Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent clinical and experimental data suggest that nitric oxide (NO) may play a role in the pathogenesis and therapy of sickle cell disease. NO, a soluble gas continuously synthesized in endothelial cells by the NO synthase (NOS) enzyme systems, regulates basal vascular tone and endothelial function, and maintains blood oxygenation via hypoxic pulmonary vasoconstriction and reduced shunt physiology. These vital homeostatic processes may be impaired in sickle cell disease and contribute to its pathogenesis. Therapeutic NO inhalation exerts significant direct effects on the pulmonary vasculature to reduce pulmonary pressures and increase oxygenation that may prove beneficial in acute chest syndrome and secondary pulmonary hypertension. Delivery of NO bound to hemoglobin or in plasma may improve blood flow and hemoglobin saturation, and thus reduce ischemia-reperfusion injury. Other NO-related effects on adhesion molecule expression and fetal hemoglobin induction are of interest. While direct evidence for a clinical benefit of NO therapy in sickle cell disease has not been reported, studies are underway to determine if inhaled NO will reduce the substantial morbidity and mortality suffered by these patients.
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PMID:Nitric oxide therapy in sickle cell disease. 1160 68

Inhaled nitric oxide (iNO) has been shown to reduce pulmonary hypertension associated with several disease states. The effects of iNO are thought to be restricted to the pulmonary vasculature because of its rapid inactivation by hemoglobin. Recent data have suggested, however, that iNO can form nitrosothiols, which can be carried throughout the circulation, thus increasing the half life and bioactivity on NO. Other studies have shown that iNO can affect intestinal ischemia and renal hemodynamics. In this study, rats were exposed to 49 +/- 4 ppm or 107 +/- 13 ppm NO for 4 h and the lung, spleen, liver, and kidney tissues were removed and measured for NOS II and NOS III protein, nitrotyrosine (NT), and phosphotyrosine (PT) immunoreactivity. Following 107 ppm iNO, increases in NOS III protein expression, NT, and PT were observed in the liver and kidney, but not in the lung or spleen. No such increases were noted after the lower dose of iNO. These results paralleled those shown for isobutyl nitrite that we reported earlier and indicated that iNO can cause changes in protein chemistry in organs and tissues beyond the lungs. Since iNO produced little systemic hemodynamic effects, it is unlikely that the observed biochemical alterations were derived secondarily from physiological changes.
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PMID:Systemic biochemical effects of inhaled NO in rats: increased expressions of NOS III, nitrotyrosine-, and phosphotyrosine-immunoreactive proteins in liver and kidney tissues. 1173 Mar 66

United Therapeutics Corp (UTC) is developing treprostinil sodium (Remodulin, UT-15), a stable structural analog of prostacyclin, for the potential treatment of primary pulmonary (arterial) hypertension (PAH), peripheral vascular disease (PVD) and other cardiovascular conditions [327593], including critical limb ischemia (CLI) [412483]. In August 2000, UTC submitted the initial, non-clinical sections of an NDA for the treatment of pulmonary hypertension [378906]. Treprostinil, which had previously been designated as an Orphan Drug, was also awarded Priority Review status by the US FDA in October 2000 [385864], [386271]. In December 2000, UTC agreed with the FDA that the NDA for treprostinil did not need to be presented to the Cardiovascular and Renal Drugs Advisory Committee, which was expected to allow UTC and the FDA to work towards the 6-month Priority Review timeline [393888]. On August 9, 2001, the advisory committee recommended approval of treprostinil and UTC refiled the NDA on the same day [418682]. In February 2002, the FDA issued an approvable letter for treprostinil injection for the treatment of PAH. The FDA proposed drug labeling for PAH consistent with the treatment of both primary and secondary pulmonary hypertension in patients with New York Heart Association (NYHA) Class II-IV symptoms. The approvable letter also stated that the FDA intended to approve treprostinil with a requirement that UTC subsequently conduct a post-marketing controlled clinical trial to verify and further describe the drug's clinical benefit [439278]. In February 2001, UTC submitted a marketing authorization application (MAA) in France for approval of treprostinil for the treatment of PAH. Upon approval of the MAA, UTC planned to file for Mutual Recognition in other European countries and was also preparing similar submissions to non-European countries [391986], [397958]. By early 2001, phase II trials of treprostinil for the treatment of CLI were underway [412483]. In March 2001, the company was planning a phase III pivotal study in late-stage PVD by the end of 2001 [424180]. In April 2000, UTC was issued US-06054486 for the method of treating PVD with treprostinil [364130]. In February 2000, UTC entered into an agreement with Paladin Labs for the exclusive Canadian distribution of treprostinil for the remainder of clinical trials and after regulatory approvals [357302]. In November 2000, UTC and Antigen Pharmaceuticals entered into a strategic alliance for the distribution of treprostinil in the UK and Ireland [390157]. In November 2000, Deutsche Banc Alex Brown predicted a sales potential of US $250 million to US $350 million [418736]. In August 2001, Merril Lynch predicted sales of US $10 million to $20 million in 2002 [420652].
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PMID:Treprostinil sodium Pharmacia. 1209 Jul 28

