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The coexistence of depression and cardiovascular disease (CVD) is regularly discussed, and much debated. There is strong evidence that there are pathophysiological mechanisms, particularly endothelial dysfunction, altered platelet aggregation, and hyperactivation of the thrombosis cascade, which coexist with hypothalamic-pituitary-adrenocortical axis dysfunction, and link depression to CVD. Therefore, depression should not be automatically considered to be a consequence of life impairment due to myocardial infarction or major stroke. Probably, it should be considered as one of the many other stressful events, or "genetic reactions to life", which are risk factors for CVD development. This review will examine the significance of depression in clinical daily practice, its pathophysiology as a determinant in vascular events, and its real importance in, before, and after many CVD events.

Besides generating renal damage, hypertension plays an important role in the progression of diabetic nephropathy. The fructose-fed rat is a well-established model both of high blood pressure and renal impairment, which is similar to diabetic nephropathy. To clarify the relationship between hypertension, glucose metabolism, and kidney remodeling, we investigated the renal level of Glut 1 and Glut 5, their relation to fibrosis and the effects of an antihypertensive drug on renal damage. Twenty-four male WK rats were divided into three groups: 8 animals received a fructose-enriched diet, 8 a control diet, and 8 animals a high-fructose diet plus amlodipine (5 mg/Kg). After six weeks of treatment, we observed a significant increase in Glut 5, fibronectin, and sorbitol in fructose-fed rats compared with control and amlodipine-treated animals; there was a positive correlation between Glut 5 and fibronectin levels (r = 0.63). Glut 1 levels were similar in all three groups, whereas collagen IV was higher in fructose-fed rats; amlodipine prevented the increase of collagen IV and sorbitol. Collagen I was statistically higher in the fructose group than in the other two groups. Therefore, prolonged fructose feeding results in renal fibrosis via polyol pathway overactivity that can be prevented by means of an antihypertensive drug.

Previous studies have suggested that endothelins could be involved in the pathogenesis of target organ damage in diabetes. The aim of this study was to evaluate the possible protective effect of Bosentan, an antagonist of endothelin receptor, on the kidney of diabetic rats. The study comprised a control group of 10 WKY rats and a group of 22 WKY rats in which diabetes was induced by streptozotocin i.v.; 10 rats were the control group. Diabetic rats received insulin and mean blood glucose was approximately mS 400 mg/dl throughout the study; they were divided into two groups: 11 rats received Bosentan 100 mg/kg/die by gastric gavage and 11 received vehicle for 1 month. Twenty-four hour urine collection was performed before and at the end of the study. Urinary protein excretion rate was expressed as microg urinary protein/mg urinary creatinine. The renal collagen I, fibronectin, and TGFbeta were evaluated by means of immunochemistry. The statistical analysis of the results demonstrates that Bosentan has prevented the increase in urinary protein excretion and that of renal immunoreactive collagen I, fibronectin, and TGFbeta induced by diabetes without reducing blood pressure. This study suggests a new clinical application for the antagonists of endothelin receptors.

NO may be responsible for the glomerular hyperfiltration observed in diabetic kidney by inducing vasodilation of the afferent arteriole. The aim of this study was to evaluate which isoform of nitric oxide synthase (NOS) is responsible for increased renal production of NO in diabetic kidney. Thirty male WKY rats were divided into 6 groups. Five rats were sacrificed immediately, five after 20 days. In the other rats, diabetes was induced by streptozotocin. The four diabetic groups were sacrificed respectively after 5, 10, 15 and 20 days. Urine excretion of NO metabolites was assayed; immunochemistry showed the presence of inducible (iNOS) and endothelial constitutive (ecNOS) synthases in the kidney. Urinary excretion of NO metabolites increased significantly in diabetic rats five days after the induction of diabetes and at the end of the study whereas it was unchanged in the control group. Renal ecNOS remained unchanged throughout the study in all rats whereas iNOS increased significantly in diabetic rats from the fifth day until the end of the study. The results demonstrate that iNOS is activated in the kidney of rats, soon after the induction of diabetes, thus suggesting its involvement in the increased production of NO observed immediately after the onset of diabetes.

