on February 7, 2005
Published online before print February 7, 2005, doi: 10.1161/01.CIR.0000155238.70797.4E
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Submitted on June 21, 2004
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. * To whom correspondence should be addressed. E-mail: a.ahluwalia{at}qmul.ac.uk.
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.
Revised on September 27, 2004
Accepted on October 5, 2004
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,
Key words: endothelium • hypertension • nitric oxide
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Circulation 2005 111: 724-727.
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