-Moreira. Endogenous production of ghrelin and beneficial effects of its exogenous administration in monocrotaline-induced pulmonary hypertension. Am J Physiol Heart Circ Physiol 287: H2885-H2890, 2004; doi:10.1152/ ajpheart.01122.2003.-We investigated the endogenous production of ghrelin as well as cardiac and pulmonary vascular effects of its administration in a rat model of monocrotaline (MCT)-induced pulmonary hypertension (PH). Adult Wistar rats randomly received a subcutaneous injection of MCT (60 mg/kg) or an equal volume of vehicle. One week later, animals were randomly assigned to receive a subcutaneous injection of ghrelin (100 g/kg bid for 2 wk) or saline. Four groups were analyzed: normal rats treated with ghrelin (n ϭ 7), normal rats injected with saline (n ϭ 7), MCT rats treated with ghrelin (n ϭ 9), and MCT rats injected with saline (n ϭ 9). At 22-25 days, right (RV) and left ventricular (LV) pressures were measured, heart and lungs were weighted, and samples were collected for histological and molecular analysis. Endogenous production of ghrelin was almost abolished in normal rats treated with ghrelin. In MCT-treated animals, pulmonary expression of ghrelin was preserved, and RV myocardial expression was increased more than 20 times. In these animals, exogenous administration of ghrelin attenuated PH, RV hypertrophy, wall thickening of peripheral pulmonary arteries, and RV diastolic disturbances and ameliorated LV dysfunction, without affecting its endogenous production. In conclusion, decreased tissular expression of ghrelin in healthy animals but not in PH animals suggests a negative feedback in the former that is lost in the latter. A selective increase of ghrelin mRNA levels in the RV of animals with PH might indicate distinct regulation of its cardiac expression. Finally, ghrelin administration attenuated MCT-induced PH, pulmonary vascular remodeling, and RV hypertrophy, indicating that it may modulate PH. myocardial hypertrophy; ventricular hemodymamics; pulmonary vasculature PULMONARY HYPERTENSION (PH) is a progressive disease associated with right ventricular (RV) hypertrophy that commonly progresses to heart failure. Endothelin (ET)-1 and several other neurohumoral agents play a central role in the complex pathophysiology of PH (11,28) and are used as therapeutic targets for this entity. For instance, several authors observed that ET-1 antagonism decreases PH, restores endothelial metabolic function, inhibits RV hypertrophy, and improves survival both in experimental (5,19,26) and clinical (27) settings.

The pathogenesis of pulmonary hypertension (PH) includes an inflammatory response. Thymulin, a zinc-dependent thymic hormone, has important immunobiological effects by inhibiting various proinflammatory cytokines and chemokines. We investigated morphological and hemodynamic effects of thymulin administration in a rat model of monocrotaline (MCT)-induced PH, as well as the pattern of proinflammatory cytokine gene expression and the intracellular pathways involved. Adult Wistar rats received an injection of MCT (60 mg/kg, sc) or an equal volume of saline. One day after, the animals randomly received during 3 wk an injection of saline, vehicle (zinc plus carboxymethyl cellulose), or thymulin (100 ng/kg, sc, daily). At d 23-25, the animals were anesthetized for hemodynamic recordings, whereas heart and lungs were collected for morphometric and molecular analysis. Thymulin prevented morphological, hemodynamic, and inflammatory cardiopulmonary profile characteristic of MCT-induced PH, whereas part of these effects were also observed in MCT-treated animals injected with the thymulin's vehicle containing zinc. The pulmonary thymulin effect was likely mediated through suppression of p38 pathway.

Thrombin induces cell proliferation and migration during vascular injury. We report that thrombin rapidly stimulated expression and release of the pro-angiogenic polypeptide fibroblast growth factor 1 (FGF1). Thrombin failed to induce FGF1 release from protease-activated receptor 1 (PAR1) null fibroblasts, indicating that this effect was dependent on PAR1. Similarly to thrombin, FGF1 expression and release were induced by TRAP, a specific oligopeptide agonist of PAR1. These results identify a novel aspect of the crosstalk between FGF and thrombin signaling pathways which both play important roles in tissue repair and angiogenesis.

In this study we found a significant prevalence of exercise-induced HTN in adult patients after successful AC repair despite adequate BP control at rest. Exercise-induced HTN was significantly related to higher peak gradient in the descending aorta and treatment with ACEI. These results highlight the complexity of the adult AC population and show that, even after a good surgical result, several patients remain at high cardiovascular risk and require long-term follow-up.