Beneficial Effects of Nitric Oxide on Cardiac Diastolic Function: 'The Flip Side of the Coin'

Modulation by NO of systolic myocardial function received widespread attention but most studies focused on potential negative inotropic properties of NO. The very original observations on the effects of NO on myocardial contraction already provided evidence that NO modified myocardial contractile performance mainly through a relaxation-hastening effect (i.e. earlier onset of relaxation) and through an increase in myocardial distensibility. The present review discusses the relaxation hastening and distensibility-increasing effects of NO in experimental preparations, in the normal human heart, in left ventricular hypertrophy of aortic stenosis, in the human allograft and in dilated nonischemic cardiomyopathy. This diastolic flip side of the myocardial effects of NO appears to be beneficial especially for patients who are dependent on the LV Frank-Starling response to maintain cardiac output.     

Nitric oxide production in rheumatoid arthritis

Abstract

Nitric oxide (NO), originally found as endothelium-derived relaxing factor (EDRF), is a free radical synthesized by NO synthases (NOS). Two isoforms exist in NOS, i.e. constitutive NOS (cNOS) and inducible NOS (iNOS). Inflammatory cytokines such as interleukin-1, interferon-γ, tumor necrosis factor-α induce iNOS expression in various cells including macrophages. Enhanced NO production is observed in arthritic conditions both in rodent models and human. The onset of arthritis in rodent models is significantly inhibited by the NOS inhibitor, N ^G-monomethyl-l-arginine. These data suggest a possible involvement of NO in the induction and/or maintenance of rheumatoid arthritis.     

Nitric oxide production in PCD: possible evidence for differential nitric oxide synthase function

Primary cilliary dyskinesia (PCD) is characterized by decreased levels of fractional exhaled nitric oxide (FeNO), thought to reflect low activity of airway inducible nitric oxide synthase (iNOS) levels. Alveolar NO (Calv) concentration and bronchial NO (JNO) flux can be calculated from FeNO measured at multiple exhalation flow rates. We hypothesised that whereas bronchial NO would be reduced in PCD due to reduced iNOS function, alveolar NO would reflect endothelial NOS (eNOS) function and be normal. We recorded the medical history; measured FeNO at multiple flow rates (50, 100, 200, 260 ml/sec); and performed spirometry in 24 children (aged 8-16 years). FeNO50 of the PCD children was significantly lower than normal mean (+/-SD) 8.1 +/- 1.3 ppb versus 12.5 +/- 1.6 ppb, P = 0.033. The mean +/- SD values of PCD (n = 24) and normal (n = 20) subjects were respectively: JNO: 383.5 +/- 307.9 versus 650.1 +/- 489 pl/s, P = 0.033, Calv: 1.60 +/- 0.78 versus 1.60 +/- 0.75 ppb, P = NS. We show that Calv is normal in PCD, demonstrating that there is no generalized disorder of NO handling in this condition. This differs from a previous report. Furthermore, we speculate that these data may provide supportive evidence that variable flow NO measurements can assess the relative activity of iNOS and eNOS.     

The Role of Nitric Oxide in the Failing Heart

Nitric oxide (NO) has effects on contractility, energetics and gene expression of failing myocardium. Initial studies on isolated cardiomyocytes showed NO to reduce systolic shortening but intracoronary infusions of NO-donors or of NO synthase (NOS) inhibitors failed to elicit changes in baseline LV contractility indices such as LVdP/dt(max). Intracoronary infusions of NO-donors or of substance P, which releases NO from the coronary endothelium, however demonstrated NO to induce a downward displacement of the left ventricular (LV) diastolic pressure-volume relation, consistent with increased LV diastolic distensibility. In end-stage failing myocardium, the increased oxygen consumption is related to reduced NO production and in isolated cardiomyocytes, NO blunts the norepinephrine-induced expression of the fetal gene programme thereby preserving myocardial calcium homeostasis.In dilated cardiomyopathy, changed endomyocardial NOS gene expression has been reported. Because of lower endomyocardial NOS gene expression in patients with higher functional class and lower LV stroke work, increased endomyocardial NOS gene expression seems to be beneficial rather than detrimental for the failing heart. A beneficial effect of increased NOS gene expression could result from NO's ability to increase LV diastolic distensibility, to augment LV preload reserve, to reduce myocardial oxygen consumption and to prevent downregulation of calcium ATPase. Upregulated endomyocardial NOS gene expression has also been reported in athlete's heart and could therefore play a role in physiological LV remodeling. Reduced endomyocardial NO content because of decreased NO or increased superoxide production could lower LV diastolic distensibility and contribute to diastolic heart failure. In many conditions such as aging, hypertension, diabetes or posttransplantation, the increased incidence of diastolic heart failure is indeed paralleled by reduced endothelium-dependent vasodilation.     

