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(Circulation. 2005;111:796-803.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Investigation of Vascular Responses in Endothelial Nitric Oxide Synthase/Cyclooxygenase-1 Double-Knockout Mice

Key Role for Endothelium-Derived Hyperpolarizing Factor in the Regulation of Blood Pressure in Vivo

Ramona S. Scotland, PhD; Melanie Madhani, PhD; Sharmila Chauhan, PhD; Salvador Moncada, MD, PhD; Jørgen Andresen; Holger Nilsson, PhD; Adrian J. Hobbs, PhD; Amrita Ahluwalia, PhD

From the Wolfson Institute for Biomedical Research (R.S.S., M.M., S.M., A.J.H.), University College London, London, United Kingdom; Clinical Pharmacology (S.C., A.A.), William Harvey Research Institute, London, United Kingdom; and the Institute of Physiology and Biophysics (J.A., H.N.), University of Aarhus, The Water and Salt Research Center, Aarhus, Denmark.

Correspondence to Dr Amrita Ahluwalia, Clinical Pharmacology, William Harvey Research Institute, Barts and The London, Charterhouse Square, London EC1M 8BQ, UK. E-mail a.ahluwalia{at}qmul.ac.uk

Received June 21, 2004; revision received September 27, 2004; accepted October 5, 2004.

Background— Endothelium-dependent dilatation is mediated by 3 principal vasodilators: nitric oxide (NO), prostacyclin (PGI₂), and endothelium-derived hyperpolarizing factor (EDHF). To determine the relative contribution of these factors in endothelium-dependent relaxation, we have generated mice in which the enzymes required for endothelial NO and PGI₂ production, endothelial NO synthase (eNOS) and cyclooxygenase-1 (COX-1), respectively, have been disrupted (eNOS^–/– and COX-1^–/– mice).

Methods and Results— In female mice, the absence of eNOS and COX-1 had no effect on mean arterial blood pressure (BP), whereas BP was significantly elevated in eNOS^–/–/COX-1^–/– males compared with wild-type controls. Additionally, endothelium-dependent relaxation remained intact in the resistance vessels of female mice and was associated with vascular smooth muscle hyperpolarization; however, these responses were profoundly suppressed in arteries of male eNOS^–/–/COX-1^–/– animals. Similarly, the endothelium-dependent vasodilator bradykinin produced dose-dependent hypotension in female eNOS^–/–/COX-1^–/– animals in vivo but had no effect on BP in male mice.

Conclusions— These studies indicate that EDHF is the predominant endothelium-derived relaxing factor in female mice, whereas NO and PGI₂ are the predominant mediators in male mice. Moreover, the gender-specific prevalence of EDHF appears to underlie the protection of female eNOS^–/–/COX-1^–/– mice against hypertension.

Key Words: endothelium • hypertension • nitric oxide

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