摘要:

Impairment of cardiac function in cardiomyopathy has been postulated to be related to decreased blood blow and increased collagen synthesis. Therefore, a therapeutic approach to alter the blood flow or fibrosis directly by means of growth factors may open a new therapeutic concept in dilated cardiomyopathy. From this viewpoint, hepatocyte growth factor (HGF) is a unique growth factor with antifibrosis and angiogenesis effects. Using the hereditary cardiomyopathic Syrian hamster as a model of genetically determined cardiomyopathy and heart failure, the effects of overexpression of HGF on fibrosis and microvascular dysfunction were examined. HGF gene or control vector was injected by the Hemagglutinating Virus of Japan–liposome method into the anterior heart of cardiomyopathic hamsters (Bio 14.6) under echocardiography once a week, from 12 to 20 weeks of age (total, 8 times). Blood flow, as assessed by a laser Doppler imager score, and the capillary density in hearts, as assessed by alkaline phosphatase staining, were significantly increased in hamsters transfected with HGF gene compared with control-vector-transfected hamsters (P<0.01). In contrast, the fibrotic area was significantly decreased in hamsters transfected with HGF gene compared with control (P<0.01). Overall, in vivo experiments demonstrated that transfection of HGF gene into the myocardium of cardiomyopathic hamsters stimulated blood flow through the induction of angiogenesis and reduction of fibrosis. These results suggest that HGF gene transfer may be useful to protect against myocardial injury in cardiomyopathy through its cardioprotective effects such as antifibrosis and angiogenesis actions.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Brain natriuretic peptide (BNP) is produced in cardiac myocytes, and increased secretion is closely associated with cardiac dysfunction. However, several fundamental aspects of BNP expression in the myocardium have not yet been resolved. In the present study, we report the presence of a precursor BNP mRNA transcript and a mature BNP mRNA transcript in normal porcine hearts. In normal pigs, the amount of precursor BNP mRNA was similar in atrial and ventricular myocardium, whereas the mature BNP transcript was 10- to 50-fold more abundant in atrial than in ventricular myocardium. Quantitation of proBNP in normal porcine hearts by radioimmunoassay disclosed abundant proBNP in the atria, whereas proBNP was undetectable in the ventricles. Laser confocal microscopy revealed proBNP in secretory granules of atrial but not in the ventricular myocardium of normal pigs. Mild streptozotocin-induced diabetes doubled the expression of BNP mRNA in porcine atrial myocardium (P=0.03), but was without effect on BNP mRNA in the ventricular myocardium. The data suggest that BNP mRNA processing and proBNP storage differ between the atrial and ventricular myocardium. The results also imply that diabetes increases cardiac BNP expression in a chamber-dependent manner.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