Anorectic drugs are widely used for the treatment of obesity. They are thought to decrease appetite through their effects on catecholamine or 5-hydroxytryptamine (5-HT) levels in the brain. Their use has been associated with epidemics of pulmonary hypertension and the development of valvular heart disease, hypertension, stroke and digital or mesenteric ischemia. Understanding the mechanism of the cardiovascular toxicity of anorectic drugs is important because of the modern epidemic of obesity and the resulting plethora of new anorexigens, many of which share similar mechanisms with those that have previously caused cardiovascular disease. In addition, the mechanism by which anorexigens cause vascular disease has relevance to the etiology and treatment of pulmonary and systemic hypertension. Recent discoveries have clarified how the anorexigens cause vasoconstriction and hypertension. Most anorexigens directly inhibit voltage-gated K+ (KV) channels in vascular smooth muscle cells (SMCs). This reduced K+ efflux leads to depolarization, the opening of voltage-sensitive Ca2+ channels, an increase in intracellular Ca2+ and vasoconstriction. Endothelial dysfunction appears to be a predisposing factor for the development of anorectic-induced vascular complications. Vasoconstriction is weak at clinically relevant doses of anorectic drugs. However, when nitric oxide synthase is inhibited, vasoconstriction is significantly enhanced. Anorexigens are the only drugs in widespread clinical use that have KV-channel-blocking properties and it is probable that much of their cardiovascular toxicity relates to this mechanism. Investigators need to examine new anorexigens and other therapeutic molecules for inhibitory effects on KV channels, as this effect may be a marker of drugs that will elicit vascular complications.
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PMID:Anorectic drugs and vascular disease: the role of voltage-gated K+ channels. 1237 23

Origin of the left main coronary artery from the pulmonary trunk is an extremely rare, fatal, but potentially treatable anomaly. Left ventricular perfusion with desaturated blood with low pressure from the pulmonary artery results in early death. Associated pulmonary hypertension can help to prevent ischemia. We present a four-month-old boy with this anomaly associated with patent ductus arteriosus and pulmonary hypertension.
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PMID:Anomalous left coronary artery from the main pulmonary trunk: physiologic and clinical importance of its association with patent ductus arteriosus and pulmonary hypertension. 1245 19

Nitric oxide (NO) has been reported to play a role in lung injury (LI) induced by ischemia-reperfusion (I/R). However, controversy exists as to the potential beneficial or detrimental effect of NO. In the present study, an in situ, perfused rat lung model was used to study the possible role of NO in the LI induced by I/R. The filtration coefficient (Kfc), lung weight gain (LWG), protein concentration in the bronchoalveolar lavage (PCBAL), and pulmonary arterial pressure (PAP) were measured to evaluate the degree of pulmonary hypertension and LI. I/R resulted in increased Kfc, LWG, and PCBAL. These changes were exacerbated by inhalation of NO (20-30 ppm) or 4 mM L-arginine, an NO precursor. The permeability increase and LI caused by I/R could be blocked by exposure to 5 mM N omega-nitro-L-arginine methyl ester (L-NAME; a nonspecific NO synthase inhibitor), and this protective effect of L-NAME was reversed with NO inhalation. Inhaled NO prevented the increase in PAP caused by I/R, while L-arginine had no such effect. L-NAME tended to diminish the I/R-induced elevation in PAP, but the suppression was not statistically significant when compared to the values in the I/R group. These results indicate that I/R increases Kfc and promotes alveolar edema by stimulating endogenous NO synthesis. Exogenous NO, either generated from L-arginine or delivered into the airway, is apparently also injurious to the lung following I/R.
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PMID:Nitric oxide mediates lung injury induced by ischemia-reperfusion in rats. 1256 87

