Vascular hyperresponsiveness in perfused lungs from monocrotaline-treated rats

Abstract

Studies were conducted in isolated, buffer-perfused lungs to determine whether altered pulmonary vascular responsiveness could contribute to the evolution of monocrotaline (MCT)-induced pulmonary hypertension. Adult male rats were given a single subcutaneous injection of either 105 mg/kg MCT or its vehicle and vascular responsiveness to angiotensin II, ventilatory hypoxia (3% O2), and KCl was assessed in isolated, buffer-perfused lungs at 4, 7, and 14 days post-treatment. Relative to preparations derived from control animals, vasopressor responses induced by 0.1 microgram, but not 0.05 microgram angiotensin, were augmented at 4 and 7 days but not at 14 days post MCT. Pulmonary vasoconstriction evoked by hypoxic ventilation was enhanced at 4 days but not at 7 or 14 days posttreatment. Pressor responses induced by 30 and 45 mg KCl were not different in treated animals relative to controls at any time post-MCT administration. MCT provoked perivascular edema, but this factor did not seem to contribute to vascular hyperresponsiveness, since the time course of edema did not parallel the time course of augmented responsiveness. Results of the present study indicate that MCT, by an unknown mechanism, causes an early and transient increase in pulmonary vascular responsiveness to some but not all vasoconstrictors. Because the enhanced responsiveness occurred prior to development of pulmonary hypertension, it is unlikely that this alteration contributes to the sustained elevation in pulmonary arterial pressure.

Impaired Vasoconstriction and Nitric Oxide-Mediated Relaxation in Pulmonary Arteries of Hypoxia- and Monocrotaline-Induced Pulmonary Hypertensive Rats

“…In the isolated perfused lung, Gillespie et al (1986) demonstrated that pulmonary vascular responsiveness to angiotensin II, but not high KCl, was augmented in MCT-treated rats at days 4 and 7, but not at day 14. Our findings of decreased PHE-induced pulmonary artery contraction on day 28 after MCT treatment are consistent with this report, and suggest that, although some enhanced responsiveness may occur before development of PH, this early alteration may not contribute to the sustained elevation in pulmonary arterial pressure.…”

“…Large vessels such as the aorta, skeletal muscle, and diaphragmatic and mesenteric arterioles could be affected (Doyle and Walker, 1991;Kuwahira et al, 1993;Toporsian and Ward, 1997;Auer and Ward, 1998). Although MCT treatment may cause both pulmonary and systemic vascular inflammation and endothelial damage, MCT-treated rats have been used as a model of progressive lung injury and PH (Gillespie et al, 1986;Fullerton et al, 1996). In our hypoxia and MCT models of PH, we found no changes in the responsiveness of the mesenteric vessels jpet.aspetjournals.org to vasoconstrictor or vasodilator stimuli, indicating specific changes in the pulmonary but not the systemic circulation in experimental PH.…”

“…Previous studies have examined pulmonary vascular function in animal models of PH with variable results (Adnot et al, 1991;Fullerton et al, 1996;Gillespie et al, 1986;Shimoda et al, 2000;Barman, 2007). The variable results could be due to differences in the pulmonary hypertensive animal model, the experimental preparation (isolated perfused lung versus vascular rings), or the vasoactive mediators used.…”

Improved pulmonary vascular reactivity and decreased hypertrophic remodeling during nonhypercapnic acidosis in experimental pulmonary hypertension

“…We and others have shown that PH in hypoxic and MCT-treated rats is associated with reduced pulmonary responsiveness to vasoconstrictors and endogenous and exogenous nitrovasodilators (2,25,27,50,67) and extensive pulmonary arteriolar thickening and remodeling (9,12,44,50,53,59). Multiple mechanisms may contribute to pulmonary vascular remodeling in PH including resident medial pulmonary VSMC hypertrophy and hyperplasia and a phenotypic switch from a contractile to a synthetic phenotype; transdifferentiation of circulating and resident progenitor, adventitial, or endothelial cells to a VSMC-like phenotype; and intimal and adventitial changes.…”

Renin-angiotensin II response to the hemodynamic pathology of ovines with ventricular septal defect.

“…12 Furthermore, the RAS is known to respond to pathologic alterations in cardiac performance. 3 Adult humans 4 and probably children 3 show a stimulation in RAS activity with congestive heart failure.…”