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Pulmonary vasoreactivity could determine the responsiveness to vasodilators and, in turn, the prognosis of pulmonary hypertension (PH). We hypothesized that pulmonary vasoreactivity is impaired, and we examined the underlying mechanisms in the Sugen-hypoxia rat model of severe PH. Male Sprague-Dawley rats were injected with Sugen (20 mg/kg s.c.) and exposed to hypoxia (9% O) for 3 weeks, followed by 4 weeks in normoxia (Su/Hx), or treated with Sugen alone (Su) or hypoxia alone (Hx) or neither (Nx). After hemodynamic measurements, the heart was assessed for right ventricular hypertrophy (Fulton's index); the pulmonary artery, aorta, and mesenteric arteries were isolated for vascular function studies; and contractile markers were measured in pulmonary arteries using quantitative polymerase chain reaction (PCR). Other rats were used for morphometric analysis of pulmonary vascular remodeling. Right ventricular systolic pressure and Fulton's index were higher in Su/Hx versus Su, Hx, and Nx rats. Pulmonary vascular remodeling was more prominent in Su/Hx versus Nx rats. In pulmonary artery rings, contraction to high KCl (96 mM) was less in Su/Hx versus Nx and Su, and phenylephrine-induced contraction was reduced in Su/Hx versus Nx, Hx, and Su. Acetylcholine (ACh)-induced relaxation was less in Su/Hx versus Nx and Hx, suggesting reduced endothelium-dependent vasodilation. ACh relaxation was inhibited by nitric oxide synthase (NOS) and guanylate cyclase blockade in all groups, suggesting a role of the NO-cGMP pathway. Nitrate/nitrite production in response to ACh was less in Su/Hx versus Nx, supporting reduced endothelial NO production. Sodium nitroprusside (10 M) caused less relaxation in Su/Hx versus Nx, Hx, and Su, suggesting a decreased responsiveness of vascular smooth muscle (VSM) to vasodilators. Neither contraction nor relaxation differed in the aorta or mesenteric arteries of all groups. PCR analysis showed decreased expression of contractile markers in pulmonary artery of Su/Hx versus Nx. The reduced responsiveness to vasoconstrictors and NO-mediated vasodilation in the pulmonary, but not systemic, vessels may be an underlying mechanism of severe PH in Su/Hx rats and appears to involve attenuation of the NO relaxation pathway and a switch of pulmonary VSM cells to a synthetic less reactive phenotype.

Objectives: Reflux is common in infancy; however, persistent signs and symptoms of gastrointestinal distress are often attributed to gastroesophageal reflux disease (GERD). In this pilot study, we aimed to characterize associations between signs and symptoms of suspected GERD and noninvasive markers of intestinal inflammation in preterm infants. Methods: We reviewed Electronic Medical Record (EMR) data to identify clinical signs and symptoms among case patients (n = 16). Controls (n = 16) were matched on gestational age. Univariate and multivariate regression analyses were used to compare fecal calprotectin and urinary intestinal fatty acid binding protein (I-FABP) levels between cases and controls. Results: We found no differences in baseline characteristics between cases and controls. In the multivariate regression analysis controlling for the proportion of mother’s milk, cases had higher fecal calprotectin levels than controls, with no differences in I-FABP levels between cases and controls. Conclusion: Our findings suggest that preterm infants with signs and symptoms of GERD have higher levels of intestinal inflammation as indicated by fecal calprotectin compared to their controls. Further studies are needed to evaluate the role of intestinal inflammation in signs and symptoms of gastrointestinal distress and whether fecal calprotectin might have predictive value in diagnosing GERD.

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