Nitric oxide and cardiac failure

Cardiac myocytes express two types of nitric oxide (NO) synthase, eNOS and iNOS. eNOS activity is regulated by the contractile state of the heart, while iNOS expression is induced by cytokines. Nitric oxide induced by cytokines causes negative inotropic and lethal effects on cardiac myocytes. Expression of iNOS in the myocardium is increased in patients with dilated cardiomyopathy with clinical evidence of heart failure. Several neurohumoral factors activated in chronic heart failure augment cardiac iNOS expression and could cause cardiac dysfunction and cell damage.     

Nitric oxide buffers renal medullary vasoconstriction induced by prostaglandins synthesis blockade.

The aim of this study was to examine whether nitric oxide (NO) buffers the renal medullary vasoconstriction induced by a prostaglandins (PG) synthesis inhibitor. Daily blood pressure measurements were made with implanted catheters and changes in cortical blood flow (CBF) and medullary blood flow (MBF) were determined by implanted optical fibers and laser-Doppler flow measurement techniques in conscious rats. Sodium and water balance were also determined. Infusion of meclofenamate, a nonisozyme-specific cyclooxygenase (COX) inhibitor, at 5 microg/kg/min over 4 consecutive days (n=12 rats) elicited a transitory increase (p<0.05) in mean arterial pressure (MAP) and a transitory decrease (p<0.05) in MBF and sodium excretion without altering CBF. In contrast, the simultaneous infusion of meclofenamate and N(G)-nitro-L-arginine methyl ester (L-NAME, 0.8 microg/kg/min), a NO synthesis inhibitor, over 4 consecutive days (n=12) produced a continuous increase (p<0.01) in MAP and a continuous decrease (p<0.05) in MBF and sodium excretion without altering CBF. The results of this study suggest that the renal medullary vasoconstrictor effects and sodium retention induced by meclofenamate are enhanced by a subpressor dose of L-NAME, and that NO may buffer the renal medullary vasoconstriction induced by the blockade of PG synthesis in conscious rats.     

Differential effects of angiotensin II receptor blockade on pressure-induced left ventricular hypertrophy and fibrosis in rats

The effects of the angiotensin II receptor type 1 (AT1) antagonist losartan on pressure overload-induced left ventricular (LV) hypertrophy were studied in female Sprague-Dawley rats. Starting on the day of surgery, losartan (L, 12 mg/kg/day) was administered as continuous intraperitoneal infusion for 2 weeks by using alzet mini-osmotic-pumps (model 2002). This dose of losartan shifted the in vivo dose-response curve of the angiotensin II-induced elevation of left ventricular systolic pressure (LVSP) to the right. Pressure overload was achieved by placing a band around the aortic arch. This caused an aortic stenosis (AS) with an outer diameter of 1.0 mm. The hemodynamic effects were measured in the intact, anesthetized rats (n = 15). The hearts were excised, and the weights of the left (LV) and right ventricle (RV) were determined. Some of these hearts (n = 7) were perfused with collagenase to obtain isolated cardiac myocytes for the measurement of cell volume. Other hearts (n = 8) were examined for morphological changes. In the animals with AS, LVSP was markedly elevated. Furthermore, LV weight and LV myocyte cell volume were increased in this group, while RV weight and RV myocyte cell volume remained stable in all the groups. L had no significant effect on the AS-induced increase in LVSP and cell size parameters, nor on the weight gain of the LV. Histological analysis revealed that the AS-induced enlargement of the mean myocyte diameter was not affected by L. The interstitial collagen fraction was increased in the AS rats and became normalized by L. These data suggest that the renin-angiotensin system might not be involved in the development of pressure-induced cardiac hypertrophy within the time-frame of these experiments, but that it does play a major role in the genesis of the interstitial fibrosis which is a typical feature of this pathophysiological condition.     

