Propranolol causes a paradoxical enhancement of cardiomyocyte foetal gene response to hypertrophic stimuli.

BACKGROUND AND PURPOSE: Pathological cardiac hypertrophy is associated with the expression of a gene profile reminiscent of foetal development. The non selective beta-adrenoceptor antagonist propranolol is able to blunt cardiomyocyte hypertrophic response in pressure-overloaded hearts. It remains to be determined whether propranolol also attenuates the expression of hypertrophy-associated foetal genes. EXPERIMENTAL APPROACH: To address this question, the foetal gene programme, of which atrial natriuretic peptide (ANP), the beta-isoform of myosin heavy chain (beta-MHC), and the alpha-skeletal muscle isoform of actin (skACT) are classical members, was induced by thoracic aortic coarctation (TAC) in C57BL/6 mice, or by phenylephrine, a selective alpha(1)-adrenoceptor agonist, in cultured rat neonatal cardiomyocytes. KEY RESULTS: In TAC mice, the left ventricular weight-to-body weight (LVW/BW) ratio increased by 35% after 2 weeks. Levels of ANP, beta-MHC and skACT mRNA in the left ventricles increased 2.2-fold, 2.0-fold and 12.1-fold, respectively, whereas alpha-MHC and SERCA mRNA levels decreased by approximately 50%. Although propranolol blunted cardiomyocyte growth, with approximately an 11% increase in the LVW/BW ratio, it enhanced the expression of ANP, beta-MHC and skACT genes (10.5-fold, 27.7-fold and 22.7-fold, respectively). Propranolol also enhanced phenylephrine-stimulated ANP and beta-MHC gene expression in cultured cardiomyocytes. Similar results were obtained with metoprolol, a selective beta(1)-adrenoceptor antagonist, but not with ICI 118551, a beta(2)-adrenoceptor antagonist. CONCLUSIONS AND IMPLICATIONS: Propranolol enhances expression of the hypertrophy-associated foetal genes mainly via the beta(1)-adrenoceptor blockade. Our results also suggest that, in pressure-overloaded hearts, cardiomyocyte growth and foetal gene expression occur as independent processes.

Nitric oxide (NO) modulation of PAF-induced cardiopulmonary action: interaction between NO synthase and cyclo-oxygenase-2 pathways.

1. To further investigate into the mechanisms of PAF-induced cardiopulmonary actions, we examined the effects of the nitric oxide synthase (NOS) inhibitor L-N(omega)-nitro-L-arginine (L-NNA), of the specific cyclooxygenase-2 (COX-2) inhibitor NS 398, and of the combined presence of both COX and NOS inhibitors on the PAF responses in the heart lung preparation of guinea-pig (HLP). 2. In HLPs perfused with homologous blood, dose-response curves for the haemodynamic and bronchial effects of PAF (1 - 32 ng) were carried out in the absence or presence of L-NNA (200 microM). L-NNA caused an increase in the resting pulmonary arterial pressure (PAP) without affecting the other basal values, and strongly potentiated the bronchoconstriction and pulmonary hypertension elicited by PAF. An enhancement of the PAF-induced actions on right atrial pressure (RAP) and cardiac output (CO) was also observed. All the effects of L-NNA were antagonized by L-arginine (2 mM). 3. The presence of L-NNA in the perfusing blood of HLPs failed to affect the pulmonary hypertensive and bronchoconstrictor responses induced by the thromboxane A(2) mimetic U46619 (0.05 - 1.6 microg), 5-hydroxytryptamine (0.1 - 1.6 microg), and histamine (0.1 - 1.6 microg), thus suggesting that these PAF secondary mediators are not responsible for the hyper-responsiveness to PAF induced by L-NNA. 4. Blocking COX-2 pathway with NS 398 (15 - 30 microM) did not alter the cardiopulmonary resting variables. However, a reduction of the PAF-mediated pulmonary hypertension, but not of bronchoconstriction, was observed. When L-NNA was added to the perfusing medium of HLPs pre-treated with NS 398 or with indomethacin (15 microM), the basal PAP values were enhanced. However, in the combined presence of COX and NOS inhibitors, only a slight increase in the hypertensive responses to the highest doses of PAF was observed, whereas the PAF mediated actions at bronchial and cardiac level were unaffected. 5. This study indicates that (i) the cardiopulmonary actions induced by PAF are specifically modulated by endogenous NO through the NOS pathway, and (ii) COX-2 isoform is involved in the pulmonary hypertensive, but not bronchoconstrictor, effects of PAF. Furthermore, an interaction between PAF stimulated COX, particularly COX-2, and NOS pathways appears to take a functional role at both bronchial and cardiovascular level.

Serum HCV RNA titer does not predict the severity of liver damage in HCV carriers with normal aminotransferase levels.

