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.
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).


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.
Scotland
Ramona S
RS
Wolfson Institute for Biomedical Research, University College London, London, United Kingdom.
Madhani
Melanie
M
Chauhan
Sharmila
S
Moncada
Salvador
S
Andresen
Jørgen
J
Nilsson
Holger
H
Hobbs
Adrian J
AJ
Ahluwalia
Amrita
A
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D001920:Bradykinin / Q000494:pharmacology; D002200:Capillary Resistance / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D051545:Cyclooxygenase 1; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology / Q000379:methods; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*; D045462:Endothelium-Dependent Relaxing Factors / Q000378:metabolism; D005260:Female; D005838:Genotype; D008297:Male; D008565:Membrane Proteins; D008638:Mesenteric Arteries / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011451:Prostaglandin-Endoperoxide Synthases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D014655:Vascular Resistance / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000235:genetics
D045462:Endothelium-Dependent Relaxing Factors; D008565:Membrane Proteins; D015121:6-Ketoprostaglandin F1 alpha; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D051545:Cyclooxygenase 1; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D000109:Acetylcholine; D001920:Bradykinin