一氧化氮与心脏的舒张功能

从冠状动脉内皮细胞释放的NO(-氧化氮)影响着心肌收缩功能的多个方面,尤其影响着左心室舒张功能。NO对人体生理与病理状态下心脏左心室的舒张功能起着重要的调节作用。本文就近年来有关NO与心脏左心室舒张功能的关系及如何调节、利用这一关系的研究现状作一简要综述。     

Effects of combined aerobic and resistance training versus aerobic training alone in cardiac rehabilitation

PURPOSE: This study examined the effects of performing combined resistance and aerobic training, versus aerobic training alone, in patients with coronary artery disease. METHODS: Thirty-six patients with coronary artery disease were randomized to either an aerobic-only training group (AE) or a combined aerobic and resistance training group (AE + R). Both groups performed 30 minutes of aerobic exercise 3 days/week for 6 months. In addition, AE + R group performed two sets of resistance exercise on seven different Nautilus machines after completion of aerobic training each day. Twenty patients (AE: n = 10; AE + R: n = 10) completed the training protocol with > 70% attendance. RESULTS: Strength gains for AE + R group were greater than for AE group on six of seven resistance machines (P < 0.05). VO2peak increased after training for both AE and AE + R (P < 0.01) with no difference in improvement between the groups. Resting and submaximal exercise heart rates and rate-pressure product were lower after training in the AE + R group (P < 0.01), but not in the AE group. AE + R increased lean mass in arm, trunk, and total body regions (P < 0.01), while AE increased lean mass in trunk region only (P < 0.01). Percent body fat was reduced for AE + R after training (P < 0.05) with a between group trend toward reduced body fat (P = 0.09). Lean mass gain significantly correlated with strength increase in five of seven resistance exercises for AE + R. CONCLUSIONS: Resistance training adds to the effects of aerobic training in cardiac rehabilitation patients by improving muscular strength, increasing lean body mass, and reducing body fat.     

Nitric oxide blockade enhances renal responses to superoxide dismutase inhibition in dogs

To examine the potential role of superoxide anion (O(2)(-)) and its interaction with NO in the regulation of renal hemodynamics and excretory function, we have evaluated the renal responses to enhancement in O(2)(-) activity before and during NO synthase inhibition in anesthetized dogs (n=6). Intraarterial infusion of a superoxide dismutase (SOD) inhibitor, diethyldithiocarbamate (DETC; 0.1 and 0.5 mg/kg per min) was made to enhance O(2)(-) activity in the kidney. Cortical (CBF), medullary (MBF), and total renal blood flow (RBF) responses were assessed using laser-Doppler needle flow probes and an electromagnetic flow probe. DETC caused dose-dependent changes in renal parameters, which were recovered within 30 minutes after the termination of DETC infusion. The high-dose infusion of DETC for 25 minutes resulted in an increase of 29 +/- 10% in renal vascular resistance (control, 35.4 +/- 4.4 mm Hg/mL per min per g) and decreases of 21 +/- 5% in RBF (control, 3.5 +/- 0.5 mL/min per g), 20 +/- 5% in CBF, 21 +/- 7% in MBF, 62 +/- 11% in urine flow (control, 10.5 +/- 2.2 microL/min per g), and 47 +/- 11% in sodium excretion (control, 2.1 +/- 0.2 micromol/min per g), without a significant change (-10 +/- 6%) in glomerular filtration rate (control, 0.74 +/- 0.09 mL/min per g). During NO synthase inhibition with intraarterial administration of nitro-L-arginine (50 microg/kg per min), the same dose of DETC showed a greater increase in renal vascular resistance (73 +/- 15%) and reductions in RBF (39 +/- 4%), CBF (32 +/- 5%), MBF (34 +/- 6%), urine flow (78 +/- 5%), and sodium excretion (67 +/- 0%), with a marked reduction in glomerular filtration rate (59 +/- 7%). These data indicate that O(2)(-) exerts renal vasoconstriction as well as antidiuretic and antinatriuretic effects. These responses are enhanced during NO synthase blockade, suggesting that NO serves a renoprotective effect against these action of O(2)(-).     