The Na(+)/Ca(2+)-exchanger (NCX) is the main mechanism by which Ca(2+) is transported out of the ventricular myocyte. NCX levels are raised in failing human heart, and the consequences of this for excitation-contraction coupling are still debated. We have increased NCX levels in adult rabbit myocytes by adenovirally-mediated gene transfer and examined the effects on excitation-contraction coupling after 24 and 48 h. Infected myocytes were identified through expression of green fluorescent protein (GFP), transfected under a separate promoter on the same viral construct. Control experiments were done with both non-infected myocytes and those infected with adenovirus expressing GFP only. Contraction amplitude was markedly reduced in NCX-overexpressing myocytes at either time point, and neither increasing frequency nor raising extracellular Ca(2+) could reverse this depression. Resting membrane potential and action potential duration were largely unaffected by NCX overexpression, as was peak Ca(2+) entry via the L-type Ca(2+) channel. Systolic and diastolic Ca(2+) levels were significantly reduced, with peak systolic Ca(2+) in NCX-overexpressing myocytes lower than diastolic levels in control cells at 2 m m extracellular Ca(2+). Both cell relengthening and the decay of the Ca(2+) transient were significantly slowed. Sarcoplasmic reticulum (SR) Ca(2+) stores were completely depleted in a majority of myocytes, and remained so despite increasingly vigorous loading protocols. Depressed contractility following NCX overexpression is therefore related to decreased SR Ca(2+) stores and low diastolic Ca(2+) levels rather than reduced Ca(2+) entry., (Copyright 2002 Academic Press.)

Enrasentan is an antagonist of endothelin (ET) receptors. Previous studies have shown that antagonism of ET receptors might represent a new approach to the treatment of hypertension. Rats with a high-fructose diet (HFD) develop hyperinsulinemia, hypertriglyceridemia, and hypertension; renal and cardiac damage. The aim of this study was to evaluate whether enrasentan could reverse the hypertension and reduce the target organ damage induced by an HFD. Fifty-five WKY rats were divided into 6 groups; 35 animals received HFD for a month; thereafter 5 animals were killed, and the others were treated either with enrasentan (n = 10), hydralazine (n = 10), or placebo (n = 10) for a further month while on the HFD. Twenty animals were kept on a standard diet throughout the study; either placebo (n = 10) or enrasentan (n = 10) was administered during the second month. Enrasentan and hydralazine completely eliminated the HFD-induced increase in blood pressure; however, only enrasentan reduced the renal and cardiac damage caused by the diet. In conclusion, enrasentan was effective both in normalizing blood pressure and in reducing renal and cardiac damage; the organ protection cannot be attributed solely to the antihypertensive effect, because it was absent in the case of hydralazine, despite successful control of blood pressure.

Background: Early glomerular hypertrophy and late glomerulosclerosis have been observed in rats fed high fructose diet (HFD), comparable with those of diabetic rats. Several studies suggest a role for nitric oxide (NO) in the pathogenesis of renal damage in diabetes. This study investigated the possible role of NO in the pathogenesis of HFD-induced glomerular changes., Methods: Three study protocols were adopted. In the first, 20 rats were divided into two groups to evaluate the effect of HFD on glomerular size and on the urinary excretion of NO. In the second, the glomerular size was evaluated in 40 rats divided into four groups receiving: (1) standard diet (SD); (2) HFD; (3) HFD + L-NAME, and (4) SD + L-NAME for 1 month. In the third, the renal expression of inducible enzyme (iNOS) was compared in 10 rats on HFD and in 10 controls after a 1-month diet., Results: The results showed: (1) increased urinary excretion of NO and glomerular size, both induced by HFD; (2) prevention by L-NAME of the HFD-increased glomerular size, and (3) increased iNOS expression in the kidneys of rats fed HFD., Conclusion: These results suggest a role for NO in the pathogenesis of the early renal changes induced by HFD., (Copyright 2002 S. Karger AG, Basel)

