摘要:

The roles of adventitial vasa vasorum have been highlighted in vascular wall homeostasis. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor in physiological and pathophysiological conditions. However, little is known regarding the changes in adventitial vasa vasorum and the mechanism of the formation in hypertensive arteries. Accordingly, endothelial cell proliferation, adventitial vasa vasorum count, and expression of VEGF signaling axis proteins were examined in the ascending aorta of hypertensive Wistar rats that underwent suprarenal aortic constriction. Hypertension not only induced medial and adventitial thickening but also significantly increased adventitial vasa vasorum count by day 28. Preceding the medial thickening, BrdU+-proliferative endothelial cells were observed in the adventitia but not in the media and intima after day 3; they peaked at day 7 and remained modestly increased at day 28. The BrdU+endothelial cells showed induction of Ets-1, a transcription factor mediating angiogenic response of VEGF. Furthermore, concomitant expression of VEGF and a hypoxia-inducible transcription factor (HIF-1&agr;) was observed in the outer layers of medial smooth muscle cells at day 3 and extended to the middle layers of medial smooth muscle cells at day 7, returning to lower levels by day 28. In conclusion, adventitial vasa vasorum formation was induced by hypertension through the HIF-1&agr;/VEGF/Ets-1 pathway during hypertensive remodeling.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Cardiac vagal control has prognostic significance in cardiac disease, but the control mechanisms of this system remain poorly understood. We have previously demonstrated a role for NO in promoting vagal control of heart rate in humans. Here we examine the influence of l-arginine, the substrate for NO synthase, on this mechanism in healthy human subjects. Eleven healthy volunteers (9 men; age, 20 to 25 years) underwent measurement of heart rate variability and baroreflex sensitivity before and during a systemic infusion of l-arginine (1 g/min; total, 30 g). To control for the fall in blood pressure, comparison was made with an infusion of the control vasodilator hydralazine. Stereospecificity of observed effects was investigated by infusion of d-arginine. Urinary nitrate and nitrite (NOx) and cGMP concentrations were measured as indexes of NO generation. l-Arginine infusion produced a drop in mean arterial pressure of 5 mm Hg. This fall in blood pressure was matched by hydralazine infusion and was not observed with either d-arginine or saline infusion. Although RR interval duration, heart rate variability, and baroreflex sensitivity all fell significantly with hydralazine, the same degree of baroreflex unloading with l-arginine produced an increase in RR interval duration and no change or even slight increases in heart rate variability and baroreflex sensitivity. In contrast, d-arginine produced falls in high-frequency indexes of heart rate variability compared with saline. Only l-arginine increased urinary NOxand cGMP excretion. In conclusion, these data demonstrate that short-term l-arginine infusion facilitates vagal control of heart rate in healthy humans, probably via increased NO synthesis.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Growth hormone (GH) application is a new strategy in the treatment of heart failure. However, clinical and experimental investigations have shown contradictory effects of GH on cardiac performance. We tested the hypothesis that GH could improve cardiac and renal function in volume overload–induced heart failure. The effect of 4 weeks of GH treatment (2 mg/kg daily) was investigated in Wistar rats with aortocaval shunt. GH application did not influence left ventricular contractility and end-diastolic pressure in rats with aortocaval shunt. In contrast, GH treatment normalized impaired diuresis (vehicle 10.8±0.6 mL/d, GH 15.8±0.7 mL/d;P<0.05) and sodium excretion (vehicle 1.5±0.1 mmol/d, GH 2.2±0.1 mmol/d;P<0.001) in shunt-operated rats, with a similar increase of fractional sodium excretion. The urinary excretion of cGMP, the second messenger of atrial natriuretic peptide and NO, was higher in animals with shunts than in sham-operated animals and was further increased by GH (vehicle 293±38 nmol/d, GH 463±57 nmol/d;P<0.01). Although the atrial natriuretic peptide plasma levels were unchanged after GH, the excretion of NO metabolites (nitrate/nitrite) was elevated (vehicle 2020±264 nmol/d, GH 2993±375 nmol/d;P<0.05) in parallel with increased renal mRNA levels of inducible NO synthase 2. The changes of renal function after GH and the increased excretion of NO metabolites and cGMP were abolished by simultaneous treatment with the NO synthase inhibitorNG-nitro-l-arginine methyl ester. GH treatment did not influence cardiac function in rats with aortocaval shunts. However, GH improved renal function by increasing diuresis and sodium excretion. The responsible mechanism might be the enhanced activity of the renal NO system.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

