The goal of this study was to determine whether hypoxia alters expression of endothelial nitric oxide synthase (eNOS) in the systemic circulation. Rats breathed either air or 10% oxygen for 12 hours, 48 hours, or 7 days. Thoracic aortas were excised and either mounted in organ bath myographs or frozen in liquid nitrogen for later extraction of protein and RNA. eNOS protein (Western blotting) was decreased (20% of normoxic control) after 12 hours, 48 hours, and 7 days of hypoxia. eNOS mRNA (ribonuclease protection assay) was similarly reduced. Acetylcholine (10(-4) mol/L) reversed phenylephrine (10(-5) mol/L) preconstriction by 53.3+/-5.6% in aortic rings from normoxic rats and 26.1+/-4.8% in rings from rats exposed to hypoxia for 48 hours (P<0.05), with comparable impairment of relaxation by the calcium ionophore A23187 (10(-5) mol/L). Responses to diethylamine nitric oxide and 8-bromo-cGMP were unaffected. Aortic cGMP levels after incubation with acetylcholine (10(-6) mol/L) averaged 14.0+/-1.8 fmol/mg in rings from normoxic rats compared with 8.7+/-1.0 fmol/mg in rings from hypoxic rats (P<0. 05). Similarly, nitrate concentration (by capillary electrophoresis) in the media in which the rings were incubated was reduced in the hypoxic group (5.6+/-0.23 micromol/L for hypoxic rats and 7.8+/-0.7 micromol/L for normoxic rats). Impaired endothelial NO release may handicap the vascular responses that defend vital organ function during hypoxia.
The effect of hypercapnia on the myogenic response was determined in arterioles (80- to 100-microm internal diameter) isolated from the diaphragms of rats killed by decapitation. All arterioles were exposed to step changes in intraluminal pressure over a range of 10-200 mmHg and had no flow through their lumen. In five separate groups of vessels (n = 7 per group), PCO2 of the superfusing buffer was adjusted to 40, 60, 80, 90, or 100 mmHg. In three further groups of vessels (n = 7 per group), the endothelium was removed by low-pressure air perfusion (2 ml at 20 mmHg) and PCO2 of the superfusing buffer was adjusted to 40, 80, or 100 mmHg. In endothelium-intact vessels, increasing PCO2 to 80 mmHg enhanced the myogenic response, as reflected by a negative slope of the pressure-diameter relationship (slope = -0.164 +/- 0.03 vs. 0.004 +/- 0.02 for vessels at PCO2 = 40 mmHg, P < 0.05). With a PCO2 of 100 mmHg, dilation accompanied increasing intraluminal pressure and the slope of the pressure-diameter curve was positive (0.154 +/- 0.03, P < 0.05 for difference from vessels at PCO2 = 40 mmHg). In deendothelialized vessels, the curve was shifted upward in a parallel manner during exposure to increased PCO2 levels. Moderate hypercapnia (PCO2 < 80 mmHg) elicits endothelium-dependent enhancement of myogenic tone. Severe hypercapnia (PCO2 > 80 mmHg) inhibits myogenic tone through a direct effect on vascular smooth muscle and through endothelium-dependent inhibitory mechanisms.
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