Resistance to the metabolic actions of insulin is thought to play a determining role in the aetiology of a great variety of disorders, including essential hypertension, accelerated atherosclerosis and cardiomyopathies. ACE inhibitors are recognised as being highly effective therapy for hypertension and cardiac insufficiency, and have a more beneficial effect on survival rate than expected on the basis of known mechanisms of action. The mechanism responsible for these extremely positive effects are just beginning to be understood and appear to be linked to the effects these drugs have on metabolism. The relationship between the insulin and angiotensin II (Ang II) signalling pathways needs to be fully clarified in order to prevent or correct the target organ damage resulting from changes in the cross-talk of these two hormonal systems. In recent years, Ang II has been shown to play a central role in cardiovascular and neuroendocrine physiology as well as in cellular cycle control. Moreover, the fact that Ang II utilises the insulin-receptor substrate (IRS)-1 to relay signals towards their intracellular destination, provides the biochemical explanation of how these two systems interact in a healthy organism and in a diseased one. Since it is overactivity of the renin-angiotensin system that seems to impair the intracellular response to insulin signalling, cardiovascular drugs that modulate the cellular transmission of Ang II have attracted particular interest. As well as the already widely-used ACE inhibitors, selective blockers of the Ang II type 1 receptor (AT(1)) have been shown to be clinically effective in the control of haemodynamic parameters, but with perhaps a less striking effect on glucose homeostasis. Many trials have investigated the effect of Ang II blockade on systemic glucose homeostasis. The inhibition of Ang II by ACE-inhibitors frequently showed a positive effect on glycaemia and insulin sensitivity, while information on the effects of AT(1) receptor antagonists on glucose homeostasis is more limited and controversial. An important limitation of these studies has been the short treatment and follow-up periods, even for the 'so called' long-term studies which were only 6 months. Several investigators have focused on the effects of the nuclear factors involved in gene transcriptions, especially with respect to the agonists/antagonists of peroxisome proliferator-activated receptors (PPARs) and their intriguing interconnections with the insulin and Ang II subcellular pathways. In fact, in vitro and in vivo experimental studies have shown that thiazolidinediones (selective PPAR-gamma ligands) are not only powerful insulin sensitisers, but also have anti-hypertensive and anti-atherosclerotic properties. In addition to conventional pharmacological approaches, attempts have been made to use genetic transfer in the treatment of cardiovascular and metabolic disorders. The development of powerful viral vectors carrying target genes has allowed us to restore the expression/function of specific proteins involved in the cellular mechanism of insulin resistance, and research now needs to move beyond animal models. Although a clearer picture is now emerging of the pathophysiological interaction between insulin and Ang II, especially from pre-clinical studies, there is much to be done before experimental findings can be used in daily clinical practice.

K. Davia, E. Bernobich, H. K. Ranu, F. del Monte, C. M. N. Terracciano, K. T. MacLeod, D. L. Adamson, B. Chaudhri, R. J. Hajjar and S. E. Harding. SERCA2a Overexpression Decreases the Incidence of Aftercontractions in Adult Rabbit Ventricular Myocytes. Journal of Molecular and Cellular Cardiology (2001) 33, 1005-1015. Slow relaxation and poor contractile response to increasing stimulation frequency in failing human heart have been strongly linked to a decrease in the activity of the sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCA2a). Restoration of SERCA2a levels using gene transfer has beneficial effects on contractile function but, like beta -adrenoceptor stimulation, could potentially produce excess SR Ca(2+), arrhythmias and cell death. We have examined the effects of SERCA2a overexpression in adult rabbit cardiac myocytes, and compared changes in relaxation with those following beta -adrenoceptor stimulation. Myocytes were infected with an adenovirus carrying both SERCA2a and green fluorescent protein (GFP) for positive identification of infected cells. Myocyte survival was significantly enhanced in the infected cultures. There was a reduction in both time-to-peak contraction and time-to-50% relaxation (R50) 48 h after infection. Time-to-90% relaxation (R90) was particularly improved (non-infected 516+/-41 ms, AD.SERCA2a-GFP 230+/-23 ms, n=7 preparations, P<0.001). There was also a decreased incidence of aftercontractions in Ad.SERCA2a-GFP infected myocytes (21+/-5%v 41+/-4% in controls, P<0.01). This contrasts with beta -adrenoceptor stimulation, which reduced R50 but prolonged R90 by 158+/-76 ms (P<0.02, n=16). At higher stimulation frequencies (2-3 Hz) contraction amplitude and SR calcium content were increased and diastolic contracture was reduced following SERCA2a overexpression. Overall, increasing levels of SERCA2a resulted in an improvement in systolic and diastolic function and a reduction in cell death and arrhythmic aftercontractions. SERCA2a overexpression therefore lacks the detrimental effects associated with some other inotropic interventions., (Copyright 2001 Academic Press.)

