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The renin-ANG system has been reported to be overexpressed in pulmonary arterial hypertension (PAH). We investigated the effects of ANG receptor-1 blockade by losartan on hemodynamics and signaling molecules in a piglet overflow model of early PAH. Twenty-six 3-wk-old piglets were randomized to placebo or losartan therapy (1 mg·kg−1·day−1) after anastomosis of the inominate to the main pulmonary artery or after a sham operation. Three months later, the animals underwent a hemodynamic evaluation, followed by pulmonary tissue sampling for morphometry, immunohistochemistry, and real-time quantitative-PCR. Chronic systemic-to-pulmonary shunting increased the pulmonary vascular resistance from 2.5 ± 0.2 to 6.2 ± 0.3 mmHg·l−1·min·m−2and arteriolar medial thickness from 13.6 to 25.4%. These changes were associated with increased expressions of ANG II and its type 1 (AT1) and type 2 (AT2) receptors, endothelin-1 (ET-1) and its type B receptor (ETB), and angiopoietin-1, together with decreased expressions of bone morphogeneic protein receptor-1A and -2 (BMPR-1A and BMPR-2, respectively) and unchanged expression of the receptor tyrosine kinase with immunoglobulin and EGF homology domains-2 (Tie 2). Pretreatment with losartan decreased shunt-induced pulmonary vascular resistance and medial thickness by 51% and 35%, respectively. Losartan therapy was associated with persistent overexpressions of ANG II, AT2, ET-1, ETB, and angiopoietin-1 and with a return to normal of the BMPR-2 expression. These results suggest that ANG II contributes to left-to-right, shunt-induced PAH.

Assessement of right ventricular (RV) contractility from end-systolic pressure-volume relationships (ESPVR) is difficult due to problems in measuring RV instantaneous volume and to effects of changes in RV preload or afterload. We therefore investigated in anesthetized dogs whether RV ESPVR and contractility can be determined without measuring RV volume and without changing RV preload or afterload. The maximal RV pressure of isovolumic beats (Pmax) was predicted from isovolumic portions of RV pressure during ejecting beats and compared with Pmaxmeasured during the first beat after pulmonary artery clamping. In RV pressure-volume loops obtained from RV pressure and integrated pulmonary arterial flow, end-systolic elastance ( E es) was assessed as the slope of Pmax-derived ESPVR, pulmonary artery effective elastance ( E a) as the slope of end-diastolic to end-systolic relation, and coupling efficiency as the E es-to- E a ratio ( E es/ E a). Predicted Pmax correlated with observed Pmax( r = 0.98 ± 0.02). Dobutamine increased E es from 1.07 to 2.00 mmHg/ml and E es/ E a from 1.64 to 2.49, and propranolol decreased E es/ E a from 1.64 to 0.91 (all P < 0.05). After adrenergic blockade, preload reduction did not affect E es, whereas hypoxia and arterial constriction markedly increased E aand somewhat increased E es due to the Anrep effect. Low preload did not affect E es/ E a and high afterload decreased E es/ E a. In conclusion, in the right ventricle 1) Pmax can be calculated from normal beats, 2) Pmax can be used to determine ESPVR without change in load, and 3) Pmax-derived ESPVR can be used to assess ventricular contractility and ventricular-arterial coupling efficiency.

In six dogs and six weight-matched miniature pigs at baseline and after pulmonary embolization, pulmonary arterial compliance was determined using the pulse pressure method (CPPM), the three-element windkessel model (CWK-3), and the ratio of stroke volume to pulse pressure (SV/PP). CPPM was lower in pigs than in dogs at baseline (0.72 ± 0.23 vs. 1.14 ± 0.29 ml/mmHg, P < 0.05) and after embolism (0.37 ± 0.14 vs. 0.54 ± 0.16 ml/mmHg, P = 0.07) at matched flow, but not at matched flow and pressure. CPPM showed the expected inverse relation with pressure and a direct relation with flow. CWK-3 was closely correlated with CPPM, except for all dogs at baseline where CWK-3 was up to 100% higher than CPPM. Excluding these data, regression analysis yielded CWK-3 = −0.01 + 1.30 ⋅ CPPM( r 2 = 0.97). CWK-3 was found to be unreliable when input impedance first harmonic modulus was close to characteristic impedance, i.e., when reflections were small. SV/PP correlated well with CPPM (SV/PP = −0.10 + 1.76 ⋅ CPPM, r 2 = 0.89). We conclude that 1) CPPM is a consistent estimate of pulmonary arterial compliance in pigs and dogs, 2) CWK-3 and SV/PP overestimate compliance, and 3) CWK-3 is unreliable when wave reflections are small.