Myocardial contractile effects of nitric oxide

Recent experimental and clinical research solved some of the controversies surrounding the myocardial contractile effects of NO. These controversies were: (1) does NO exert a contractile effect at baseline? (2) is NO a positive or a negative inotrope? (3) Are the contractile effects of NO similar when NO is derived from NO-donors or from the different isoforms of NO synthases (NOS)? (4) Does NO exert the same effects in hypertrophied, failing or ischemic myocardium? Transgenic mice with cardioselective overexpression of NOS revealed NO to produce a small reduction in basal developed LV pressure and a LV relaxation-hastening effect mainly through myofilamentary desensitization. Similar findings had previously been reported during intracoronary infusions of NO-donors in isolated rodent hearts and in humans. The LV relaxation hastening effect was accompanied by increased diastolic LV distensibility, which augmented LV preload reserve especially in heart failure patients. This beneficial effect on diastolic LV function always overrode the small NO-induced attenuation in LV developed pressure in terms of overall LV performance. In most experimental and clinical conditions, contractile effects of NO were similar when NO was derived from NO-donors or produced by the different isoforms of NOS. Because expression of inducible NOS (NOS2) is frequently accompanied by elevated oxidative stress, NO produced by NOS2 can lead to peroxynitrite-induced contractile impairment as observed in ischemic or septic myocardium. Finally, shifts in isoforms or in concentrations of myofilaments can affect NO-mediated myofilamentary desensitization and alter the myocardial contractile effects of NO in hypertrophied or failing myocardium.     

Nitric oxide synthase activity in rat cardiac mitochondria

Abstract. Recent publications shown mitochondrial localization of the enzyme nitric oxide synthase (NOS) in a number of tissues. However, conflicting results about mitochondrial NOS (mtNOS) immunoreactivity and enzymatic activity are available to date in the literature. In this study we purified mitochondria from rat hearts and analysed these preparations for NOS immunoreactivity and activity, showing the presence of either a constitutive (the endothelial isoform) and an inducible NOS immunoreactivity. A basal NOS activity (64.2 ± 5.1 pmol/mg protein/30 min) was detectable. 1 mM N^G-Monomethyl-L-arginine (L-NMMA), a competitive inhibitor of all NOS isoforms, caused a drop in NOS activity to 33.8 ± 1.9 pmol/mg protein/30 min. Simultaneous administration of 10 µM (S)-2-amino-(1-iminoethylamino)-5- thiopentanoic acid (GW274150), a specific NOS2 inhibitor, together with removal of Ca²⁺ and calmodulin (CaM) from the assay buffers, known to interfere with the activity of constitutive NOS isoforms, caused a reduction in NOS activity (17.4 ± 1.2 pmol/mg protein/30 min). 10 µM GW274150 reduced NOS activity to 41.6 ± 4 pmol/mg protein/30 min, while Ca²⁺/CaM withdrawal reduced basal NOS activity to 45.8 ± 5 pmol/mg protein/30 min. This dual mtNOS machinery is suggested to be involved in modulating cardiac O₂ consumption in different (patho)physiological conditions.     

Nitric oxide at a glance

In healthy blood vessels excessive platelet activation is counterbalanced by negative signalling cascades that modulate activation. This is achieved primarily through endothelial-derived nitric oxide (NO) and prostacyclin (PGI2). The biological effects of NO are mediated through stimulation soluble guanylyl cyclase (sGC) activation of cyclic AMP and GMP-mediated signalling pathways. In the present review examine our current understanding of NO-mediated regulation of platelets and highlight key issues that remain unresolved.     

