Primary pulmonary hypertension (PPH) is a disease characterized pathologically by pulmonary artery medial hypertrophy, adventitial thickening, and neointimal proliferation. Increasing recognition of the importance of remodeling to the pathogenesis of PPH suggests new therapeutic possibilities, but it will be necessary to (1) identify essential mediators of remodeling, and (2) demonstrate that inhibiting those mediators suppresses remodeling before new antiremodeling therapies can be considered feasible. The effect of angiotensin-converting enzyme (ACE) inhibition on pulmonary vascular remodeling was studied in a newly developed rat model in which neointimal lesions develop between 3 and 5 wk after monocrotaline injury is coupled with increased pulmonary artery blood flow after contralateral pneumonectomy. Neointimal formation was significantly suppressed at 5 wk by ACE inhibition whether it was started 10 d before or 3 wk after remodeling was initiated, although medial hypertrophy and adventitial thickening still developed. By 11 wk, the extent of neointimal formation in rats treated with ACE inhibition was similar to rats without ACE inhibition at 5 wk. Pulmonary artery pressures and right ventricular weights correlated with the extent of neointimal formation. Northern blot analysis and in situ hybridization demonstrated marked suppression of lung tropoelastin and type I procollagen gene expression in the presence of ACE inhibition. An angiotensin II type I receptor antagonist partially, but not completely, replicated the effects of ACE inhibition. These data suggest that the tissue angiotensin system may be a target for therapeutic efforts to suppress the vascular remodeling that is characteristic of primary pulmonary hypertension.
The effects of surface-induced deep hypothermia on organ blood flow and on the distribution of cardiac output were investigated in the anesthetized dog. Organ flows were determined by the radioactive microsphere technique. Phenoxybenzamine (POB) was administered prior to hypothermia to minimize vasoconstriction and hence facilitate cooling. Measurements were made before POB, on stabilization after POB, and during hypothermia. Cardiac output was reduced by POB as was blood flow to the pancreas, small intestine, and skeletal muscle. Hypothermia, following POB, produced a further fall in Q and during this maneuver blood flow fell in all organs and vascular beds studied. The relative distribution of Q during hypothermia was essentially the same as in the control except the brain, kidneys, and pancreas received a smaller fraction of the total output. The relatively normal distribution of a reduced cardiac output during hypothermia was in marked contrast to distribution of comparable low cardiac output induced by hemorrhage. In the latter condition, the fraction of the cardiac output perfusing the brain, kidneys, adrenals, and hepatic artery was increased.
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