P253	Transgenic rat models of the human ETA receptor develop arterial hypertension and show blunted response to adrenergic receptor stimulation.
1A.Saxena, 1F.Zollmann, 1S.Kliesch, 1S.Gschwend, 2M.Bader, 3A.Oksche, 1M.Paul, 1H-D.Orzechowski
1Charité - Campus Benjamin Franklin, Institute of Clinical Pharmacology and Toxicology, Berlin, DE; 2Max-Delbruck Center, Berlin, DE; 3Institute of Pharmacology, Berlin, DE.

Pharmacological studies in rat models have revealed contradictory results with respect to the role of the ETA receptor in arterial hypertension and associated vascular hypertrophy. To address a putatively causal role of ETA in hypertension and vascular remodelling, we established transgenic models overexpressing the human ETA receptor in vascular smooth muscle cells. An expression construct containing human ETA cDNA under control of a 1.3 kB fragment of the murine SM22[α] promoter was microinjected in fertilised oocytes of Sprague-Dawley rats. Five transgene-positive (tg) founders were identified by genomic PCR and two established tg lines (L6351 and L6878) were investigated in detail. (1) Construct copy number and transgene-specific transcript levels were analysed by real-time PCR. (2) Despite significant downregulation of endogenous ETA mRNA, we found 9-fold increased ETA-specific binding to mesenteric artery, but not to aortic membranes of tg L6351 rats. Unexpectedly, mesenteric ETB-specific binding was also more than 6-fold increased in tg L6351 transgenic rats. (3) Compared to controls, tg animals (L6351) showed significantly (p< 0.001) increased basal blood pressure (e.g., +73 mm Hg systolic). Maximum increments in blood pressure after ET-1 bolus injection were not different. However, phenylephrine (PE) bolus injection showed significantly (p>0.001) attenuated systolic arterial pressure response in tg animals (L6351: -45%, L6878: -77%). (4) Pressurized (70 mm Hg) isolated mesenteric arteries (L6351) showed significantly increased sensitivity against ET-1, but maximal constriction was unchanged. Mesenteric artery constriction to PE was significantly decreased (-65%) in tg rats (L6351, L6878), whereas constriction to TXA2 agonist or Angiotensin II remained unaltered. The functional and structural vascular phenotype of our ETA transgenic rats not only provides evidence of its pathophysiological role in vivo, but has revealed a specific interaction of the endothelin with the adrenergic system.

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