一氧化氮合酶/一氧化氮系统与心血管疾病

一氧化氮在心血管疾病中发挥了重要作用；一氧化氮是在一氧化氮合酶催化下生成的。三种不同的一氧化氮合酶在心血管疾病中的作用各不相同，通过对一氧化氮合酶的干预将成为心血管疾病治疗的新策略。现就国内外在一氧化氮合酶／一氧化氮系统与心血管疾病方面的主要研究进展进行综述。     

诱导型一氧化氮合酶在心肌缺血/再灌注损伤中的研究进展

采用溶栓疗法、动脉搭桥术、冠状动脉血管成形术等技术,使缺血组织和器官重新恢复血流,挽救了众多危急重病人的生命,然而,缺血器官及组织在恢复血流的同时,均伴随着缺血/再灌注损伤,是目前临床上亟待解决的问题。在对心血管疾病的研究过程中,随着心肌保护研究的不断深入,如何减轻心肌缺血/再灌注损伤成为心肌保护问题的关键。越来越多的研究表明,心肌缺血/再灌注损伤与诱导型一氧化氮合酶表达过量一氧化氮紧密相关。研究表明,诱导型一氧化氮合酶既有心肌保护作用,也有促心肌损伤作用,而通过对诱导型一氧化氮合酶抑制剂的应用,有望减轻心肌损伤的进展,保护损伤心肌。     

Nitric oxide synthase gene polymorphisms and nephropathy in Asians with Type 2 diabetes

OBJECTIVE: Recent studies on Caucasians have reported an association between diabetic microvascular complications and polymorphisms in the inducible nitric oxide synthase (iNOS) gene. In view of the differences in the pattern of diabetic complications in Asians, we studied these iNOS polymorphisms in Asians with Type 2 diabetes who do and those who do not have nephropathy. METHODS: Two hundred fifty-eight Asians who have had Type 2 diabetes for at least 10 years, with overt nephropathy or with normoalbuminuria, were genotyped for the (AAAT)(n) and (CCTTT)(n) polymorphisms in the promoter region of the iNOS gene. A subanalysis was made of the findings from the three ethnic groups (Chinese, Malays, and Indians). RESULTS: The (AAAT)(3) polymorphism, which is the most common allele in Caucasians, was completely absent in our entire cohort of 258 Asian diabetics. The (AAAT)(4) polymorphism was the commonest, with a frequency of 0.984 as compared with 0.2 in Caucasians. We also found previously unreported alleles: (AAAT)(5) in 6 patients and (AAAT)(6) in 1 patient. There was no statistically significant association with nephropathy, in view of the highly skewed distribution of the alleles. However, the higher repeats (AAAT)(5) and (AAAT)(6) were found in the patients with a very rapid onset of severe nephropathy. The (CCTTT)(n) polymorphism also showed significant differences in allele distribution between the Asian and the Caucasian and African populations (P=.001). However, there was also no significant association with nephropathy and no significant difference in the ethnic distribution of alleles. CONCLUSIONS: We have identified significant differences in the (AAAT)(n) and (CCTTT)(n) polymorphisms in Asian diabetics. We have shown that there are significant differences in the overall allele distribution between the Asian and the Caucasian and African populations. However, our study did not demonstrate an association between iNOS gene polymorphisms and diabetic nephropathy.     

Nitric Oxide and its Role in Blastocyst Implantation

Reviews in Endocrine and Metabolic Disorders -     

吸烟对大鼠肺动脉压和一氧化氮合酶的影响

目的 :探讨长期吸烟对大鼠肺动脉压及一氧化氮合酶的影响。方法 :SD雄性大鼠 40只 ,随机分为吸烟组和对照组 ,吸烟组暴露于点燃之烟卷 ,每日 6 h,于 9个月时检测吸烟组及对照组大鼠的肺动脉平均压 （m PAP）、血清一氧化氮 （NO）、肺动脉结构型一氧化氮合酶 （c NOS）和诱导型一氧化氮合酶 （i NOS）。结果 :吸烟组大鼠 m PAP明显高于对照组 ,血清 NO浓度与对照组相比明显减低 ,吸烟组肺细小动脉 c NOS平均吸光度值较对照组明显降低 ,吸烟组大鼠肺细小动脉 i NOS的平均吸光度值较对照组明显增高。结论 :烟雾可致肺动脉高压的形成 ,抑制肺细小动脉 c NOS表达、促进肺细小动脉 i NOS表达可能为其重要作用机制之一。     

Nitric oxide synthase distribution in esophageal mucosa and hemodynamic changes in rats with cirrhosis

SubjectheadingsesOPhagUs;nitricoxidesynthase;livercirrhosis;hemodynamicsINTRODUCTIONCirrhosiswithportalhypertensionisassociatedwithhyperdynamiccirculationcharacterizedbygeneralizedvasodilationandincreasedcardiacoutputandsplanchnicregionalbloodflows.EndogenousNO,averypotentvasodilatorfactor,mayplayaveryimportantroleinthepathogenesisofhemodynamicchangesincirrhosis.ItisnuclearwhetherNOisinvolvedinthepathogenesisofesophagealvaricesasoneofseverecomplicationsofhepaticcirrhosis.Thepresentstud…     