There is sound experimental evidence that cardiovascular sympathetic afferent fibers mediate cardiovascular reflexes largely excitatory in nature with positive-feedback characteristics. This afferent neural channel is likely to normally participate in the neural regulation of cardiovascular function. The hypothesis, which is the core of this article, is that in some pathophysiological conditions, sympathetic overactivity may be partly due to an emerging excitatory reflex action of cardiovascular sympathetic afferents. In fact, the early phase of congestive heart failure can be characterized by an increase in arterial pressure and heart rate and/or by a diastolic dysfunction, leaving unchanged the cardiac output; in these conditions, in which no baroreceptor deactivation should occur, it is possible that cardiovascular sympathetic afferents with sensory endings in the thoracic low-pressure areas, highly responsive to volume loading, are responsible for mediating the reflex sympathetic excitation. Similarly, during acute myocardial infarction, ventricular sympathetic afferents are likely to mediate a reflex sympathetic overactivity, which is known to facilitate sudden death. Finally, numerous reports have described in essential arterial hypertension an increased sympathetic activity that may be due, at least in part, to the reinforcing action of sympathosympathetic reflexes. Thus, in pathophysiological conditions, cardiovascular sympathetic afferents would mediate a reflex sympathetic overactivity independently of baroreceptive mechanisms, and such an absence of a homeostatic purpose would provide a better rationale for some beneficial effects of therapeutic correction.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Leptin regulates cardiovascular function. Leptin levels are elevated in obesity and hypertension and may play a role in cardiovascular dysfunctions in these comorbidities. This study was designed to determine the influence of hypertension on the cardiac contractile response of leptin. Mechanical and intracellular Ca2+properties were evaluated using an IonOptix system in ventricular myocytes from spontaneously hypertensive (SHR) and age-matched Wistar Kyoto (WKY) rats. The contractile properties included peak shortening (PS), duration and maximal velocity of shortening/relengthening (TPS/TR90, ±dL/dt), and fura-fluorescence intensity change (&Dgr;FFI). NO and nitric oxide synthase (NOS) activity were assessed by the Griess and the3H-arginine/citrulline conversion assays, respectively. The leptin receptor (Ob-R) and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway were evaluated by Western blot analysis. SHR animals displayed significantly elevated blood pressure and plasma leptin levels. Leptin elicited a concentration-dependent inhibition of PS and &Dgr;FFI in WKY, but not in SHR myocytes. Leptin did not affect TPS, TR90, or ± dL/dt. The difference in leptin-induced contractile response between the WKY and the SHR groups was abolished by the NOS inhibitor, N&ohgr;-nitro-l-arginine methyl ester (L-NAME), but not by elevated extracellular Ca2+. Either the JAK2 inhibitor AG-490 or the mitogen-activated protein (MAP) kinase inhibitor SB203580 abrogated the leptin-induced response in the WKY myocytes, whereas AG-490 unmasked a negative response in PS in the SHR myocytes. SHR myocytes displayed similar Ob-R protein abundance and basal NO levels, a blunted leptin-induced increase in NOS activity as well as enhanced basal STAT3 levels compared with the WKY group. These data indicate that the leptin-induced cardiac contractile response is abolished by spontaneous hypertension, possibly because of mechanisms involving altered JAK/STAT, MAP kinase signaling, and NO response.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

