Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This is a brief overview of experimental and clinical studies exploring the hemodynamic functions of the alpha2A and alpha2B adrenergic receptor (AR) subtypes in animals submitted to genetic manipulations or gene treatment, as well as the clinical effects of central sympathetic suppression with the alpha2-AR agonist clonidine in patients with ischemic heart disease and/or heart failure. The animal experiments have led us to conclude that the sympathetic outflow is regulated by activation of the presynaptic alpha2A-AR subtype, which is the predominant alpha2-AR subtype in the central nervous system and exerts a sympathoinhibitory (hypotensive) action; on the contrary, activation of the central alpha2B-AR elicits a sympathoexcitatory response (such as seen in salt-induced hypertension, which requires functionally intact alpha2B-AR). Since there are no selective pharmacologic agents yet capable of discriminating among alpha2-AR subtypes, clinical studies utilize clonidine, the central sympathetic suppressant effect of which has been used for 35 years to treat hypertension. In small clinical trials, clonidine was used successfully for treatment of acute or chronic heart failure, acute myocardial infarct or hypertensive cardiomyopathy with subclinical diastolic dysfunction. We speculate that future development of agents capable of selectively activating the alpha2A-AR or blocking the alpha2B-AR may further improve our capability to treat hypertension, ischemic heart disease and heart failure.
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PMID:The alpha2 -adrenergic receptors in hypertension and heart failure: experimental and clinical studies. 1172 52

We investigated the potential roles of adrenomedullin (AM) in cardiovascular and renal function by somatic gene delivery. We showed that a single intravenous injection of the human AM gene under the control of cytomegalovirus promoter/enhancer induces a prolonged delay in blood pressure rise for several weeks in spontaneously hypertensive rats, Dahl salt-sensitive, DOCA-salt, and two-kidney one-clip hypertensive rats as compared to their respective controls injected with a reporter gene. Expression of the human AM transcript was identified in the heart, kidney, lung, liver and aorta of the rat after adenovirus-mediated AM gene delivery by RT-PCR followed by Southern blot analysis. Immunoreactive human AM levels were measured in rat plasma and urine following AM gene delivery. AM gene delivery induced significant reduction of left ventricular mass in these hypertensive animal models. It also reduces urinary protein excretion and increases glomerular filtration rate, renal blood flow and urinary cAMP levels. AM gene transfer attenuated cardiomyocyte diameter and interstitial fibrosis in the heart, and reduced glomerular sclerosis, tubular disruption, protein cast accumulation and renal cell proliferation in the kidney. In the rat model with myocardial ischemia/reperfusion injury, AM gene delivery significantly reduced myocardial infarction, apoptosis, and superoxide production. Furthermore, local AM gene delivery significantly inhibited arterial thickening, promoted re-endothelialization and increased vascular cGMP levels in rat artery after balloon angioplasty. Collectively, these results indicate that human AM gene delivery attenuates hypertension, myocardial infarction, renal injury and cardiovascular remodeling in animal models via cAMP and cGMP signaling pathways. These findings provide new insights into the role of AM in cardiovascular and renal function.
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PMID:Human adrenomedullin gene delivery protects against cardiovascular remodeling and renal injury. 1175 58

In the transition period from a communist to market-oriented economy, Bulgaria faces several public health challenges. One of them is the decline in population (estimated fall from current 8.25 million to around 6 million in 2045), mainly due to emigration and pronounced fall in fertility. Infant mortality is still relatively high (over 15/1,000 live births), and the incidence of tuberculosis is on the rise. Total mortality shows a steady upward trend from 12.1/1,000 in 1990 to 14.3/1,000 in 1998. Trends in ischemic heart disease are comparable to those in other Central and Eastern European countries, but stroke mortality is notably higher. This calls for detailed epidemiological studies of risk factors, such as salt consumption, as well as preventive programs for detection and control of high blood pressure. The problems of smoking and alcohol abuse should be addressed by a coordinated public health and legal measures.
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PMID:Bulgarian population in transitional period. 1188 54

Ischaemic heart disease is one of the leading causes of cardiovascular morbidity and mortality. Because most factors leading to cardiovascular disease have a silent course, early screening is needed for prevention and for halting disease progression. In our centre, a programme was implemented in apparently healthy subjects for the early diagnosis and treatment of factors known to increment the risk of developing cardiovascular and metabolic disease. We present data from the first 153 individuals evaluated. The incidence of modifiable risk factors in our healthy population was as follows: overweight 33% (BMI: 25-30 kg/m(2)), obesity 45% (BMI >30 kg/m(2)), sedentarism 84%, arterial hypertension 15% (>140/90 mm Hg), hyperinsulinaemia 50%, glucose intolerance 14% (>160 mg/dl 120 min after 75 g glucose load), type 2 diabetes mellitus 5%, hypercholesterolaemia 50%, hypertriglyceridaemia 28%, and salt sensitivity 25%. Clustering of three or more cardiovascular risk factors was observed in 59% of the apparently healthy subjects. Obesity was associated with greater clustering of risk factors. The cardiovascular dysmetabolic syndrome was present in 72% of the obese individuals. These findings revealed a very high prevalence of cardiovascular risk factors in apparently healthy Hispanics. Even though these individuals were clinically asymptomatic, they are at increased risk for developing cardiovascular disease and type 2 diabetes mellitus. Mechanisms for the early detection and correction of modifiable risk factors in the healthy population must be implemented. Only through prevention will a reduction in the incidence of cardiovascular atherosclerotic disease and of type 2 diabetes mellitus be achieved.
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PMID:Clustering of silent cardiovascular risk factors in apparently healthy Hispanics. 1198 12

