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Chronic ouabain treatment induces vasa recta endothelial dysfunction in the rat

Departments of ¹Medicine and ²Physiology, University of Maryland School of Medicine, Baltimore, Maryland

Submitted 22 July 2008 ; accepted in final form 20 October 2008

Descending vasa recta (DVR) are 15-µm vessels that perfuse the renal medulla. Ouabain has been shown to augment DVR endothelial cytoplasmic Ca²⁺ ([Ca²⁺]_CYT) signaling. In this study, we examined the expression of the ouabain-sensitive Na-K-ATPase 2 subunit in the rat renal vasculature and tested effects of acute ouabain exposure and chronic ouabain treatment on DVR. Immunostaining with antibodies directed against the 2 subunit verified its expression in both DVR pericytes and endothelium. Acute application of ouabain (100 or 500 nM) augmented the DVR nitric oxide generation stimulated by acetylcholine (ACh; 10 µM). At a concentration of 1 mM, ouabain constricted microperfused DVR, whereas at 100 nM, it was without effect. Acute ouabain (100 nM) did not augment constriction by angiotensin II (0.5 or 10 nM), whereas L-nitroarginine methyl ester-induced contraction of DVR was slightly enhanced. Ouabain-hypertensive (OH) rats were generated by chronic ouabain treatment (30 µg·kg^–1·day^–1, 5 wk). The acute endothelial [Ca²⁺]_CYT elevation by ouabain (100 nM) was absent in DVR endothelia of OH rats. The [Ca²⁺]_CYT response to 10 nM ACh was also eliminated, whereas the response to 10 µM ACh was not. The endothelial [Ca²⁺]_CYT response to bradykinin (100 nM) was significantly attenuated. We conclude that endothelial responses may offset the ability of acute ouabain exposure to enhance DVR vasoconstriction. Chronic exposure to ouabain, in vivo, leads to hypertension and DVR endothelial dysfunction, manifested as reduced [Ca²⁺]_CYT responses to both ouabain- and endothelium-dependent vasodilators.

kidney; medulla; microcirculation; nitric oxide; blood flow

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