Nitric oxide, prostacyclin, and glucagon have been implicated in promoting the hyperdynamic circulatory state of portal hypertension. Recent evidence also indicates that increased tumor necrosis factor-α (TNF-α) production is involved in the pathogenesis of this hemodynamic abnormality. This study was aimed at investigating in rats with portal vein stenosis (PVS) the effects on splanchnic hemodynamics of blocking circulating TNF-α and the factors mediating the vascular action of this cytokine in this setting. Anti-TNF-α polyclonal antibodies or placebo was injected into rats ( n = 96) before and 4 days after PVS (short-term inhibition) and at 24 h and 4, 7, 10 days after PVS (long-term inhibition). Short-term TNF-α inhibition reduced portal venous inflow and cardiac index and increased splanchnic and systemic resistance. Portal pressure was unchanged, but portal-systemic shunting was decreased. After long-term TNF-α inhibition, portal venous inflow and portal pressure were unchanged, but arterial pressure and systemic resistance rose significantly. Anti-TNF-α PVS rats exhibited lower increments of systemic resistance after N ω-nitro-l-arginine methyl ester and indomethacin administration and lower serum levels of TNF-α, nitrates-nitrites, and 6-keto-PGF1α, both over the short and the long term. Serum glucagon levels rose after long-term inhibition. In conclusion, the specific role played by TNF-α in the development of the hyperdynamic state of portal hypertension appears to be mainly mediated through an increased release of nitric oxide and prostacyclin. Maintenance of the splanchnic hyperemia after long-term TNF-α inhibition could be due to a compensatory release of glucagon.

1 Mesangial cells play an active role in the in¯ammatory response to glomerular injury. We have studied in cultured human mesangial cells (CHMC) several eects of 9-cis retinoic acid (9-cRA), an activator of both retinoic acid receptors (RARs) and retinoid X receptors (RXRs). 2 9-cRA inhibited foetal calf serum-induced CHMC proliferation. It also prevented CHMC death induced by the in¯ammatory mediator H 2 O 2 . This preventive eect was not due to any increase in H 2 O 2 catabolism and it persisted even when both catalase and glutathione synthesis were inhibited. Finally, 9-cRA diminished monocyte adhesion to FCS-stimulated CHMC. Interestingly, the retinoid also inhibited in FCS-stimulated cells the protein expression of two mesangial adhesion molecules, ®bronectin and osteopontin, but it did not modify the protein expression of intercellular adhesion molecule-1 and vascular adhesion molecule-1. 3 All major RARs and RXRs isotypes were expressed in CHMC regardless of the presence or absence of 9-cRA. Transcripts to RAR-a, RAR-b and RXR-a increased after incubation with 9-cRA whereas RXR-g was inhibited, suggesting a major role for RARs and RXRs in 9-cRA-antiin¯ammatory eects. 4 9-cRA was toxic only at 50 mM (a concentration 50 ± 5000 times higher than required for the eects above). Cell death occurred by apoptosis, whose onset was associated with a pronounced increase in catalase activity and reduced glutathione content, being more eectively induced by alltrans retinoic acid. Modulation of the oxidant/antioxidant balance failed to inhibit apoptosis. 5 We conclude that mesangial cells might be a target for the treatment of in¯ammatory glomerulopathies with 9-cRA.

Arterial hypertension is commonly observed in orthotopic liver transplantation (OLT) recipients receiving cyclosporin A (CsA), but the precise pathogenetic mechanisms remain partially unknown. The aim of this study was to investigate endothelium-dependent and -independent dilation and adrenergic constriction of resistance vessels of OLT recipients treated with CsA. Vascular reactivity was examined in 22 OLT patients, 10 with and 12 without arterial hypertension, and in 10 control subjects by assessing the forearm blood flow response to the brachial artery infusion of increasing concentrations of methacholine chloride, sodium nitroprusside, and phenylephrine. In 10 OLT patients, the response to methacholine was also examined after acetylsalicylate. The ratio of serum nitrite and nitrate to serum creatinine was lower (P F .05) in OLT patients with hypertension than in nonhypertensive patients and controls. Basal forearm flow was similar in the three groups. Methacholine vasodilation was impaired in the hypertensive patients as shown by a lower maximum forearm vasodilator response and a shift in the dose response curve to methacholine to the right compared with the nonhypertensive OLT patients and the controls. The response to methacholine was not modified after salicylate. Forearm flow response to nitroprusside was similar in the three groups. No differences between the patients and the controls were found in the maximum forearm flow contraction in response to phenylephrine. An impairment in endothelium-dependent vasodilation could mediate arterial hypertension in OLT patients immunosuppressed with CsA. (HEPATOLOGY 1998;27:332-338.)Arterial hypertension is a side-effect commonly observed in patients with an allogeneic solid organ graft receiving an immunosuppressive regimen based on cyclosporin A (CsA). 1,2 Published reports show that between 60% and 85% of transplant recipients treated with CsA develop hypertension. 3 The precise pathogenetic pathways underlying CsA-induced hypertension remain partially unknown. This problem is further hindered by the frequent discrepancy between the results obtained in humans and in animal models, and the relative resistance of rats that receive CsA to develop systemic hypertension. These facts make it difficult to extrapolate data from the experimental to the human setting. 4 Recent lines of evidence point to a disturbance in the local mechanisms of vascular regulation as the most likely cause of hypertension after transplantation. In this regard, several studies that have focused on the effects of CsA on arachidonic acid metabolites and endothelium-dependent and -independent vasodilation suggest that the arterial hypertension developed during CsA therapy reflects a shift in favor of vasoconstriction through an impairment of vasodilating mechanisms. [5][6][7][8][9][10][11] These studies have been performed in animal models, in vessels from healthy humans incubated with CsA, or in vessels from CsA-treated patients. However, no study to date has investigated the pattern of reacti...

No abstract

Aims: Hypertrophic cardiomyopathy (HCM) is often accompanied by increased trabeculated myocardium (TM)—which clinical relevance is unknown. We aim to measure the left ventricular (LV) mass and proportion of trabeculation in an HCM population and to analyze its clinical implication. Methods and Results: We evaluated 211 patients with HCM (mean age 47.8 ± 16.3 years, 73.0% males) with cardiac magnetic resonance (CMR) studies. LV trabecular and compacted mass were measured using dedicated software for automatic delineation of borders. Mean compacted myocardium (CM) was 160.0 ± 62.0 g and trabecular myocardium (TM) 55.5 ± 18.7 g. The percentage of trabeculated myocardium (TM%) was 26.7% ± 6.4%. Females had significantly increased TM% compared to males (29.7 ± 7.2 vs. 25.6 ± 5.8, p < 0.0001). Patients with LVEF < 50% had significantly higher values of TM% (30.2% ± 6.0% vs. 26.6% ± 6.4%, p = 0.02). Multivariable analysis showed that female gender and neutral pattern of hypertrophy were directly associated with TM%, while dynamic obstruction, maximal wall thickness and LVEF% were inversely associated with TM%. There was no association between TM% with arterial hypertension, physical activity, or symptoms. Atrial fibrillation and severity of hypertrophy were the only variables associated with cardiovascular death. Multivariable analysis failed to demonstrate any correlation between TM% and arrhythmias. Conclusions: Approximately 25% of myocardium appears non-compacted and can automatically be measured in HCM series. Proportion of non-compacted myocardium is increased in female, non-obstructives, and in those with lower contractility. The amount of trabeculation might help to identify HCM patients prone to systolic heart failure.