The effects of agents that bind to cytochrome P-450 on hypoxic pulmonary vasoconstriction.

Abstract

SUMMARY The relationship between pulmonary arterial pressure (Ppa) and blood flow (Q) was determined during normoxia and hypoxia in ventilated pig lungs perfused in situ with the animal's own blood. Hypoxia shifted the Ppa-Q relationship to the right and decreased its slope, indicating pulmonary vasoconstriction. Carbon monoxide (11.5% in the inspired gas) and metyrapone ditartrate (10 mg/min into the perfusate) caused vasodilation when oxygenation was normal and reduced the vasoconstriction caused by hypoxia. Since the only pharmacological property CO and metyrapone are thought to have in common at the concentrations employed is the ability to bind to the heme iron of cytochrome P-450, these results are consistent with the hypothesis that desaturation of this cytochrome leads to pulmonary vasoconstriction. Prostaglandin F 2a , infused into the pulmonary artery at 0.01 mg/min, when oxygenation was normal, had effects on the Ppa-Q relationship similar to those of hypoxia. The F 2o response was also reduced by CO and metyrapone, suggesting either that P-450 was involved in the F 2o response or that CO and metyrapone were toxic to pulmonary vascular smooth muscle. Proadifen hydrochloride (1 mg/min), which is thought to bind to the protein moiety of P-450, also reduced the hypoxic response, but was a vasoconstrictor during normoxia and did not affect the F 2 ,, response.

Relationship between alveolar PO2 and the rate of p-nitroanisole O-demethylation by the cytochrome P-450 pathway in isolated rabbit lungs.

“…The results presented in this study provide some evidence to define whether cytochrome P-450 may fuinction physiologically as a carrier to facilitate oxygen transport or as a sensor of alveolar hypoxia as proposed by other investigators (8)(9)(10). These functions require the effeCts of 02 to be manifest at Po2 levels approximnately 100-fold greater than those found to inhibit p-nitroanisole O-demethylation in the rabbit lung.…”

“…This biotransformation may inactivate some compounds (2) but in other cases may generate toxic (6) or carcinogenic species (7). It has been suggested recently that the cytochrome P-450 system may have additional functions in the lung to facilitate oxygen diffusion (8) or to mediate the pulmonary arterial response to hypoxia (9,10). These latter potential roles would be expected to be critically dependent upon the affinity of the pulmonary cytochrome P-450 system for 02 However, this information for the pulmonary cytochrome P-450 system is lacking.…”

5-Aminolevulinic acid combined with ferrous iron induces carbon monoxide generation in mouse kidneys and protects from renal ischemia-reperfusion injury

“…Previous studies have shown that CO could regulate nonadrenergic/ noncholinergic intestinal relaxation (50,68), intrahepatic vascular resistance (58), pulmonary vascular resistance (59), and relaxation of tail artery tissues (66). Exogenously delivered CO has exerted potent protective functions in numerous experimental models of inflammation, sepsis/endotoxemia, hemorrhagic shock, autoimmune diseases, and fibrosis (7,18,52,57,65,70).…”

Carbon Monoxide: Endogenous Production, Physiological Functions, and Pharmacological Applications

“…The relaxation of pulmonary vasculature induced by exogenous CO under nomoxic conditions was reported as early as the late 1970s (Sylvester and McGowan, 1978). However, cardiovascular researchers struggled for many years to find the evidence for the vasoactive effect of endogenous CO. By inhibiting HO activity with zinc protoporphyrin-IX (ZnPP), Suematsu et al (1994) provided the evidence that ZnPP treatment reduced endogenous CO generation and increased vascular resistance in rat liver.…”