To investigate the relationship between soluble markers of platelet, endothelial and rheological function, and target organ damage and their response to intensified management in a population of middle-age hypertensive patients at high risk of cardiovascular complications, we studied 382 consecutive patients (308 men; mean age, 63 years, SD 8) along with 60 normotensive controls free of cardiovascular disease. Patients were divided into those with target organ damage (TOD; n=107) and those free of end-organ damage. Plasma levels of soluble P-selectin (sP-sel), a marker of platelet activation, and von Willebrand factor (vWF), an index of endothelial damage/dysfunction (both enzyme-linked immunosorbent assay), and the rheological indices fibrinogen, plasma viscosity, hematocrit, platelet, and white cell count were measured. In 53 patients, variables were further measured after 6 months of intensified cardiovascular risk management. Patients with TOD had significantly higher vWF, 137 (SD 33) versus 125 (SD 33) IU/dL (P=0.002,) and a greater proportion of smokers, 31% versus 16% (P=0.002). There were no statistically significant differences in plasma viscosity, fibrinogen, hematocrit, white blood cell count, platelet count, or sP-sel between the 2 subgroups. In multivariate analysis, vWF was a significant independent predictor for TOD. After 6 months of intensified management in 53 patients who entered the trial, there were significant reductions in systolic blood pressure, total cholesterol, hematocrit, plasma viscosity, sP-sel, and vWF (allP<0.01) but no significant change in fibrinogen. In conclusion, there is a relationship between TOD and endothelial damage/dysfunction in hypertension. Intensified management results in improvements in hemorheology, endothelial and platelet function.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Proteinuria is an important risk factor for cardiovascular and renal morbidity and mortality. The effects of 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitor (statin) therapy on proteinuria in normolipidemic patients with well-controlled hypertension have not been studied. A total of 63 normolipidemic (total cholesterol <240 mg/dL) and proteinuric (300 to 3000 mg/d) patients with well-controlled blood pressure (<140/90 mm Hg) were randomized to receive either placebo (n=32) or pravastatin (10 mg/d; n=31) after a 3-month placebo period. Pravastatin lowered proteinuria after 6 months by 54% (P<0.0001). Creatinine clearance was stable throughout the study in the 2 groups. Despite unchanged plasma endothelin-1 levels throughout the study, urinary excretion of the peptide was decreased and significantly correlated with improvement in urinary protein excretion in pravastatin-treated patients (r=0.64,P=0.001). The urinary excretion of retinol-binding protein decreased after pravastatin administration, probably reflecting an improvement in tubular function. In contrast, the urinary excretion of IgG did not change significantly throughout the study in either group. Multivariate analysis revealed that proteinuria was only significantly correlated with statin use (P<0.0001,R2= 0.66). Linear regression analysis in the statin-treated group did not show any correlation between changes in lipid profiles and proteinuria regression. Thus, in addition to their primary function of antilipidemia, the addition of pravastatin to treatment for well-controlled hypertension may have an additive effect on reducing proteinuria independent of hemodynamics and lipid-lowering effects, possibly through inhibiting renal endothelin-1 synthesis and improving tubular function.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Endothelial function is noninvasively assessed by measuring nitric oxide–dependent increase in radial artery diameter accompanying the elevation in shear stress induced by increasing blood flow through a short-lasting ischemia of the hand. However, shear stress also depends on blood viscosity, whose changes might thus affect nitric oxide increase in a manner that is not properly reflected by blood flow changes. In 12 subjects with hemochromatosis, we measured ultrasonographically radial artery diameter and blood flow responses to a 4-minute ischemia of the hand. This was done also after removing 500 mL of blood (and concomitantly infusing 500 mL of saline), which significantly (P<0.01) reduced hemoglobin concentration and hematocrit. The increase in blood flow induced by the 4-minute ischemia was similar before and after blood removal (+76% and +80%), which, in contrast, markedly attenuated the accompanying increase in radial artery diameter (+25% versus +13%,P<0.01). Thus, in humans, blood viscosity is involved in the endothelial response to an increase in shear stress. This implies that this response may not be accurately assessed and compared by quantifying the stimulus only through an increase in blood flow.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Although insulin-mediated vasodilation is impaired in insulin resistance, the mechanisms of this are unknown. We investigated factors mediating vasoactive responses to insulin in control and insulin-resistant rats. Responses to insulin in small mesenteric arteries from control and insulin-resistant rats were investigated after blocking endothelin-A receptors, cyclooxygenase, nitric oxide synthase, and potassium channels. In addition, insulin’s effect on prostacyclin production in small mesenteric blood vessels was assessed by enzyme immunoassay. Insulin induced a concentration-dependent vasodilation in control arteries that was absent in arteries from insulin-resistant rats. However, in the presence of BQ610, an endothelin-A receptor antagonist, the response to insulin was normalized in insulin-resistant arteries. In control arteries, insulin-induced vasodilation was completely inhibited by indomethacin, meclofenamate, glibenclamide, or potassium chloride. In contrast, neither n-nitro-l-arginine nor the combination of charybdotoxin and apamin altered vasodilation to insulin. In insulin-resistant arteries in the presence of BQ610, vasodilation was also inhibited by indomethacin, glibenclamide, and potassium chloride. Insulin increased prostacyclin production in small mesenteric blood vessels from both groups of rats to a similar degree. Insulin-induced vasodilation in small rat mesenteric arteries is mediated through prostacyclin- and ATP-dependent potassium channels. However, insulin-resistant arteries do not vasodilate to insulin unless endothelin-A receptors are blocked. Thus, impaired relaxation to insulin in insulin-resistant rats is due to enhanced vasoconstriction by endothelin, which offsets a normal vasodilatory response to insulin.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

A high-salt diet, which is known to contribute to the pathogenesis of hypertension, is also reportedly associated with insulin resistance. We investigated the effects of a high-salt diet on insulin sensitivity and insulin signaling in salt-sensitive (Dahl-S) and salt resistant (Dahl-R) strains of the Dahl rat. Evaluation of hyperinsulinemic-euglycemic clamp studies and glucose uptake into the isolated soleus muscle revealed that salt loading (8% NaCl) for 4 weeks induced hypertension and significant insulin resistance in Dahl-S rats, whereas no significant effects were observed in Dahl-R rats. Despite the presence of insulin resistance, insulin-induced tyrosine phosphorylation of the insulin receptor and insulin receptor substrates, activation of phosphatidylinositol 3-kinase, and phosphorylation of Akt were all enhanced in Dahl-S rats fed a high-salt diet. The mechanism underlying this form of insulin resistance thus differs from that previously associated with obesity and dexamethasone and is likely due to the impairment of one or more metabolic steps situated downstream of phosphatidylinositol 3-kinase and Akt activation. Interestingly, supplementation of potassium (8% KCl) ameliorated the changes in insulin sensitivity in Dahl-S rats fed a high-salt diet; this was associated with a slight but significant decrease in blood pressure. Evidence presented suggest that there is an interdependent relationship between insulin sensitivity and salt sensitivity of blood pressure in Dahl-S rats, and it is suggested that supplementing the diet with potassium may exert a protective effect against both hypertension and insulin resistance in salt-sensitive individuals.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