We investigated whether cardiac apoptosis is stimulated in the heart of hypertensive patients and whether angiotensin II plays a role in such alteration. The study was performed in 28 patients with essential hypertension and no evidence of either ischemic cardiomyopathy or heart failure. After randomization, 14 patients were assigned to losartan and 14 patients to amlodipine treatment. At baseline and after 12 months, right septal endomyocardial biopsies were performed, and the number of apoptotic nuclei was assessed by DNA end-labeling (TUNEL). In addition, immunostaining for the active form of caspase-3 was also performed to assess apoptosis. Compared with normotensive autopsied hearts, both cardiomyocyte and noncardiomyocyte apoptosis were increased (P<0.001) in hypertensive hearts. Time-course changes in blood pressure during treatment were similar in the 2 groups of patients. In losartan-treated patients, both cardiomyocyte and noncardiomyocyte apoptosis decreased (P<0.05). Neither cardiomyocyte nor noncardiomyocyte apoptosis changed significantly in amlodipine-treated patients. These findings indicate that apoptosis is abnormally stimulated in the heart of patients with essential hypertension. Our data also suggest that the ability of antihypertensive treatment to inhibit cardiac apoptosis is independent of its antihypertensive efficacy. We propose that angiotensin II may participate in the stimulation of cardiac apoptosis in essential hypertension.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The activator protein 1 (AP-1) transcriptional complex, containing Jun and Fos proteins, is involved in regulating many cellular processes such as proliferation and differentiation. However, little is known about a direct relationship between AP-1 activities and cardiomyocyte hypertrophy. To elucidate the roles of myocardial AP-1 activities, dominant negative mutant of c-Jun (DNJun) was overexpressed in cultured rat neonatal ventricular myocytes by adenovirus vector to abrogate endogenous AP-1 activation. Cardiomyocytes were treated with 100 nmol/L endothelin 1 (ET) and 10 &mgr;mol/L phenylephrine (PE) to induce myocardial cell hypertrophy. Both ET and PE significantly enhanced AP-1 DNA binding activities (3.4-fold by ET and 4.8-fold by PE at 3 hours,P<0.01). At 48 hours after stimulation, ET and PE significantly increased incorporation of3H-phenylalanine (1.4-fold by ET and 1.5-fold by PE,P<0.01), cell size (2.3-fold and 2.5-fold,P<0.01), and mRNA expression of atrial natriuretic peptide (ANP; 1.9-fold and 1.8-fold,P<0.01) and brain natriuretic peptide (BNP; 1.6-fold and 1.6-fold,P<0.01). Adenovirus carrying DNJun prevented the transcriptional activation of the AP-1 by ET and PE, using AP-1 reporter enzyme firefly luciferase assay. Moreover, DNJun prevented the increase in incorporation of3H-phenylalanine, cell size, and the mRNA expression of ANP and BNP by ET and PE. In conclusion, we provide the first evidence that DNJun inhibits cardiomyocyte hypertrophy through inhibition of AP-1 transcriptional activity.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

NO acting through soluble guanylyl cyclase and cGMP formation is a negative regulator of cardiomyocyte hypertrophy. Downstream targets mediating the inhibitory effects of NO/cGMP on cardiomyocyte hypertrophy have not been elucidated. In addition to its antihypertrophic effects, NO promotes apoptosis in cardiomyocytes, presumably through cGMP-independent pathways. We investigated the role of cGMP-dependent protein kinase (PKG) in the antihypertrophic and proapoptotic effects of NO. Incubation of neonatal rat cardiomyocytes with the NO donorS-nitroso-N-acetyl-d,l-penicillamine (SNAP) (250 &mgr;mol/L) or the PKG-selective cGMP analog 8-pCPT–cGMP (500 &mgr;mol/L) activated endogenous PKG type I, as shown by the site-specific phosphorylation of vasodilator-stimulated phosphoprotein, a well-characterized PKG substrate. SNAP (250 &mgr;mol/L) and 8-pCPT–cGMP (500 &mgr;mol/L) modestly attenuated the hypertrophic response to &agr;1-adrenergic stimulation with phenylephrine. Although a high concentration of SNAP (1000 &mgr;mol/L) promoted apoptosis in cardiomyocytes, as evidenced by the formation of histone-associated DNA fragments, antihypertrophic concentrations of SNAP (250 &mgr;mol/L) and 8-pCPT–cGMP (500 &mgr;mol/L) did not promote cell death. Because chronic activation downregulated endogenous PKG I, we explored whether gene transfer of PKG I would enhance the sensitivity of cardiomyocytes to the antihypertrophic effects of NO/cGMP. Indeed, after adenoviral overexpression of PKG I&bgr;, SNAP (250 &mgr;mol/L) and 8-pCPT–cGMP (500 &mgr;mol/L) completely suppressed the hypertrophic response to &agr;1-adrenergic stimulation. As observed in noninfected cells, SNAP (250 &mgr;mol/L) and 8-pCPT–cGMP (500 &mgr;mol/L) did not promote apoptosis in cardiomyocytes overexpressing PKG I&bgr;. Moreover, overexpression of PKG I&bgr; did not enhance the proapoptotic effects of 1000 &mgr;mol/L SNAP, implying PKG-independent effects of NO on apoptosis. Endogenous PKG I mediates antihypertrophic but not proapoptotic effects of NO in a cell culture model of cardiomyocyte hypertrophy. Adenoviral gene transfer of PKG I selectively enhances the antihypertrophic effects of NO without increasing the susceptibility to apoptosis.