Vascular sensitivity to phenylephrine in rats submitted to anaerobic training and nandrolone treatment

The effect of anaerobic physical training and nandrolone treatment on the sensitivity to phenylephrine in thoracic aorta and lipoprotein plasma levels of rats was studied. Sedentary and trained male Wistar rats were treated with vehicle or nandrolone (5 mg/kg IM; twice per week) for 6 weeks. Training was performed by jumping into water (4 sets, 10 repetitions, 30-second rest, 50% to 70% body weight load, 5 days/week, 6 weeks). Two days after the last training session, the animals were killed and blood samples for lipoprotein dosage were obtained. Thoracic aorta was isolated and concentration-effect curves of phenylephrine were performed in intact endothelium and endothelium-denuded aortic rings in the absence or presence of NG-L-arginine-methyl ester. No changes were observed in endothelium-denuded aortic rings. However, in endothelium-intact thoracic aorta, anaerobic physical training induced subsensitivity to phenylephrine (pD2=7.11+/-0.07) compared with sedentary group (7.55+/-1.74), and this effect was canceled by the inhibition of nitric oxide synthesis. No difference was observed between trained (7.22+/-0.07) and sedentary (7.28+/-0.09) groups treated with nandrolone. Anaerobic training induced an increase in high-density lipoprotein levels in vehicle-treated rats, but there were no changes in nandrolone-treated groups. Training associated with nandrolone induced an increase in low-density lipoprotein levels but no change in the other groups. If altering endothelium-dependent vasodilatation is considered to be a beneficial adaptation to anaerobic physical training, it is concluded that nandrolone treatment worsens animals' endothelial function, and this effect may be related to lipoprotein blood levels.     

Nitric oxide and cardiac autonomic control in humans

Cardiac autonomic control is of prognostic significance in cardiac disease, yet the control mechanisms of this system remain poorly defined. Animal data suggest that nitric oxide (NO) modulates cardiac autonomic control. We investigated the influence of NO on the baroreflex control of heart rate in healthy human subjects. In 26 healthy male volunteers (mean age, 23+/-5 years), we measured heart rate variability and baroreflex sensitivity during inhibition of endogenous NO production with N(G)-monomethyl-L-arginine (L-NMMA) (3 mg/kg per hour) and during exogenous NO donation with sodium nitroprusside (1 to 3 mg/h). Increases from baseline (Delta) in high-frequency (HF) indexes of heart rate variability were smaller with L-NMMA in comparison to an equipressor dose of the control vasoconstrictor phenylephrine (12 to 42 microg/kg per hour): Deltaroot mean square of successive RR interval differences (DeltaRMSSD)=23+/-32 versus 51+/-48 ms (P<0.002); Deltapercentage of successive RR interval differences >50 ms (DeltapNN50)=5+/-15% versus 14+/-12% (P<0.05); and DeltaHF normalized power=-2+/-7 versus 9+/-8 normalized units (P<0.01), respectively. Relative preservation of these indexes was observed during unloading of the baroreflex with sodium nitroprusside compared with a matched fall in blood pressure produced by a control vasodilator, hydralazine (9 to 18 mg/h): DeltaRMSSD=-8+/-8 versus -24+/-15 ms (P<0.001); DeltapNN50=-6+/-11% versus -15+/-19% (P<0.01); DeltaHF normalized power=-7+/-13 versus -13+/-11 normalized units (P<0.05), respectively. The change in cross-spectral alpha-index calculated as the square root of the ratio of RR interval power to systolic spectral power in the HF band (although not alpha-index calculated in the same way for the low-frequency bands or baroreflex sensitivity assessed by the phenylephrine bolus method) was attenuated with L-NMMA compared with phenylephrine (Delta=4+/-8 versus 14+/-15 ms/mm Hg, respectively; P<0.02) and with sodium nitroprusside compared with hydralazine (Delta=-7+/-6 and -9+/-7 ms/mm Hg, respectively; P<0.05). In conclusion, these data demonstrate that NO augments cardiac vagal control in humans.     

