholine are due to a decr eased acetylcholine-receptor mediated release of NO rather than increased r elease of EDGE Thus, Ren-2 hypertension leads to marked alterations of vascular functions in the aorta. These changes could contribute to hypertension and its vascul ar complications in TGR(mRen2)27 rats.