Nitric oxide synthase inhibitors in post-myocardial infarction cardiogenic shock--an update

Cardiogenic shock (CS) in acute myocardial infarction, after successful coronary angioplasty, still carries a case fatality rate of 50%. These patients succumb to a systemic metabolic storm, superimposed on extensive myocardial necrosis and stunning. Nitric oxide (NO) overproduction contributes to the pathophysiology of this morbid state. Current data regarding the physiologic effects of NO and nitric oxide synthase (NOS) inhibitors on the cardiovascular system are reviewed. Clinical trials assessing the safety and efficacy of NOS inhibitors in CS are summarized.     

Nitric oxide does not mediate the vasodilation of early human pregnancy

Background: In early pregnancy, a substantial drop in arterial blood pressure occurs, that might be attributed to enhanced vascular nitric oxide synthesis. We investigated whether nitric oxide mediates the vasodilation that occurs in early human pregnancy.

Methods: Resting and stimulated forearm vascular resistance were measured (venous occlusion plethysmograph) in six women at 10 ± 3 weeks of uncomplicated pregnancy and in the same women 7 ± 5 weeks after elective termination of pregnancy. Forearm vascular resistance was also measured in six non-pregnant, healthy controls.

Results: Resting forearm vascular resistance was similar during pregnancy (33 ± 16 arbitrary units (AU)), after pregnancy (31 ± 10 AU) and in controls (41 ± 13 AU, P > 0.05). The decreases in forearm vascular resistance to intrabrachial infusions of acetylcholine (2 and 20 pg/min), serotonin (10 and 100 ng/min) and sodium nitroprusside (1 and 2.5 gg/min) were similar in all groups. The nitric oxide synthase inhibitor N^G-monomethyl-L-arginine (16 pmol/min) produced similar increases in vascular resistance in pregnant women (38 ± 17 AU), after pregnancy (36 ± 14 AU) and in control subjects (42 ± 8 AU, P = NS).

Conclusions: These results indicate that neither basal nor stimulated nitric oxide levels are altered in the forearm circulation during first trimester pregnancy.     

Nitric oxide and cardiovascular protection

Nitric oxide (NO) plays a critical role in ischemic heart disease and ischemia-reperfusion. There is an increasing body of evidence to support the role of NO in myocardial and vascular protection in disease. The finding that NO might act as a trigger of late ischemic preconditioning (IPC) might lead to the development of novel anti-ischemic therapy. The role of NO signaling in the cardioprotective effects of ACE inhibitors and angiotensin II type 1 receptor(AT₁) receptor antagonists is an active area of study.     

Cytochrome c oxidase regulates endogenous nitric oxide availability in respiring cells: a possible explanation for hypoxic vasodilation

One of the many routes proposed for the cellular inactivation of endogenous nitric oxide (NO) is by the cytochrome c oxidase of the mitochondrial respiratory chain. We have studied this possibility in human embryonic kidney cells engineered to generate controlled amounts of NO. We have used visible light spectroscopy to monitor continuously the redox state of cytochrome c oxidase in an oxygen-tight chamber, at the same time as which we measure cell respiration and the concentrations of oxygen and NO. Pharmacological manipulation of cytochrome c oxidase indicates that this enzyme, when it is in turnover and in its oxidized state, inactivates physiological amounts of NO, thus regulating its intra- and extracellular concentrations. This inactivation is prevented by blocking the enzyme with inhibitors, including NO. Furthermore, when cells generating low concentrations of NO respire toward hypoxia, the redox state of cytochrome c oxidase changes from oxidized to reduced, leading to a decrease in NO inactivation. The resultant increase in NO concentration could explain hypoxic vasodilation.     

Nitric oxide, caveolae, and vascular pathology

Endothelial nitric oxide synthase (eNOS) is an enzyme that plays a critical role in normal cardiovascular function. Caveolae are structures within the surface membrane of cells in which many signaling and second messenger pathways, including nitric oxide, are regulated. Many interventions in cardiovascular disease act, in part, either by changing factors that directly influence eNOS, or by changing a complex set of proteins that act indirectly on caveolae, to alter eNOS activity. In this review, we will focus on the regulation of eNOS activity by circulating factors which are altered in cardiovascular disease and the effects of pharmacological interventions that act partially through effects on eNOS.