Nitric oxide and cardiac muscarinic control in humans

Cardiac parasympathetic activity reduces susceptibility to potentially lethal ventricular arrhythmias in heart failure and ischemic heart disease. This influence is mediated in large part by antagonism of the adverse cardiac effects of sympathetic overactivity ("indirect" parasympathetic activity) in addition to the "direct" effects of muscarinic stimulation. Nitric oxide modulates parasympathetic cardiac signaling in some animal models, but human data are lacking. We have investigated the influence of endogenous nitric oxide on cardiac responses to parasympathetic stimulation in healthy humans. In 18 volunteers, we studied chronotropic and inotropic responses to muscarinic stimulation, both before and after prestimulation with isoproterenol. Cardiac muscarinic stimulation was achieved using an intravenous bolus of the short-acting cholinesterase inhibitor, edrophonium. Responses were assessed during a background infusion of a nitric oxide synthase inhibitor (N(G)-monomethyl-L-arginine [L-NMMA]), placebo (saline), or phenylephrine (vasoconstrictor control) in a single-blind, random order, crossover protocol. L-NMMA did not affect chronotropic responses to edrophonium alone (direct parasympathetic activity). The decrease in heart rate attributable to "indirect" parasympathetic activity (derived by comparison with the effect of edrophonium during concurrent adrenergic stimulation) was substantially attenuated by L-NMMA in comparison to both control infusions. No modification of muscarinic inotropic responses by L-NMMA was apparent in comparison to the vasoconstrictor control. Nitric oxide exerts a powerful facilitating influence on indirect (antiadrenergic) but not direct human cardiac parasympathetic control. Stimulation of the endogenous nitric oxide pathway might enhance parasympathetic protection against the adverse influences of cardiac sympathetic overactivity.     

Nitric oxide synthase inhibition increases aortic stiffness measured by pulse wave velocity in rats

OBJECTIVE: The present study was to examine whether endogenous nitric oxide (NO) plays a role in the regulation of vascular stiffness. METHODS: Pulse wave velocity (PWV) was determined as the time delay between the foot of pressure waves recorded simultaneously at the aortic arch and abdominal aorta (just above the bifurcation) in anesthetized Sprague-Dawley rats. A decrease in vascular compliance results in an increase in PWV. RESULTS: A bolus injection of a NO synthase inhibitor, L-NAME (30 mg/kg), significantly increased PWV, accompanied by an increase in blood pressure. Since changes in blood pressure are known to affect PWV, phenylephrine (PE) was administered to mimic the blood pressure changes induced by L-NAME, thus compensating for the pressure-dependent component of the PWV changes. At each given level of mean arterial pressure (MAP), PWV was significantly higher with L-NAME than with PE treatment, suggesting that acute withdrawal of endogenous NO reduces aortic compliance independent of changes in MAP. In rats chronically treated with L-NAME (0.5 g/l in drinking water) for 3 weeks, PWV was even higher than those acutely treated with L-NAME (at MAP=150 mmHg). This additional increase in vascular stiffness may be due to the remodeling of the vascular wall as a result of chronic NOS inhibition and hypertension. CONCLUSION: These data demonstrate that NO modulates vascular compliance independent of blood pressure changes and that an intact endogenous NO system is required to maintain normal vascular compliance.     

Collagen synthesis in development and reversal of cardiac hypertrophy in spontaneously hypertensive rats.

