Compensatory adaptation of the heart to chronic rate overload: increase in calcium transport ATPase activity of myocardial sarcoplasmic reticulum

This study was undertaken to test the hypothesis that a compensatory response of the heart to a chronic and continuous, metabolic and heart rate overload was an increase in the calcium sequestering activity of the myocardial sarcoplasmic reticulum. Calcium sequestering activity was estimated by determination of the calcium-dependent ATPase (Ca2+-ATPase) activity of isolated microsomes. Chronic rate overload was modelled by comparing: dysthyroid and control rats; control swine and swine with implanted cardiac pacemakers set at 180 beats/min; and different species of mammals with widely different heart rates. The myocardial sarcoplasmic reticulum Ca2+-ATPase pump activity was significantly increased by 39% for hyperthyroid rats compared to control rats and by 87% for control rats compared to thyroidectomized rats; by 63% for paced swine compared to control swine; and by 43% for rats compared to guinea pigs, by 140% for guinea pigs compared to dogs and by 120% for dogs compared to cows. These data indicate that calcium sequestering activity of myocardial sarcoplasmic reticulum increases in equivalent proportion to the chronotropic demand and that heart rate is a hemodynamic correlate of the sarcoplasmic reticulum Ca2+-ATPase activity.     

Role of nitric oxide in the pathophysiology of heart failure

Nitric oxide (NO) plays critical roles in the regulation of integrated cardiac and vascular function and homeostasis. An understanding of the physiologic role and relative contribution of the three NO synthase isoforms (neuronal—NOS1, inducible—NOS2, and endothelial—NOS3) is imperative to comprehend derangements of the NO signaling pathway in the failing cardiovascular system. Several theories of NO and its regulation have developed as explanations for the divergent observations from studies in health and disease states. Here we review the physiologic and pathophysiologic influence of NO on cardiac function, in a framework that considers several theories of altered NO signaling in heart failure. We discuss the notion of spatial compartmentalization of NO signaling within the myocyte in an effort to reconcile many controversies about derangements in the influences of NO in the heart and vasculature.     

Relationship between basal nitric oxide and ventricular repolarization in an intact heart

Recent studies suggest that endogenous nitric oxide (NO) attenuates ischemia- or reperfusion-induced shortening in the action potential duration of ventricular myocytes. The effect of basal NO on ventricular repolarization in an intact heart remains unclear. The activation-recovery interval was measured from 32 epicardial electrocardiograms in six anesthetized, open-chest sheep. Intravenous administration of N^G-nitro-L-arginine, a NO synthase inhibitor, increased left ventricular systolic pressure from 101±7 mmHg to 118±10 mmHg (P=0.02), and left ventricular end diastolic pressure from 6.3±1.5 mmHg to 8.8±1.8 mmHg (P<0.01) without changing the heart rate (96±4 beats/min versus 94±3 beats/min, P=0.06). The average activation-recovery interval from the 32 ventricular sites remained unchanged in each animal after the administration of N^G-nitro-L-arginine (P>0.05). The pooled activation-recovery interval in the six animals before and 60 min after drug administration was 287±21 ms and 288±27 ms, respectively (P>0.05). It was concluded that basal NO is important in maintaining hemodynamics but has limited impact on ventricular repolarization.     

Role of nitric oxide in matrix remodeling in diabetes and heart failure

Accumulation of oxidized-matrix between the endothelium and myocytes is associated with endocardial endothelial (EE) dysfunction in diabetes and heart failure. High levels of circulating homocysteine (Hcy) have been demonstrated in diabetes mellitus (DM). These high levels of Hcy (hyperhomocysteinemia, HHcy) have a negative correlation with peroxisome proliferator activated receptor (PPAR) expression. Studies have demonstrated that Hcy decreases bioavailability of endothelial nitric oxide (eNO), generates nitrotyrosine, and activates latent matrix metalloproteinase (MMP), instigating EE dysfunction. PPAR ligands ameliorate endothelial dysfunction and DM. In addition Hcy competes with PPAR ligands. The understanding of molecular, cellular, and extracellular mechanisms by which Hcy amplifies DM will have therapeutic ramifications for diabetic cardiomyopathy.     