To clarify the role of the kallikrein-kinin system in cardiovascular homeostasis, the systemic and regional hemodynamics of kinin B2receptor–deficient (B2−/−) and tissue kallikrein–deficient (TK−/−) mice were compared with their wild-type (WT) littermates on a pure C57BL/6 genetic background. B2−/−, TK−/−, and WT adult mice were normotensive and displayed normal hemodynamic (left ventricular [LV] pressure, cardiac output, total peripheral resistance, dP/dtmax) and echocardiographic (septum and LV posterior wall thickness, LV diameter, LV mass, and LV fractional shortening) parameters. However, heart rate was lower in B2−/−mice compared with TK−/−and WT mice. In addition, B2−/−mice, but not TK−/−mice, exhibited lower coronary and renal blood flows and greater corresponding vascular resistances than did WT mice, indicating a tonic physiological vasodilating effect of bradykinin in these vascular beds. However, maximal coronary vasodilatation capacity, estimated after dipyridamole infusion, was similar in the 3 groups of mice. B2−/−mice were significantly more sensitive than were TK−/−mice to the vasoconstrictor effects of angiotensin II and norepinephrine. Finally, renin mRNA levels were significantly greater in B2−/−mice and smaller in TK−/−mice compared with WT mice. Taken together, these results indicate that under basal conditions, the kinin B2receptor is not an important determinant of blood pressure in mice but is involved in the control of regional vascular tone in the coronaries and the kidneys. The phenotypic differences observed between TK−/−and B2−/−mice could be underlain by tissue kallikrein kinin–independent effect and/or kinin B1receptor activation.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Central infusions of benzamil prevent/reverse salt-induced hypertension in genetic models of salt-sensitive hypertension. Benzamil acts by blockade of ion—presumably sodium—channels. In the present study, we assessed in Dahl salt-sensitive (S) rats on high salt intake whether these channels mediate increases in brain “ouabain” and, thereby, hypertension. Intracerebroventricular (icv) infusions of a low (1.2 &mgr;g/kg per hour) or high (4.0 &mgr;g/kg per hour) dose of benzamil were given to Dahl S rats on high salt diet (1370 &mgr;mol Na+/g food) for 2 or 4 weeks. “Ouabain” content was measured using a specific enzyme-linked immunosorbent assay (ELISA). Systolic blood pressure (BP) in Dahl S rats on high salt for 4 weeks increased markedly (188±10 versus 128±4 mm Hg, n=8,P<0.05). Benzamil fully blocked this increase (131±7 mm Hg after the high dose of benzamil). Hypothalamic and pituitary “ouabain” increased significantly (22±7 versus 12±3 and 151±38 versus 69±6 ng/g tissue, respectively,P<0.05) in Dahl S rats on high salt versus regular salt diet for 2 weeks. Benzamil blocked these increases of brain “ouabain” to high salt intake. Similarly, high salt intake for 4 weeks increased hypothalamic (18±2 versus 13±1 ng/g tissue,P<0.05) and pituitary (183±30 versus 78±8 ng/g tissue,P<0.05) “ouabain.” Benzamil also inhibited these increases of brain “ouabain.” Both hypothalamic and pituitary “ouabain” showed significant positive correlations with BP. In contrast, high salt intake did not affect “ouabain” levels in the adrenal gland or plasma in Dahl S rats on high salt for either 2 or 4 weeks. These findings indicate that in Dahl S rats high salt intake only increases brain and not peripheral “ouabain” and that benzamil-blockable brain sodium channels mediate the increases in brain “ouabain” and the subsequent hypertension.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

In an attempt to elucidate whether there is a specific &agr;1-adrenergic receptor (&agr;1-AR) subtype involved in the genesis or maintenance of hypertension, the &agr;1D-AR subtype was evaluated in a model of salt-induced hypertension. The &agr;1D-AR–deficient (&agr;1D−/−) and control (&agr;1D+/+) mice (n=8 to 14 in each group) were submitted to subtotal nephrectomy and given 1% saline as drinking water for 35 days. Blood pressure (BP) was monitored by tail-cuff readings and confirmed at the end point by direct intraarterial BP recording. The &agr;1D−/−mice had a significantly (P=0.0004) attenuated increase in BP response in this protocol (baseline 94.6±2.8 versus end point 107.4±4.5 mm Hg) compared with that of their wild-type counterparts (&agr;1D+/+), from a baseline 97.4±2.9 to an end point 139.4±4.5 mm Hg. Seven of 15 &agr;1D+/+mice died with edema, probably owing to renal failure, whereas 14 of 15 &agr;1D−/−mice were maintained for 35 days. Body weight, renal remnant weight, and residual renal function were similar in the 2 groups, whereas the values of plasma catecholamines (epinephrine, norepinephrine, and dopamine) were higher in &agr;1D+/+than in the &agr;1D−/−mice. These data suggest that &agr;1D-AR plays an important role in developing a high BP in response to dietary salt-loading, and that agents having selective &agr;1D-AR antagonism could have significant therapeutic potential in the treatment of hypertension.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID