Pulmonary vascular adaptations to augmented polycythemia during chronic hypoxia.

We previously found that augmentation of polycythemia by exogenous human recombinant erythropoietin (EPO) failed to worsen the severity of hypoxic pulmonary hypertension in rats. We asked whether this unexpected finding was related to reductions in cardiac output, left ventricular end-diastolic pressure, pulmonary vascular resistance, or some combination of these factors. Four groups of Sprague-Dawley rats were studied over a 3-wk period: hypoxic (0.5 ATM) and normoxic animals each injected with EPO (500 U/kg sc thrice weekly) or saline (control animals). As observed previously, we found that pulmonary arterial (PA) pressures and right ventricular hypertrophy were not increased in EPO-treated rats despite significant increases in hematocrit and blood viscosity. Cardiac outputs, blood volumes, and left ventricular end-diastolic pressures were similar in EPO-treated and control rats. Acute PA pressure responses to acute normoxia in hypoxic rats and to acute hypoxia in normoxic rats were similar, suggesting no differences in vasoreactivity. However, lungs isolated from EPO-treated hypoxic rats had lower pulmonary vascular resistance than saline-treated hypoxic rats when perfused with blood from normocythemic donor rats. PA medial thickness and the percentage of muscularized small PAs were significantly lower in EPO-treated hypoxic rats. These results indicate that augmented polycythemia fails to worsen hypoxic pulmonary hypertension in rats because of a decrease in the severity of structural remodeling.

Neutral endopeptidase inhibition attenuates development of hypoxic pulmonary hypertension in rats.

Neutral endopeptidase (NEP) inhibition is thought to blunt hypoxic pulmonary hypertension by reducing atrial natriuretic peptide (ANP) metabolism, but this hypothesis has not been confirmed. We measured NEP activity, guanosine 3',5'-cyclic monophosphate (cGMP) production, plasma ANP levels, and cardiac ANP synthesis in rats given an orally active NEP inhibitor (SCH-34826) during 3 wk of hypoxia. Under normoxic conditions, SCH-34826 had no effect on plasma ANP levels but reduced pulmonary and renal NEP activity by 50% and increased urinary cGMP levels (60 +/- 6 vs. 22 +/- 4 pg/mg creatinine; P < 0.05). Under hypoxic conditions, SCH-34826-treated rats had lower plasma ANP levels (1,259 +/- 361 vs. 2,101 +/- 278 pg/ml; P < 0.05), lower right ventricular systolic pressure (53 +/- 5 vs. 73 +/- 2 mmHg; P < 0.05), lower right ventricle weight-to-left ventricle+septum weight ratio (0.47 +/- 0.04 vs. 0.53 +/- 0.03; P < 0.05), and less muscularization and percent medial wall thickness of peripheral pulmonary arteries (22 +/- 5 vs. 45 +/- 8% and 17 +/- 1 vs. 25 +/- 1%, respectively; P < 0.05 for all values) than did rats treated with vehicle alone. These values were not affected by SCH-34826 under normoxic conditions. SCH-34826 decreased right ventricular ANP tissue levels in hypoxic rats (27 +/- 10 vs. 8 +/- 1 ng/mg protein; P < 0.05) but did not affect steady-state ANP mRNA levels. We conclude that NEP inhibition blunts pulmonary hypertension without increasing plasma ANP levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiopulmonary responses to chronic hypoxia in transgenic mice that overexpress ANP.

Elevated plasma atrial natriuretic peptide (ANP) levels have been shown to blunt pulmonary hemodynamic responses to chronic hypoxia, but whether elevated circulating ANP levels negatively feedback on cardiac expression of the ANP gene is unknown. Using a recently developed strain of transgenic mouse (TTR-ANF) that expresses a transthyretin promoter-ANP fusion gene in the liver, we studied the effect of chronically elevated plasma ANP levels on cardiac hypertrophic and pulmonary hemodynamic responses and expression of the endogenous cardiac ANP gene during chronic hypoxia. Plasma ANP levels were 10-fold higher in TTR-ANF mice than in their non-transgenic littermates. After 3 wk of hypobaric hypoxia (0.5 atm), right ventricular hypertrophy and pulmonary hypertension had developed in both groups of mice, but TTR-ANF mice had lower right ventricle-to-left ventricle plus septum weight ratios (0.39 +/- 0.01 vs. 0.45 +/- 0.02), right ventricular systolic pressures (25 +/- 2 vs. 29 +/- 2 mmHg), and lung dry weight-to-body weight ratios (0.48 +/- 0.03 vs. 0.57 +/- 0.01 mg/g) and less muscularization of peripheral pulmonary vessels (8.3 +/- 1.4 vs. 17.4 +/- 2.5%) than nontransgenic controls. Right atrial and ventricular steady-state ANP mRNA levels were the same in both groups of mice under normoxic and hypoxic conditions despite much higher plasma ANP levels and less pulmonary hypertension in TTR-ANF mice. We conclude that chronically elevated plasma ANP levels attenuate the development of hypoxic pulmonary hypertension in mice but do not suppress cardiac expression of the endogenous ANP gene under normoxic conditions nor blunt the upregulation of right ventricular ANP expression during chronic hypoxia.

Hematologic responses and the early development of hypoxic pulmonary hypertension in rats.

We have previously described the development of greater right ventricular hypertrophy after 7 days of hypoxia in the altitude-susceptible H strain compared to the resistant M strain of Sprague-Dawley rat. Greater polycythemia also occurs in the H strain after 2-3 weeks of hypoxia and is characterized by increased mean red cell volume (MCV), reticulocyte count (Retic), and blood viscosity after 4 weeks of hypoxia. In the present study, we determined the time course of development of these hematologic responses, whether differences in MCV are associated with differences in red cell deformability, and whether the hematologic differences might contribute to the early cardiopulmonary differences between the strains. We found that although hematocrit (Hct) did not differ between the strains until 21 days of hypoxia, MCV and Retic were greater in the H strain after only 3 days and whole blood viscosity was greater after 7 days. However, no differences in the viscosity or deformability of reconstituted red cells (Hcts 10% and 25%) were apparent at any time during hypoxic exposure. Furthermore, pressure-flow curves obtained using blood and lungs isolated from 7-day hypoxic rats suggested that the largest component of pressure elevation in the H rats was related to pulmonary vascular rather than hematologic factors. We conclude that although H rats have exaggerated hematologic responses to hypoxia, differences in pulmonary vascular structure and tone are more likely to be responsible for the strain differences in cardiopulmonary responses occurring after 7 days of hypoxia.

Exogenous erythropoietin fails to augment hypoxic pulmonary hypertension in rats.

In two rat strains (H and M) with differing susceptibilities to chronic hypoxia we examined the role of polycythemia in the differing hypoxic pulmonary hemodynamic responses. We hypothesized that augmentation of hematocrit (Hct) during hypoxia in the resistant M strain would render cardiopulmonary responses similar to those obtained in the susceptible H strain. Administration of human recombinant erythropoietin (EPO) in doses of 100, 250 and 500 U.kg-1 s.c. thrice weekly for three weeks raised Hct similarly in both strains indicating that normoxic rats had similar sensitivities to EPO. In rats exposed to hypobaric hypoxia (0.5 atm) for 21 days, EPO (500 U.kg-1 thrice weekly) significantly increased Hct and whole blood viscosity as expected. Surprisingly, right ventricular (RV) to body weight (BW) ratio as an index of right ventricular hypertrophy (RVH) and RV peak systolic pressure did not increase in EPO-injected rats of either strain compared to hypoxic controls. Among hypoxic animals, Hct correlated highly with viscosity but not with RV/BW. We conclude, contrary to our hypothesis, that polycythemia does not appear to be responsible for the strain difference in RVH and pulmonary hypertension.