Endothelium-derived nitric oxide and vascular physiology and pathology

In 1980, Furchgott and Zawadzki demonstrated that the relaxation of vascular smooth muscle cells in response to acetylcholine is dependent on the anatomical integrity of the endothelium. Endothelium-derived relaxing factor was identified 7 years later as the free radical gas nitric oxide (NO). In endothelium, the amino acid L-arginine is converted to L-citrulline and NO by one of the three NO synthases, the endothelial isoform (eNOS). Shear stress and cell proliferation appear to be, quantitatively, the two major regulatory factors of eNOS gene expression. However, eNOS seems to be mainly regulated by modulation of its activity. Stimulation of specific receptors to various agonists (e.g., bradykinin, serotonin, adenosine, ADP/ATP, histamine, thrombin) increases eNOS enzymatic activity at least in part through an increase in intracellular free Ca²⁺. However, the mechanical stimulus shear stress appears again to be the major stimulus of eNOS activity, although the precise mechanisms activating the enzyme remain to be elucidated. Phosphorylation and subcellular translocation (from plasmalemmal caveolae to the cytoskeleton or cytosol) are probably involved in these regulations. Although eNOS plays a major vasodilatory role in the control of vasomotion, it has not so far been demonstrated that a defect in endothelial NO production could be responsible for high blood pressure in humans. In contrast, a defect in endothelium-dependent vasodilation is known to be promoted by several risk factors (e.g., smoking, diabetes, hypercholesterolemia) and is also the consequence of atheroma (fatty streak infiltration of the neointima). Several mechanisms probably contribute to this decrease in NO bioavailability. Finally, a defect in NO generation contributes to the pathophysiology of pulmonary hypertension. Elucidation of the mechanisms of eNOS enzyme activity and NO bioavailability will contribute to our understanding the physiology of vasomotion and the pathophysiology of endothelial dysfunction, and could provide insights for new therapies, particularly in hypertension and atherosclerosis.     

Inhaled and exhaled nitric oxide

Inhaled nitric oxide (NO) is used to treat various cardiopulmonary disorders associated with pulmonary hypertension. The rationale is based on the fact that NO, given by inhalation, only dilates those pulmonary vessels that perfuse well-ventilated lung units. As a result, pulmonary gas exchange is improved while pulmonary vascular resistance is reduced and pulmonary blood flow is increased. Inhaled NO has been succesfully applied to treat persistent pulmonary hypertension of the newborn, reducing the need for extracorporeal life support. Although pulmonary hypertension and altered vasoreactivity contribute to profound hypoxaemia in adult and paediatric acute respiratory distress syndrome (ARDS), the benefit of inhaled NO still remains to be established in patients with ARDS. ARDS is a complex response of the lung to direct or indirect insults, leading to pulmonary vasoconstriction and various inflammatory responses. Recent randomized trials suggest that inhaled NO only causes a transient improvement in oxygenation. Whether this effect is important in the long-term management of ARDS remains to be established. NO, measured in the exhaled breath, is an elegant and non-invasive means to monitor inflammation of the upper and lower respiratory tract. In the normal upper airways, the bulk of exhaled NO originates from the paranasal sinuses. Exhaled NO is increased in nasal allergy and decreased in cystic fibrosis, nasal polyposis and chronic sinusitis. That NO production is increased in asthmatic airways is also well established. However, several questions still need to be addressed, in particular evaluation of the sensitivity and specificity of the measurement techniques, and assessment of the bronchodilator action of endogenous NO.     

Cholinergic, monoaminergic and glutamatergic changes following perinatal asphyxia in the rat

Perinatal asphyxia (PA) is considered to lead to a variety of brain disorders including spasticity, epilepsy, mental retardation, and minimal brain disorder syndromes and may form the basis for psychiatric and neurodegenerative diseases later in life. We examined markers for neuronal transmission involved in the pathomechanisms of PA and candidates as mediators for long-term sequelae. We tested tyrosine hydroxylase (TH) and the vesicular monoamine transporter (VMAT) representing the monoaminergic system, the vesicular acetylcholine transporter (VAChT), and the excitatory amino acid carrier 1 (EAAC1), a neuronal subtype of the glutamate transporter, using immunohistochemistry on brain sections of rats subjected to graded PA. Three months following the asphyxiant insult immunoreactive (IR)-TH was decreased in striatum, hippocampus, thalamus, frontal cortex, and cerebellum; IR-VMAT was increased, and IR-VAChT was decreased in striatum. IR-EAAC1 glutamate transporter was increased in frontal cortex. The cholinergic, monoaminergic, and glutamatergic changes, still observed 3 months after the asphyxiant insult, may reflect their involvement in the pathomechanisms of PA and indicate mechanisms leading to long-term complications of PA. The variable consequences on the individual markers in several brain regions may be explained by specific susceptibility of cholinergic, monoaminergic, and glutamatergic neurons to the asphyxiant insult. Received 16 March 1999; received after revision 20 May 1999; accepted 8 July 1999     

Maize HapMap2 identifies extant variation from a genome in flux

Whereas breeders have exploited diversity in maize for yield improvements, there has been limited progress in using beneficial alleles in undomesticated varieties. Characterizing standing variation in this complex genome has been challenging, with only a small fraction of it described to date. Using a population genetics scoring model, we identified 55 million SNPs in 103 lines across pre-domestication and domesticated Zea mays varieties, including a representative from the sister genus Tripsacum. We find that structural variations are pervasive in the Z. mays genome and are enriched at loci associated with important traits. By investigating the drivers of genome size variation, we find that the larger Tripsacum genome can be explained by transposable element abundance rather than an allopolyploid origin. In contrast, intraspecies genome size variation seems to be controlled by chromosomal knob content. There is tremendous overlap in key gene content in maize and Tripsacum, suggesting that adaptations from Tripsacum (for example, perennialism and frost and drought tolerance) can likely be integrated into maize.     

Adrenaline depletion induced by light in the dark-adapted retina

Resumen Una depleción inmediata de la adrenalina retiniana ocurre cuando sapos adaptados a la oscuridad son expuestos a una luz relativamente fuerte, alcanzándose un máximo en aproximadamente 5 min. La repleción de la adrenalina es más rápida cuando los animales, después de ser expuestos por 5 min a la luz, son devueltos a la oscuridad. En un período de 24 h la adrenalina alcanzó aproximadamente 85% de su valor original. Por otra parte, cuando los animales se mantienen expuestos a la luz, la repleción es más lenta y la adrenalina retiniana alcanza un máximo de sólamente 65% de su valor original en adaptación a la oscuridad.