Role of nitric oxide in reactive hyperemia of the guinea pig heart.

To evaluate the role of nitric oxide (NO) in the flow response after brief coronary arterial occlusion, NO formation by the isolated guinea pig heart was assessed by a specific difference spectrophotometric assay. Release of NO under basal conditions was 121.8 +/- 10.5 pmol x min-1 and increased to 211.1 +/- 16.8 pmol x min-1 after 60 seconds of coronary occlusion. Simultaneously, release of cGMP and adenosine increased by 87% and 652%, respectively. The kinetics of NO release paralleled the reactive hyperemic flow response. Inhibition of NO synthesis with nitro-L-arginine methyl ester (L-NAME, 30 microM) significantly reduced basal flow and attenuated reactive hyperemia, flow repayment, and repayment ratio. L-NAME decreased release of cGMP but significantly increased adenosine release under basal conditions and during reactive hyperemia. Oxyhemoglobin (5 microM) potentiated the effects of L-NAME. The stereoisomer nitro-D-arginine methyl ester was ineffective. Our results suggest 1) NO is an important regulator of coronary flow during reactive hyperemia as well as under basal flow conditions and 2) the significance of the increased adenosine release when NO synthesis is inhibited remains to be determined.     

Effect of nitric oxide and nitric oxide donors on red blood cell oxygen transport

A mechanism has been proposed in which nitric oxide (NO) may bind to cysteine beta93 and be transported by haemoglobin from the lungs to the tissues and modify vascular tone. In addition, it has been reported that treatment of sickle cell anaemia blood with 80 p.p.m. NO gas in air shifts the oxygen affinity, as measured by P50 to the left. We exposed normal and sickle cell anaemia blood to 80 p.p.m. NO in air for 1 h in vitro and found no change in P50 of either normal or sickle cell blood. In addition, we exposed normal and sickle cell blood in buffer to aqueous NO (NO gas dissolved in buffer) at varying concentrations and found that the induced left shift in P50 correlates strongly and linearly with methaemoglobin formation. We also treated normal and sickle cell blood with other nitric oxide donors, such as sodium 2-(N, N-diethylamino)-diazenolate-2-oxide (DEANO), S-nitrosocysteine (CysNO) and sodium trioxodinitrate (OXINO, or Angeli's salt). In all cases, we found a dose-dependent increase in methaemoglobin that was strongly correlated with the dose-dependent P50 reduction. Our data do not support the report that low NO concentrations can selectively increase the oxygen affinity of sickle cell blood without affecting methaemoglobin levels significantly. NO, however, may have benefit in sickle cell disease by other mechanisms.     

Effects of nitric oxide inhibition on basal forearm blood flow in patients with nonischemic chronic heart failure

Summary Increased peripheral vascular tone in patients with chronic heart failure (CHF) is an important factor which contributes to increased cardiac afterload and reduced exercise capacity, and consequent further deterioration in CHF. The role of endogenous nitric oxide (NO) in the regulation of basal vascular tone in CHF is controversial. This study has investigated (1) whether basal NO bioavailability is reduced in the peripheral vasculature of patients with nonischemic CHF in the absence of confounding factors influencing endothelial function, and (2) if a difference is found, what clinical characteristics are related to the decreased NO-dependent vasodilation. Basal forearm blood flow (FBF) of 12 patients with CHF and 14 healthy volunteers was measured before and after administration ofN ^G-monomethyl-l-arginine (l-NMMA) by venous occlusion plethysmography. Afterl-NMMA administration, basal FBF in both healthy subjects and patients with CHF decreased significantly, with the decrease in CHF patients being less than that in healthy volunteers (–0.7 ± 0.2 vs –1.5 ± 0.2ml/min per 100ml tissue,P < 0.01). When both groups were considered together, basal FBF was closely related to the decrease in FBF afterl-NMMA administration (r = –0.83.P < 0.001). When CHF patients were divided into two groups according to NYHA class, thel-NMMA-induced decrease in FBF in moderate CHF (NYHA III;n = 7) was significantly less than that in mild CHF (NYHA II;n = 5) (–0.36 ± 0.13 vs –1.16 ± 0.72ml/min per 100ml tissue,P < 0.05). In conclusion, basal bioavailability of NO in the peripheral vascular bed in nonischemic CHF is impaired, with an increase in basal vascular tone and with progression of this disorder. This suggests that impaired basal NO bioactivity may make an important contribution to the elevated peripheral vascular tone and expression of symptoms seen in CHF.     