Background: Rats fed a high-fructose diet develop hyperinsulinaemia, hypertriglyceridaemia, hypertension, renal changes similar to those in diabetic rats and left ventricular hypertrophy with deposition of collagen. Bosentan is an antagonist of endothelin receptors. Other authors have demonstrated that bosentan is effective in preventing the increase in blood pressure induced by a high-fructose diet but, until now, the effect of the drug on the target organs has not been investigated., Objective: To evaluate whether bosentan is effective, not only in reducing blood pressure, but also in limiting the renal and cardiac changes induced by a high-fructose diet, Methods: Forty Wistar-Kyoto (WKY) male rats were divided into four groups: groups 1 and 2 received a high-fructose diet, groups 3 and 4 received a standard diet for 1 month. Thereafter, the following treatments were administered: group 1, high-fructose diet plus bosentan 100 mg/kg per day; group 2, high-fructose diet plus placebo; group 3, standard diet plus bosentan 100 mg/kg per day; group 4, standard diet plus placebo. After a further 1 month, all animals were killed. A morphometric analysis was performed by examining 100 glomeruli for each animal. Renal deposits of collagen and fibronectin and cardiac deposits of collagen III were measured by means of immunochemistry., Results: By the end of the study, bosentan had completely reversed the increase in blood pressure induced by a high-fructose diet, without modifying the blood pressure in normotensive rats. Moreover, bosentan reduced glomerular hypertrophy and deposits of collagen and fibronectin in the kidney and cardiac deposits of collagen III., Conclusions: The results of this study demonstrate that bosentan not only normalizes blood pressure, but also protects target organs in rats receiving a high-fructose diet.

Objective: Normotensive rats fed a high fructose diet (HFD) develop hypertriglyceridemia, hyperinsulinemia and hypertension. The glomerular changes observed in the kidneys of these animals are similar to those observed in diabetic rats. The aim of this study was to evaluate whether lacidipine could be effective not only in preventing, but also in inducing the regression of hypertension, and renal and cardiac damage in rats fed HFD., Methods: Thirty male Wistar-Kyoto (WKY) rats received HFD for 1 month; thereafter, five rats were sacrificed (Group 1) and the other 25 rats were divided into three groups: Group 2 (five rats) received HFD plus placebo, Group 3 (10 rats) HFD plus lacidipine 3 mg/kg per day, and Group 4 (10 rats) HFD plus hydralazine 10 mg/kg per day. At the end of the second month all animals were sacrificed. Kidneys and hearts were immediately removed. Renal deposits of collagen I, collagen IV, fibronectin and cardiac deposits of collagen III were assessed by means of immunohistochemistry., Results: In the rats receiving HFD plus placebo, blood pressure was increased after the first and the second month of diet. This increase was reversed by lacidipine and hydralazine but, although both drugs normalized blood pressure, only lacidipine was effective in reducing renal and cardiac damage., Conclusions: These data suggest that lacidipine is effective in reversing hypertension and reducing target organ damage induced by HFD. Moreover, this protective effect on target organs appears to be not simply a consequence of blood pressure reduction, but seems to be connected to the type of hypotensive drug administered.

The authors have previously reported that oscillatory potentials (O.P.) of the electroretinogram are impaired in essential hypertensive patients before the appearance of funduscopic changes. They can therefore be considered an early marker of the nervous damage induced by hypertension. Aim of this study was to evaluate whether an antihypertensive regimen could influence the progression of this damage. O.P. were recorded in 35 essential hypertensives before antihypertensive treatment and after one-year treatment. The patients were randomly allocated into 4 treatment groups: 1) beta-blockers 2) ACE-Inhibitors 3) calcium antagonists 4) no pharmacological treatment. At the end of the study, blood pressure was significantly decreased in all but group 4. O.P., similar in the 4 groups at the beginning, were significantly higher at the end of the study only in patients treated with ACE-inhibitors. The results of this study suggest that although all hypotensive agents reduced blood pressure only ACE-I showed a protective effect on the retinal electric electrophysiology in hypertensive patients.

Normotensive rats fed a high-fructose diet (HFD) develop hypertriglyceridemia, hyperinsulinemia, and hypertension. The glomerular changes observed in the kidneys of these animals are similar to those observed in diabetic rats. The aim of this study was to evaluate whether lacidipine, a calcium antagonist, could have a protective effect with this animal model. Forty male Wistar-Kyoto (WKY) rats were divided into four groups treated with HFD + placebo; HFD + lacidipine, 0.3 mg/kg/day; HFD + lacidipine, 3 mg/kg/day; or standard diet + placebo for 4 weeks. Urinary excretion of the stable metabolic products of nitric oxide (NO) was determined, because this vasoactive agent has been found to cause hemodynamic changes in the diabetic kidney. Glomerular size was determined by means of morphometric analysis. The results of this study show that lacidipine prevents (a) the HFD-induced increase in blood pressure in a dose-dependent manner; (b) the HFD-induced increase in glomerular size and fibronectin synthesis; and (c) the increase of collagen III synthesis in the heart. The drug had no effect on the increased urinary excretion of the stable metabolic products of NO. These data suggest that lacidipine might be useful in preventing the renal and cardiac damage caused by hypertension and non-insulin-dependent diabetes mellitus.

Objective: To evaluate the additive effect of metoprolol treatment on long-term incidence of fatal and non-fatal cardiac events in idiopathic dilated cardiomyopathy., Design: 586 patients with idiopathic dilated cardiomyopathy were prospectively enrolled in a multicentre registry and followed up for a mean (SD) of 52 (32) months. Metoprolol, carefully titrated to the maximum tolerated dose, was added to conventional heart failure treatment in 175 patients., Results: Survival and transplant-free survival at seven years were significantly higher in the 175 metoprolol treated patients than in the remaining 411 on standard treatment (81% v 60%, p < 0.001, and 69% v 49%, p < 0.001, respectively). By multivariate analysis, metoprolol independently predicted survival and transplant-free survival (relative risk reduction values for all cause mortality and combined mortality or transplantation 51% (95% confidence interval 21% to 69%), p = 0.002, and 34% (5% to 53%), p = 0.01, respectively). New York Heart Association class, left ventricular end diastolic diameter, and pulmonary wedge pressure were also predictive. Seven year survival (80% v 62%, p = 0.004) and transplant-free survival (68% v 51%, p = 0.005) were significantly higher in 127 metoprolol treated cases than in 127 controls selected from the entire control cohort and appropriately matched. Metoprolol was associated with a 30% reduction in all cause mortality (7% to 48%, p = 0.015) and a 26% reduction in mortality or transplantation (7% to 41%, p = 0.009)., Conclusions: The addition of metoprolol to standard heart failure treatment, including angiotensin converting enzyme inhibitors, was effective in the long-term, reducing both all cause mortality and transplantation in patients with idiopathic dilated cardiomyopathy.

High blood pressure (BP), often borderline hypertension, can be also found in adolescents. In these subjects the haemodynamic pattern, high cardiac output and normal vascular resistance, differs from that of older hypertensives. Although the risk for hypertension is higher in this group than in the general population, only a minority of them will develop sustained hypertension later in life. They can therefore be viewed as an enriched pool of future hypertensives but not as true prehypertensives. The aim of this longitudinal study was to analyse the relation between casual BP measured in high school students and in the same subjects 3 years later. In 1990, an extensive study on BP was carried out in 1062 high school students aged 18 years. Sitting BP, heart rate, weight, and body mass index (BMI) were measured in each subject. After 3 years, the 50 subjects with the highest BP level recorded in 1990 were recalled. Forty-five subjects (90%, 30 males and 15 females) agreed to undergo a second examination. They were seen as outpatients in the Hypertension Centre of our institute. BP was measured with a mercury sphygmomanometer after a 10 min rest three times in 5 min. Systolic and diastolic BP were significantly reduced after 3 years (137 +/- 13 vs 132 +/- 10 P = 0.002; 92 +/- 4 vs 85 +/- 6 P = 0.0001, mm Hg). By means of a multiple regression test, including parameters recorded in 1990, systolic blood pressure (SBP) (R = 0.53 Slg F = 0.0002) and diastolic blood pressure (DBP) (R = 0.60 Slg F = 0.0001) were shown as the main determinants of SBP, while DBP was related only to previous BMI (R = 0.37 Slg F = 0.01). The reduction of both SBP and DBP after 3 years could be explained either by a true, spontaneous decrease of BP or as a consequence of different environmental conditions during the second examination (more prolonged resting time, repeated measurements). However, data of this study demonstrate that casual SBP and DBP are the main determinants of future SBP, thus confirming the prognostic value of casual BP measurement in young people. Moreover, our data emphasises the role of BMI as the main determinant of future high DBP.