AIMS/BACKGROUND: Many HCV RNA positive subjects with normal aminotransferase levels have significant liver damage despite normal liver biochemistry. In these patients it is not possible to discriminate between "healthy" carriers and subjects with chronic liver damage, unless liver biopsy is performed. The aim of this study was to evaluate the usefulness of HCV RNA quantitation as a non invasive tool to predict the severity of liver injury in a group of HCV carriers with normal amino-transferase levels. METHODS: 59 HCV RNA positive subjects (20 males) with persistently normal ALT levels were studied. All patients underwent HCV RNA quantitation and percutaneous liver biopsy. RESULTS: No correlation was found between serum HCV RNA titers and grading, while viraemia did correlate with staging. Patients were categorized into four subgroups, according to arbitrary serum HCV RNA cut-offs. Grading was not different between the four groups. Staging was significantly higher among subjects with viraemia > 1000 x 10(3) copies/mL than in patients with HCV RNA titers < 1000 x 10(3) copies/mL. CONCLUSIONS: In HCV carriers with normal aminotransferase levels viraemia does not predict the grade of HCV-related chronic liver disease (CLD), although subjects with higher HCV RNA levels seem to have more severe fibrosis. Although these data suggest that patients with higher viraemia might have more intense architectural changes and more severe progression of liver disease than those with lower levels of HCV replication, the weak and imprecise correlation leads us to conclude that HCV RNA quantitation is not a useful indicator in clinical practice in the selection of patients for liver biopsy.

Clinical, histological, and virological features of hepatitis C virus carriers with persistently normal or abnormal alanine transaminase levels.

This study was aimed to evaluate demographic, clinical, histological, and virological characteristics of 46 hepatitis C virus (HCV) carriers with persistently normal alanine transaminase (ALT) levels and to compare the results with those obtained in a group of 52 HCV-RNA-positive patients with elevated ALT levels. Subjects with normal ALT were more often females (P < .001), were more likely to be asymptomatic (P < .001), and have a lower incidence of risk factors for HCV transmission (P < .01). All patients with normal ALT had significant histological liver damage. The mean grading and staging did not differ between patients with normal and those with raised ALT concentrations. Moderate to severe hepatitis was more frequently found among subjects with normal than with elevated ALT. HCV genotype 2a was far more common in subjects with normal (43%) than with abnormal ALT levels (6%; P < .002), genotype 1b being more frequent in these latter (50% vs. 17%; P < .001). Patients with normal ALT levels had similar serum HCV-RNA titers than subjects with raised ALT. Neither HCV genotype distribution nor viral load correlated with the severity of liver damage. We conclude that significant liver disease may occur irrespective of clinical symptoms, ALT levels, HCV genotypes, and viral load.

Sonographic survey of the upper abdomen in 10 families of patients with immotile cilia syndrome.

Ten patients affected by the immotile cilia syndrome (ICS) and their families received an ultrasound examination of the upper abdomen to observe the possible familial occurrence of biliary, pancreatic, and splenic alterations. In 9 patients the liver was localized in the left hypochondrium, and in 1 patient there was an accessory spleen. In all the examined kin, the subdiaphragmatic organs were normally positioned. Two parents had an accessory spleen. We conclude that the supposed increased frequency of polysplenia, asplenia, and biliary atresia among ICS subjects and their kin is overestimated and based only upon anecdotal reports.

ETB receptor mediating pulmonary hypertension and bronchoconstriction induced by endothelin-1 in the guinea pig.

Endothelin (ET-1) caused dose-related contraction of isolated superfused bronchus and pulmonary artery and bronchoconstriction and pulmonary vascular hypertension of the heart lung preparation (HLP) of guinea pig. The specific ETA receptor antagonist BQ 123 completely blocked the responses of the pulmonary artery, but failed to affect those of bronchus and of HLPs. The specific ETB receptor agonist Sarafotoxin S6c caused contractions of bronchus, but not of pulmonary artery, and bronchoconstriction and pulmonary hypertension in HLPs. It is concluded that non-ETA subtype receptors, perhaps ETB, appear to be the main responsible for the potent pulmonary hypertensive effects of ET-1.

Effects of cardioplegic solutions and their components on human saphenous vein contractility.

Cardioplegic solution administration into the vein graft is an established method to ensure cardioplegic distribution beyond coronary artery stenoses. The ultrastructural demonstration of severe endothelial damage after cardioplegic exposure suggests that intravenous cardioplegic administration can contribute to early and late graft thrombosis. The direct effect on human saphenous vein contractility of three cardioplegic solutions and their components was compared. A solution with 30 mmol/L K+ and 82 mmol/L Na+ produced intense venoconstriction. Lowering the potassium level to 10 mmol/L and increasing the sodium level to 92 mmol/L reduced its vasoconstricting action. A third solution with 16 mmol/L K+, 16 mmol/L Mg2+, and lidocaine caused venodilatation. Analysis of the single component effects showed that high potassium level, low sodium level, and the addition of lidocaine produced concentration-dependent vasoconstriction. High magnesium concentration resulted in vasodilatation. The present data suggest that cardioplegic solution composition may cause marked vasomotor effects on saphenous vein and thus influence its endothelial integrity. In the search for an "ideal solution" to the cardioplegic controversy, a venoconstrictor infusate should be avoided to improve patency rates of coronary artery bypass grafts.