Augmented basal nitric oxide production contributes to maintenance of coronary blood flow in dogs with pacing-induced heart failure

It remains controversial whether basal nitric oxide (NO) production in coronary resistance vessels in heart failure is enhanced or not. A transonic Doppler flow probe was placed around the left anterior descending coronary artery, and complete atrioventricular block was produced in fifteen dogs. The coronary pressure-flow relationships during long diastole were analyzed without and with pacing-induced heart failure. Three weeks after pacing at 240/min, plasma norepinephrine and renin activity significantly rose. Right atrial pressure and left ventricular end-diastolic pressure increased, and cardiac output and coronary perfusion pressure decreased; however, mean coronary blood flow did not change after pacing (55 +/- 5 to 52 +/- 5 ml/min/100 g, mean +/- SEM). The slope of the diastolic coronary pressure-flow relationship became steeper (1.22 +/- 0.13 to 1.62 +/- 0.09 ml/min/100 g/mmHg, p < 0.05) with a slight increase in the measured zero-flow pressure (29.5 +/- 1.1 to 32.8 +/- 1.5 mmHg, p < 0.05) after pacing. After pretreatment with indomethacin, administration of NG-nitro-L-arginine methyl ester caused an equal increase in the zero-flow pressure before (31.4 +/- 1.7 to 39.2 +/- 2.2 mmHg, p < 0.05) and after heart failure (33.9 +/- 2.5 to 41.6 +/- 2.2 mmHg, p < 0.05), and more decline of the slope of the coronary pressure-flow relationship in heart failure (1.86 +/- 0.22 to 1.20 +/- 0.05 ml/min/100 g/mmHg, p < 0.05) than before heart failure (1.11 +/- 0.12 to 1.05 +/- 0.11 ml/min/100 g/mmHg, N.S.). This indicates that in failing hearts the vasodilatory action of NO in small vessels predominates despite the presence of several vasoconstricting factors. These results suggest that coronary blood flow is maintained despite detrimental hemodynamic and activated neurohumoral factors in the initial stage of heart failure, and that increased basal NO production plays a central role in the maintenance of basal coronary blood flow.     

Inhibition of platelet aggregation by nitric oxide donors improves with rest

It has been suggested that the platelets of patients with acute coronary syndromes (ACS) exist in a more activated state than those of patients with stable coronary heart disease (CHD) or healthy individuals. “Platelet nitrate responsiveness” (PNR) has been suggested as a measure of platelet activation, and has been shown to be reduced in both ACS and stable CHD. We examined the effect of a short period of undisturbed supine rest, an intervention aimed at reducing levels of “stress”, on PNR. In 8 healthy subjects we found that 45?minutes of rest led to a highly significant reduction in platelet aggregation and increase in PNR. Our finding supports the hypothesis that stress contributes to platelet activation as reflected in reduced PNR, which may contribute to the link between acute stress and cardiovascular events. It also emphasises that standardisation of sampling conditions in vitally important in studies utilizing PNR.     

Inhibition of platelet aggregation by nitric oxide donors improves with rest

It has been suggested that the platelets of patients with acute coronary syndromes (ACS) exist in a more activated state than those of patients with stable coronary heart disease (CHD) or healthy individuals. "Platelet nitrate responsiveness" (PNR) has been suggested as a measure of platelet activation, and has been shown to be reduced in both ACS and stable CHD. We examined the effect of a short period of undisturbed supine rest, an intervention aimed at reducing levels of "stress", on PNR. In 8 healthy subjects we found that 45 minutes of rest led to a highly significant reduction in platelet aggregation and increase in PNR. Our finding supports the hypothesis that stress contributes to platelet activation as reflected in reduced PNR, which may contribute to the link between acute stress and cardiovascular events. It also emphasises that standardisation of sampling conditions in vitally important in studies utilizing PNR.     

