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1.
J Mol Cell Cardiol ; 46(4): 482-9, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19166856

ABSTRACT

Heightened sympathetic excitation and diminished parasympathetic suppression of heart rate, cardiac contractility and vascular tone are all associated with cardiovascular diseases such as hypertension and ischemic heart disease. This phenotype often exists before these disease states have been established and is a strong correlate of mortality in the population. However, the causal role of the autonomic phenotype in the development and maintenance of hypertension and myocardial ischemia remains a subject of debate, as are the mechanisms responsible for regulating sympathovagal balance. Emerging evidence suggests oxidative stress and reactive oxygen species (such as nitric oxide (NO) and superoxide) play important roles in the modulation of autonomic balance, but so far the most important sites of action of these ubiquitous signaling molecules are unclear. In many cases, these mediators have opposing effects in separate tissues rendering conventional pharmacological approaches non-efficacious. Novel techniques have recently been used to augment these signaling pathways experimentally in a targeted fashion to central autonomic nuclei, cardiac neurons, and myocytes using gene transfer of NO synthase. This review article discusses these recent advances in the understanding of the roles of NO and its oxidative metabolites on autonomic imbalance in models of cardiovascular disease.


Subject(s)
Genetic Therapy , Myocardium/enzymology , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase/therapeutic use , Sympathetic Nervous System/pathology , Vagus Nerve/pathology , Angiotensin II/metabolism , Animals , Humans , Sympathetic Nervous System/enzymology , Sympathetic Nervous System/physiopathology , Vagus Nerve/enzymology , Vagus Nerve/physiopathology
2.
Am J Physiol Heart Circ Physiol ; 295(3): H990-H998, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18621854

ABSTRACT

Myocardial infarction (MI) is associated with oxidative stress, which may cause cardiac autonomic impairment. We tested the hypothesis that acute MI disrupts cardiac cholinergic signaling by impairing nitric oxide (NO)-cGMP modulation of acetylcholine (ACh) release and whether the restoration of this pathway following cardiac neuronal NO synthase (nNOS) gene transfer had any bearing on the neural phenotype. Guinea pigs underwent four ligature coronary artery surgery (n = 50) under general anesthesia to induce MI or sham surgery (n = 32). In a separate group, at the time of MI surgery, adenovirus encoding nNOS (n = 29) or enhanced green fluorescent protein (eGFP; n = 30) was injected directly into the right atria, where the postganglionic cholinergic neurons reside. In vitro-evoked right atrial [3H]ACh release, right atrial NOS activity, and cGMP levels were measured at 3 days. Post-MI 24% of guinea pigs died compared with 9% in the sham-operated group. Evoked right atrial [3H]ACh release was significantly (P < 0.05) decreased in the MI group as was NOS activity and cGMP levels. Tetrahydrobiopterin levels were not significantly different between the sham and MI groups. Infarct sizes between gene-transferred groups were not significantly different. The nNOS transduced group had significantly increased right atrial [3H]ACh release, right atrial NOS activity, cGMP levels, and decreased cAMP levels. Fourteen percent of the nNOS transduced animals died compared with 31% mortality in the MI + eGFP group at 3 days. In conclusion, cardiac nNOS gene transfer partially restores the defective NO-cGMP cholinergic pathway post-MI, which was associated with a trend of improved survival at 3 days.


Subject(s)
Cyclic GMP/physiology , Heart/physiology , Myocardial Infarction/physiopathology , Nitric Oxide Synthase Type I/physiology , Nitric Oxide/physiology , Parasympathetic Nervous System/physiology , Signal Transduction/physiology , Acetylcholine/metabolism , Animals , Biopterins/metabolism , Blotting, Western , Cyclic AMP/metabolism , Cyclic GMP/metabolism , Gene Transfer Techniques , Guinea Pigs , Heart/innervation , Immunohistochemistry , In Vitro Techniques , Myocardial Infarction/mortality , Nitric Oxide Synthase Type I/genetics , Phenotype
3.
J Mol Cell Cardiol ; 39(1): 159-64, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15893765

ABSTRACT

Nitric oxide (NO) derived from neuronal nitric oxide synthase (nNOS) facilitates cardiac vagal neurotransmission and bradycardia in vitro. Here we provide evidence of rapid (within 9 h) protein expression and increased vagal responsiveness in vivo following targeted gene transfer of nNOS into the cardiac vagus of the pig. Right vagi were injected with vector encoding nNOS (Ad.nNOS) or saline, while left vagi received an injection of vector encoding enhanced green fluorescent protein (Ad.eGFP). Enhanced nNOS protein expression was detected exclusively in the right vagus nerve, with no evidence of iNOS expression. This was associated with increased baroreflex sensitivity and greater heart rate responsiveness to right vagal stimulation. In contrast, responsiveness of left vagi, or sham-injected right vagi remained constant over the same time period. Basal heart rate was unchanged following gene transfer, suggesting no change in vagal tone. These results support the pre-/post-ganglionic synapse as a site for NO-mediated facilitation of vagal bradycardia in the pig. In addition they demonstrate in vivo that functional gene expression induced with adenoviral vectors occurs earlier than first thought, and may therefore, provide a novel intervention to acutely modulate the neural control of cardiac excitability.


Subject(s)
Gene Transfer Techniques , Nerve Tissue Proteins/genetics , Nitric Oxide Synthase/genetics , Parasympathetic Nervous System/physiology , Vagus Nerve/physiology , Animals , Baroreflex/physiology , Bradycardia/genetics , Electric Stimulation , Female , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Heart Rate/genetics , Male , Nerve Tissue Proteins/metabolism , Nitric Oxide Synthase/metabolism , Nitric Oxide Synthase Type I , Swine
9.
Br Med J (Clin Res Ed) ; 296(6628): 1070, 1988 Apr 09.
Article in English | MEDLINE | ID: mdl-3130148
11.
Lancet ; 1(8482): 682, 1986 Mar 22.
Article in English | MEDLINE | ID: mdl-2869372
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