Pulmonary vascular iNOS induction participates in the onset of chronic hypoxic pulmonary hypertension

Abstract

Pathogenesis of hypoxic pulmonary hypertension is initiated by oxidative injury to the pulmonary vascular wall. Because nitric oxide (NO) can contribute to oxidative stress and because the inducible isoform of NO synthase (iNOS) is often upregulated in association with tissue injury, we hypothesized that iNOS-derived NO participates in the pulmonary vascular wall injury at the onset of hypoxic pulmonary hypertension. An effective and selective dose of an iNOS inhibitor, L-N 6 -(1-iminoethyl)lysine (L-NIL), for chronic peroral treatment was first determined (8 mg/l in drinking water) by measuring exhaled NO concentration and systemic arterial pressure after LPS injection under ketamineϩxylazine anesthesia. A separate batch of rats was then exposed to hypoxia (10% O2) and given L-NIL or a nonselective inhibitor of all NO synthases, N G -nitro-L-arginine methyl ester (L-NAME, 500 mg/l), in drinking water. Both inhibitors, applied just before and during 1-wk hypoxia, equally reduced pulmonary arterial pressure (PAP) measured under ketamineϩxylazine anesthesia. If hypoxia continued for 2 more wk after L-NIL treatment was discontinued, PAP was still lower than in untreated hypoxic controls. Immunostaining of lung vessels showed negligible iNOS presence in control rats, striking iNOS expression after 4 days of hypoxia, and return of iNOS immunostaining toward normally low levels after 20 days of hypoxia. Lung NO production, measured as NO concentration in exhaled air, was markedly elevated as early as on the first day of hypoxia. We conclude that transient iNOS induction in the pulmonary vascular wall at the beginning of chronic hypoxia participates in the pathogenesis of pulmonary hypertension. pulmonary circulation; nitric oxide; rat; inducible nitric oxide synthase SINCE THE DISCOVERY THAT NITRIC OXIDE (NO) is formed in mammalian cells as an endogenous mediator, many attempts were made to define its possible role in the pathogenesis of pulmonary hypertension (reviewed in Ref. 23). Although the capacity of lung vessels to produce NO can be reduced in terminal phases of severe pulmonary hypertension (15), possibly due to the progressive endothelial damage, less advanced stages (at least in adults) are associated with increased expression of NO synthase (NOS) and augmented NO production (reviewed in Ref. 23). This is particularly well documented in the frequently used and clinically relevant model of pulmonary hypertension elicited by chronic hypoxia.In principle, as the actions of NO in the body are multifaceted, two main functional consequences of the elevated lung NO synthesis in chronic hypoxic pulmonary hypertension are possible. On one hand, the vasodilator and antiproliferative effects of NO may limit the extent of pulmonary vascular resistance elevation. This possibility is supported by numerous reports that acute administration of NOS blockers, such as N G -nitro-L-arginine methyl ester (L-NAME), increases perfusion pressure in lungs isolated from chronically hypoxic animals more than in normoxic controls (rev...

Regulatory Effect of Hydrogen Sulfide on Vascular Collagen Content in Spontaneously Hypertensive Rats

“…Recent studies have revealed that gaseous molecules such as nitric oxide (NO) and carbon monoxide (CO) play important roles in the pathogenesis of vascular structural remodeling (4,9,10). In vitro experimental studies have revealed that relative cell size, total protein content per cell, and the number of polyploid cells were significantly decreased in VSMCs isolated from SHRs after chronic L-arginine treatment (11).…”

Pulmonary Hypertension Is a Probable NO/ONOO−Cycle Disease: A Review

“…One type of evidence that strongly supports such a local mechanism is the response of the disease to lung transplantation [23,24]. e local nature of the �brosis and remodeling, discussed in the previous paragraph, also supports a local mechanism, as do various other types of histological studies, showing local changes [25][26][27][28].…”

“…ey concluded that "TRPV1 may be a critical pathway or mediator in chronic hypoxia-induced proliferation of human pulmonary artery smooth muscle cells. " Hampl et al [26] and Palmer et al [106] showed that hypoxia induces iNOS in the pulmonary arteries. Loot and Fleming [107] showed that hypoxia-mediated vasoconstriction in the mouse was associated with increased calcium in�ux in mouse pulmonary arteries but that there was much lower calcium in�ux and much lower vasoconstriction when the arteries came from a transgenic mouse missing the TRPC6 receptor.…”

Direct effect of cigarette smoke on human pulmonary artery tension

“…Cigarette smoke leads to the induction of iNOS expression in pulmonary arteries [9][10][11]. To understand the relaxing effect of CSE on 5-HT-induced pulmonary arterial tension, we examined the pattern of iNOS expression in the pulmonary arteries of the M A N U S C R I P T…”

“…In smokers and COPD patients, CSE causes intimal thickening in small pulmonary muscular arteries, which increases pulmonary resistance [8]. In contrast to its effect on eNOS, cigarette smoke leads to the induction of inducible nitric oxide synthase (iNOS) expression, especially in the media of the pulmonary vessels; this has been explained as compensatory vasodilator and antiproliferative effects of NO to limit the extent of pulmonary vascular resistance [9][10][11]. In contrast, NO may contribute to oxidative injury to the walls of the pulmonary vessels, which appears to initiate their morphological remodelling [12].…”