Role of calcium antagonists for heart rate control in atrial fibrillation.

Atrial fibrillation is one of the most common symptomatic sustained arrhythmias seen in clinical practice. Many patients with atrial fibrillation and a ventricular response greater than 120 beats/min will experience cardiac symptoms. In the past, control of heart rate in these patients consisted of administration of intravenous digoxin, but this often proved to be ineffective or limited by toxicity. Recently, intravenous beta blockers such as esmolol have been used to slow the ventricular rate during atrial arrhythmias, but in some studies their use has been limited by hypotension. Alternatively, a bolus of an intravenous calcium antagonist, e.g., diltiazem or verapamil, may be administered to achieve acute slowing of the ventricular response. An intravenous bolus of diltiazem or verapamil may be effective, but use of either may be limited by its short duration of action and the inability to administer repeated boluses to tightly control or "fine tune" the heart rate. However, a new bolus plus maintenance infusion technique with diltiazem has shown promise in initial studies. It appears that in the future, continuous infusion techniques with intravenous calcium antagonists will be available that provide safe and effective sustained control of the ventricular response during atrial arrhythmias.     

阿托伐他汀对冠心病患者血清一氧化氮及一氧化氮合酶含量的影响

目的　观察阿托伐他汀对冠心病患者血清一氧化氮 (NO)及一氧化氮合酶 (NOS)含量水平的影响。方法　对用阿托伐他汀治疗的 79例冠心病患者依据是否合并高胆固醇血症分为两组 ,对其治疗前后血清 NO及 NOS含量水平进行对比分析。结果　不论是否合并高胆固醇血症的冠心病 ,阿托伐他汀均可升高其血清 NO及 NOS水平。结论　阿托伐他汀可通过调脂治疗抑制脂质的过氧化反应 ,保护血管内皮功能 ,但其保护内皮功能的作用不受患者是否存在高脂血症的影响 ,改善内皮功能 ,对冠心病的防治具有重要意义。     

Role of prostacyclin and nitric oxide in regulation of basal microvascular hydraulic permeability in cat skeletal muscle.

The effects of prostacyclin, nitric oxide (NO) and beta2-receptor stimulation on capillary filtration coefficient (CFC) and vascular tone were analyzed in an autoperfused cat skeletal muscle in vivo preparation, to evaluate if these substances are involved in regulation of basal microvascular hydraulic permeability. CFC was increased from control (100%) to 124% with the prostacyclin-synthase inhibitor tranylcypromine and restored by simultaneous infusion of prostacyclin at 0.1 ng.kg-1. min-1, with further reduction to 76% at 1 ng. kg-1.min-1. Prostacyclin at these doses did not influence vascular tone. NO inhibition by L-NAME increased CFC to 116% of control, with a vascular resistance increase of 45%. CFC was restored by simultaneous infusion of the NO precursor L-arginine. L-arginine given alone reduced CFC to 86% of control. Tranylcypromine and L-NAME given together increased CFC to 141% of control and CFC was reduced to 86% by prostacyclin at 1 ng.kg-1. min-1 with no significant further reduction by adding L-arginine. Adrenaline alone, in a vasodilating dose verifying beta2 stimulation, or when followed by simultaneous beta-blockade with propranolol, did not influence CFC. We conclude that NO and especially prostacyclin are involved in bi-directional regulation of basal microvascular hydraulic permeability and can account for up to 30-40% increase or decrease from a basal value. Physiological beta2 stimulation has no effect on basal hydraulic permeability. The permeability-reducing effects of prostacyclin and NO are additive. NO, but not prostacyclin, is involved in regulation of basal vascular tone.     