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Adrenomedullin and the natriuretic peptides exert vasodilator, natriuretic, and aldosterone-inhibitory actions, making augmentation of both systems potential therapeutic strategies in heart failure. Adrenomedullin and an endopeptidase inhibitor (SCH32615) were administered separately and in combination in 8 sheep with heart failure. Compared with the control condition, SCH32615 (5 mg bolus+1 mg/kg per hour infusion for 3 hours) reduced arterial pressure, left atrial pressure, and peripheral resistance and increased cardiac output, urinary volume, sodium, creatinine, and cAMP excretion. Plasma atrial and brain natriuretic peptide and cGMP concentrations were increased, whereas aldosterone tended to fall. Adrenomedullin (50 ng/kg per minute infusion for 3 hours) induced directionally similar but significantly greater changes in all hemodynamic variables compared with SCH32615. Urinary cAMP, sodium, and creatinine excretion rose, whereas urinary volume was maintained. Circulating adrenomedullin, cAMP, renin, and angiotensin II levels were increased, aldosterone was reduced, and natriuretic peptide levels were unchanged. Coadministration of adrenomedullin and SCH32615 produced hemodynamic effects greater than those achieved during adrenomedullin administration alone. Despite the larger falls in blood pressure, renal function (urinary volume, sodium excretion, and creatinine clearance) was improved to a level similar to that during SCH32615 administration. Elevations in plasma adrenomedullin and cAMP were greater than those during adrenomedullin administration alone, whereas increments in natriuretic peptides were similar to those during SCH32615 alone. Plasma renin and angiotensin II were increased and aldosterone levels were reduced. In conclusion, cotreatment with adrenomedullin and an endopeptidase inhibitor has beneficial hemodynamic and renal effects in heart failure beyond those of either agent separately.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

N-terminal pro-brain natriuretic peptide (NT-proBNP) is increased early after acute myocardial infarction. We assessed the relationship of NT-proBNP with left ventricular function and mass as well as with renal function, hemodynamic, and anthropometric variables in 625 outpatients in the chronic phase after myocardial infarction and 465 siblings without infarction (control). NT-proBNP was measured by nonextracted, enzyme-linked, sandwich immunoassay. NT-proBNP was correlated with left ventricular ejection fraction, mass index, and renal function, in addition to infarction history, gender, and age, in univariate and multivariate analysis (allP<0.01). Increases in NT-proBNP observed in subjects with infarction (96.6±13.7 versus 31.2±1.8 pmol/L in control subjects,P<0.001) were particularly pronounced in the presence of significant left ventricular dysfunction (182.8±41.9 pmol/L), left ventricular hypertrophy (214.5±61.7 pmol/L), and renal dysfunction (210.3±51.4 pmol/L, allP<0.01). Patients with an ejection fraction <35% were detected by NT-proBNP with a sensitivity, specificity, and negative predictive value of 75%, 62%, and 99%, respectively, at an optimal cutoff of 44 pmol/L. Patients with an ejection fraction <35% and concomitant left ventricular hypertrophy were detected with a sensitivity, specificity, and negative predictive value of 90%, 80%, and 99.9%, respectively, at a cutoff of 76 pmol/L. Similar results were obtained for patients with an ejection fraction <35% and concomitant renal dysfunction at a cutoff of 162 pmol/L. NT-proBNP is a biochemical marker of integrated cardio-renal function in the chronic phase after myocardial infarction and a potential diagnostic tool for the detection and exclusion of significant left ventricular dysfunction. Cutoff concentrations have to be chosen according to renal function to optimize the predictive value of NT-proBNP.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID