Investigation of vascular responses in endothelial nitric oxide synthase/cyclooxygenase-1 double-knockout mice: key role for endothelium-derived hyperpolarizing …

RS Scotland, M Madhani, S Chauhan, S Moncada… - Circulation, 2005 - Am Heart Assoc
RS Scotland, M Madhani, S Chauhan, S Moncada, J Andresen, H Nilsson, AJ Hobbs
Circulation, 2005Am Heart Assoc
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 …
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.
Am Heart Assoc