Inhalation of nitric oxide (NO) has been advocated as a method to prevent ischemia-reperfusion injury after lung transplantation. We enrolled 84 patients into a concealed, randomized, placebo-controlled trial to evaluate the effect of inhaled NO (20 ppm NO or nitrogen) initiated 10 minutes after reperfusion on outcomes after lung transplantation. The groups (n = 42) were balanced with respect to age, sex, lung disease, procedure, and total ischemic times. PaO2/FIO2 ratios were similar on admission to the intensive care unit (ICU) (NO 361 +/- 134; control patients 357 +/- 132), and over the duration of the study. There were no differences in hemodynamics between the two groups. Severe reperfusion injury (PaO2/FIO2 < 150) was present at the time of admission to the ICU in 14.6% NO patients versus 9.5% of control patients (p = 0.48). The groups had similar median times to first successful trial of unassisted breathing (25 vs. 27 hours; p = 0.76), successful extubation (32 vs. 34 hours; p = 0.65), ICU discharge (3.0 days for both groups), and hospital discharge (27 vs. 29 days; p = 0.563). Five NO versus six control patients died during their hospital stay. Adjusting for age, sex, lung disease etiology, presence of pulmonary hypertension, and total ischemic time did not alter these results. In conclusion, we did not detect a significant effect of inhaled NO administered 10 minutes after reperfusion on physiologic variables or outcomes in lung transplant patients.
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PMID:A randomized trial of inhaled nitric oxide to prevent ischemia-reperfusion injury after lung transplantation. 1277 Aug 51

Pulmonary ischemia is usually related with embolics mechanisms, and this mechanic artery occlusion is not always followed by severe ischemic consequences, because the bronchial circulation changes supply the areas without blood flow. However, small artery vascular remodeling occurs, related to persistent high pulmonary pressure levels, mainly in the chronic pulmonary thromboembolism. Experimental models have been produced to study the relation-ship between mechanic artery occlusion, pulmonary hypertension and vascular remodeling, however, more systematic evaluation is necessary to understand such a these relation-ship, in the ischemic and not ischemic lung parenchyma.
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PMID:[Pulmonary embolic ischemia: clinical and experimental aspects]. 1466 63

The cardiovascular and respiratory systems play key roles in O(2) homeostasis. Physiological responses to hypoxia involve changes in gene expression that are mediated by the transcriptional activator hypoxia-inducible factor (HIF)-1. Analysis of mice heterozygous for a knockout allele at the locus encoding the O(2)-regulated HIF-1alpha or HIF-2alpha subunit has revealed that these proteins are required for multiple physiological responses to chronic hypoxia, including erythrocytosis and pulmonary vascular remodeling. In mice with partial HIF-2alpha deficiency, hypoxia-induced expression of endothelin-1 and norepinephrine is dramatically impaired, and the mice fail to develop pulmonary hypertension after 4 wk of exposure to 10% O(2). In mice with partial HIF-1alpha deficiency, the ability of the carotid body to sense and/or respond to acute or chronic hypoxia is lost. In wild-type mice, brief episodes of intermittent hypoxia are sufficient to induce production of erythropoietin (EPO), which protects the heart against apoptosis after ischemia-reperfusion, whereas in mice with partial HIF-1alpha deficiency, intermittent hypoxia does not induce EPO production or cardiac protection. Parenteral administration of EPO to rodents is sufficient to induce dramatic protection against ischemia-reperfusion injury in the heart. Thus HIF-1 mediates critical physiological responses to hypoxia, and the elucidation of these homeostatic mechanisms may lead to novel therapies for the most common causes of mortality in the US population.
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PMID:O2-regulated gene expression: transcriptional control of cardiorespiratory physiology by HIF-1. 1476 67

Phosphodiesterase type-5 (PDE-5) inhibitors including sildenafil, vardenafil and tadalafil are a new class of vasoactive drugs that have been developed for treatment of erectile dysfunction in patients. A growing number of studies in recent years suggest that sildenafil may be used clinically for treatment of pulmonary hypertension and endothelial dysfunction. In addition, recent studies primarily from our laboratory suggested that sildenafil has preconditioning-like powerful cardioprotective effect in the animal models of ischemia-reperfusion injury. Sildenafil has been found to exert cardioprotection through nitric oxide generated from endothelial and/or inducible nitric oxide synthases and opening of mitochondrial ATP-sensitive potassium channels. Future demonstration of the cardioprotective effect in patients with the relatively safe and effective FDA-approved PDE-5 inhibitors, such as sildenafil, could have an enormous impact on bringing the long-studied phenomena of ischemic and pharmacologic preconditioning to the clinical forefront.
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PMID:Cardioprotection with phosphodiesterase-5 inhibition--a novel preconditioning strategy. 1487 43


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