Nebivolol induces nitric oxide release in the heart through inducible nitric oxide synthase activation

Nebivolol is a beta1-adrenergic receptor antagonist that also reduces blood pressure by evoking endothelial NO production and vasodilation. We aimed at assessing whether nebivolol induces NO production also in the heart and delineating the molecular mechanisms involved. Using the fluorescent probe diaminofluorescein, we found that nebivolol induces a dose-dependent NO production in the heart, statistically significant already at 10(-7) mol/L. It is not an effect because of the blockade of beta1-adrenergic receptor, because this effect is not shared by another drug of the same class, atenolol. Because nebivolol has been reported to act as an agonist on other beta-adrenergic receptors, we tested NO production in the presence of receptor antagonists. Nebivolol was not able to induce NO production in presence of the beta3-antagonist SR59230A, indicating a fundamental role for beta3-adrenergic receptors in cardiac NO production by nebivolol. Moreover, inducible NO synthase inhibition abolishes NO release in the heart, indicating that nebivolol induces NO production by acting on the inducible isoform of the enzyme. The action of nebivolol on inducible NO synthase was confirmed by real-time PCR experiments, showing cardiac overexpression of inducible NO synthase but not neuronal NO synthase or endothelial NO synthase, after 5 hours of treatment with nebivolol. In conclusion, our study demonstrates that nebivolol also stimulates NO production in the heart. This action of nebivolol is exerted via a signaling pathway starting from the activation of beta3-adrenergic receptors and leading to overexpression of inducible NO synthase. Cardiac NO production by nebivolol could participate in the cardiovascular effects of nebivolol treatment in patients affected by hypertension and heart failure.     

Rosuvastatin improves basal nitric oxide activity of the renal vasculature in patients with hypercholesterolemia

ObjectiveImpaired endothelium-dependent vasodilation represents an early manifestation of atherosclerosis. Prospective studies have demonstrated that impaired endothelial function in the peripheral circulation of hypercholesterolemic patients predicts CV events and can be restored by statin treatment. Whether this also holds true in the renal circulation has not yet been adequately addressed.MethodsIn a double-blind, randomized, placebo-controlled cross-over trial, 40 hypercholesterolemic patients were randomly assigned to receive rosuvastatin (10 mg/day) and matching placebo. The primary objective of the study was to assess the effect of 6-week treatment with rosuvastatin on basal NOS activity of the renal vasculature, as assessed by measuring renal plasma flow (RPF) both before and after blockade of NOS with systemic infusion of N^G-monomethyl-l-arginine (l-NMMA). In a subgroup of 20 patients we also studied the effects of a 3-day treatment regimen.ResultsCompared to placebo treatment, rosuvastatin decreased LDL-cholesterol levels both after 3 days and 6 weeks of treatment. The decrease in RPF in response to l-NMMA was significantly more pronounced after 6-week therapy with rosuvastatin compared to placebo (?13.7 ± 1.0% versus ?11.3 ± 0.7%; p = 0.046), indicating increased basal NOS activity with rosuvastatin treatment. A trend towards improved basal NOS activity was already evident after 3-day treatment.ConclusionTreatment with rosuvastatin improved basal NOS activity in the renal circulation of hypercholesterolemic patients, suggestive of a nephroprotective effect. In view of the close relation between altered renal function and cardiovascular events, these nephroprotective effects may contribute to the improved CV prognosis associated with statin treatment.     

一氧化氮对大鼠在体心肌缺血预适应作用的研究

目的:实验以缺血预适应模型为基础,研究一氧化氮(NO)在心肌缺血预适应延迟相中的作用。方法:实验将Wistar大鼠随机分为5组:假手术组、仅行缺血预适应处理的对照组、于延迟相给药的S-甲基琉脲硫酸盐(SMT)组、硝普钠(SNP)组和SMT+SNP组。测算各组动物血清NO2-+NO3-含量及CK-MB定量,观察NO的释放对心肌损伤、梗死面积的影响。心肌细胞超微结构的变化。结果:限制内源性NO的释放可降低心肌损伤的程度,缩小心肌损伤、梗死面积。结论:在心肌缺血预适应延迟相过程中,内源性NO加重心肌损伤程度,而外源性NO可减轻心肌损伤程度。