An alteration in the rate of collagen synthesis was observed in spontaneously hypertensive rats during evolution of hypertension. An increase in rate of synthesis of collagen and a parallel increase in collagen content were observed in 4–8 week and 24 week old hypertensive rats. In the 4 week old rats, blood pressure was normal or nearly normal, whereas in the 24 week old rats the arterial pressure was significantly elevated. Use of some antihypertensive drugs, namely, α-methyldopa, converting enzyme inhibitor and a combination of reserpine, hydrochlorothiazide and apresoline, prevented hypertension and the late increase in collagen synthesis that was observed in the 24 week old hypertensive rats. In these rats, prevention of hypertension also reversed myocardial hypertrophy and reduced collagen content of the myocardium. The alteration of myocardial collagen synthesis in spontaneously hypertensive rats is a complex process in which at least two phases can be observed. In the young rats, in which blood pressure is normal, the stimulus to increase in collagen may be a humoral factor or a hemodynamic alteration such as hyperkinetic circulation or it may be a genetic factor. In the older hypertensive rats hypertension seemed more important in altering collagen synthesis because antihypertensive therapy inhibited the rate of collagen synthesis and protected the heart from excess accumulation of collagen.     

Long-term blockade of nitric oxide synthesis in rats modulates coronary capillary network remodeling

Long-term blockade of nitric oxide synthesis with N^ω-nitro-L-arginine methyl ester (L-NAME) induces cardiac perivascular fibrosis in rats. Its relationship to expression of angiogenic growth factors and capillary network remodeling is not understood. This study was designed to determine whether capillary proliferation and angiogenic growth factor regulation occur in response to L-NAME. Three groups of rats were studied: C, control; L1, L-NAME 13 mg/kg/day; L2, 130 mg/kg/day. One and eight weeks later the hearts were removed and subjected to morphometric analysis and analysis of gene expressions of molecules related to angiogenesis. Arterial hypertension was observed within 8 weeks in the L1 and L2 groups compared with control. After 1 week immunohistochemical assays demonstrated basic fibroblast growth factor (bFGF) in the arteriolar media. Northern blot analysis revealed increase in bFGF and transforming growth factor-β (TGF-β) mRNA during this period. At 8 weeks arteriolar medial thickening and perivascular fibrosis were seen microscopically in the L1 and L2 groups, which were accompanied by only a modest remodeling of capillary network due to increase in venular or intermediate capillary portions. Concomitantly immunoreactivity for vascular endothelial growth factor (VEGF) and TGF-β were detected in perivascular area. These results suggest that (1) blockade of NO synthesis induces expression of angiogenic growth factors as well as vessel wall remodeling, and (2) TGF-β may counteract angiogenic growth factors and limit subsequent alterations in capillary network remodeling. This revised version was published online in June 2006 with corrections to the Cover Date.     

Role of osteopontin in cardiac fibrosis and remodeling in angiotensin II-induced cardiac hypertrophy

Osteopontin (OPN) is upregulated in several experimental models of cardiac fibrosis and remodeling. However, its direct effects remain unclear. We examined the hypothesis that OPN is important for the development of cardiac fibrosis and remodeling. Moreover, we examined whether the inhibitory effect of eplerenone (Ep), a novel aldosterone receptor antagonist, was mediated through the inhibition of OPN expression against cardiac fibrosis and remodeling. Wild-type (WT) and OPN-deficient mice were treated with angiotensin II (Ang II) for 4 weeks. WT mice receiving Ang II were divided into 2 groups: a control group and an Ep treatment group. Ang II treatment significantly elevated blood pressure and caused cardiac hypertrophy and fibrosis in WT mice. Ep treatment and OPN deficiency could reduce the Ang II-induced elevation of blood pressure and ameliorate the development of cardiac fibrosis, whereas Ep-only treatment abolished the development of cardiac hypertrophy. Most compelling, the reduction of cardiac fibrosis led to an impairment of cardiac systolic function and subsequent left ventricular dilatation in Ang II-treated OPN-deficient mice. These results suggest that OPN has a pivotal role in the development of Ang II-induced cardiac fibrosis and remodeling. Moreover, the effect of Ep on the prevention of cardiac fibrosis, but not cardiac hypertrophy, might be partially mediated through the inhibition of OPN expression.