Elena Bernobich

The role of the angiotensin system in cardiac glucose homeostasis: Therapeutic implications

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 (AT1) 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 AT1 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-γ 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.

Nephroprotective effect of Bosentan in diabetic rats

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 ≃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 &mgr;g urinary protein/mg urinary creatinine. The renal collagen I, fibronectin, and TGF&bgr; 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 TGF&bgr; induced by diabetes without reducing blood pressure. This study suggests a new clinical application for the antagonists of endothelin receptors.

Early effects of diabetes on inducible nitric oxide synthase in the kidney

Abstract 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.

Bosentan reduces blood pressure and the target-organ damage induced by a high-fructose diet in rats.

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.

Percutaneous Management of Renal Artery Aneurysm With a Stent-Graft

A 53-year-old woman presented with systemic hypertension that was not responsive to medical treatment with lacidipine 4 mg. daily. The patient had no risk factors for atherosclerosis. Laboratory results were normal. Abdominal color Doppler ultrasound and selective renal angiography showed fibromuscular dysplasia of the main right renal artery consisting of multiple stenoses and 1 cm. saccular aneurysm (fig. 1). The left renal artery was normal. Various therapeutic options were discussed with the patient, and she elected to undergo an endovascular stent-graft procedure to avoid surgery. The procedure was performed percutaneously via the left axillary artery, in order to obtain a better angle while positioning the stent, through a 7Fr introducer sheath. Heparin 5,000 IU was administered. After renal artery selective catheterization with a multipurpose catheter, the lesion was crossed with a 0.014-inch guide wire. The wire was exchanged via the same catheter with a 0.035-inch Amplatz Super Stiff Guide Wire (Boston, Scientific Corp., Natick, Massachusetts). A 28 mm. Jostent Periphel Stent Graft (JOMED, Helsingborg, Sweden) was then mounted on a 5 40 mm. balloon catheter and advanced through the guide wire. The stent was delivered across the lesion and inflated at 8 atm. for 15 seconds. A final right renal arteriogram showed excellent graft position, aneurysmal exclusion and no sign of residual stenosis (fig. 2). There were no complications, and the patient was discharged home on postoperative day 2 on a regimen of aspirin 100 mg. daily for 3 months. The patient remained normotensive for 10 months. At 24month followup blood pressure was observed in the normal range with amlodipine 5 mg. daily, and serum creatinine was 1.2 mg./dl. (normal 0.4 to 1.3). Color Doppler ultrasound showed wide patency of the renal artery, normal renal perfusion and aneurysmal exclusion.

Lacidipine prevents the hypertension and renal and cardiac changes induced by high-fructose diet in WKY rats.

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.

Antihypertensive treatment and renal damage: amlodipine exerts protective effect through the polyol pathway.

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.

Role of Nitric Oxide in the Early Renal Changes Induced by High Fructose Diet in Rats

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.

Lacidipine reduces high blood pressure and the target organ damage induced by high fructose diet in rats.

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.

Depression in vascular pathologies: the neurologist's point of view

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.