Vasopeptidase inhibitors are a new class of drugs that have dual inhibitory effects on two key enzymes involved in the metabolism of vasoactive peptides. Essentially, they inhibit angiotensin-converting enzyme (ACE), thereby blocking the generation of angiotensin II (Ang II); at the same time they prevent the breakdown of natriuretic peptides by the enzyme neutral endopeptidase. The combination of reduction of Ang II on a background of increased natriuretic peptide activity has several potential advantages for the treatment of cardiovascular and renal disease and in particular, hypertension and congestive heart failure (CHF). Several vasopeptidase inhibitors, such as sampatrilat, fasidotril, gemopatrilat and omapatrilat (Vanlev, the most clinically developed vasopeptidase inhibitor to date) are under intensive clinical investigation. Recent clinical trials have demonstrated effective antihypertensive activity in hypertension, independent of age, renin and salt status or ethnic origin, and have also highlighted the potential for vasopeptidase inhibition as a new therapeutic modality for the treatment of CHF. Moreover, ongoing research suggests that this new class of drugs may be an important approach, not only for the treatment of hypertension and of conditions associated with overt volume overload but also for ischaemic heart disease.
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PMID:Vasopeptidase inhibitors. 1222 48

Inhibition of Na(+)/H(+) (NHE) and Na(+)/Ca(2+) (NCE) exchangers prevents myocardial ischemia/reperfusion injury by preventing cardiomyocyte Ca(2+) overload. We hypothesized that it may influence ischemic/reperfused myocardium also indirectly by preventing endothelial Ca(2+) accumulation, and thereby by attenuating reperfusion-induced formation of nitric oxide (NO) and/or oxygen free radicals. Langendorff-perfused rat hearts were subjected to 30-min ischemia and 30-min reperfusion. Myocardial outflow of NO (nitrite+nitrate) and hydroxyl radical (*OH, salicylate method), and functional recoveries were followed during reperfusion. In all groups, there was a transient rise in NO and *OH outflow upon reperfusion. An inhibitor of NHE, cariporide (10 microM) [(4-Isopropyl-3-methylsulfonyl-benzoyl)-quanidine methanesulfonate], and an inhibitor of the reverse mode of NCE, KB-R7943 (5 microM) (2-[4-(4-Nitrobenzyloxy)phenyl]ethyl]isothiourea mesylate), decreased NO and *OH formation, reduced contracture, and improved the recovery of mechanical function during reperfusion, compared to the untreated hearts. The formation of NO was reduced by 40% by 100 microM N(G)-methyl-L-arginine acetate salt (L-NMMA, NO synthase inhibitor), and not affected by 50 microM L-NMMA. *OH formation, contracture, and the functional recoveries were affected neither by 50 nor by 100 microM L-NMMA. Also, the effects of cariporide and KB-R7943 were unaffected by 100 microM L-NMMA. This study shows for the first time that the inhibition of NHE and NCE attenuates post-ischemic myocardial formation of NO and *OH, suggesting that prevention of Ca(2+) overload is cardioprotective via these mechanisms. The results indicate, however, that NO synthase pathway did not interfere with the protection afforded by NHE or NCE in our model.
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PMID:Role of nitric oxide and free radicals in cardioprotection by blocking Na+/H+ and Na+/Ca2+ exchange in rat heart. 1258 9

The 1,3,4,5-tetrahydro-benzo[c][1,6]- and [c][1,7]-napthyridin-6-ones are presented as a potent class of PARP-1 inhibitors. Derivatives of these partially saturated aza-5[H]-phenanthridin-6-ones were designed and synthesized with tertiary amines for salt formation, thus enhancing aqueous solubility, iv formulation and their potential use in acute ischemic injuries (i.e., myocardial ischemia and stroke). We found that partial saturation of the C-ring results in derivatives that are several times more potent than the aromatic C-ring derivatives. The general synthetic routes are presented herein as well as thorough in vitro potencies and SAR discussion for selected derivatives.
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PMID:Design and synthesis of poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors. Part 3: In vitro evaluation of 1,3,4,5-tetrahydro-benzo[c][1,6]- and [c][1,7]-naphthyridin-6-ones. 1285 55

The current public health recommendations are to reduce salt intake from 9 to 12 g/d to 5 to 6 g/d. However, these values are based on what is feasible rather than the maximum effect of salt reduction. In a meta-analysis of longer-term trials, we looked at the dose response between salt reduction and fall in blood pressure and compared this with 2 well-controlled studies of 3 different salt intakes. All 3 studies demonstrated a consistent dose response to salt reduction within the range of 12 to 3 g/d. A reduction of 3 g/d predicts a fall in blood pressure of 3.6 to 5.6/1.9 to 3.2 mm Hg (systolic/diastolic) in hypertensives and 1.8 to 3.5/0.8 to 1.8 mm Hg in normotensives. The effect would be doubled with a 6 g/d reduction and tripled with a 9 g/d reduction. A conservative estimate indicates that a reduction of 3 g/d would reduce strokes by 13% and ischemic heart disease (IHD) by 10%. The effects would be almost doubled with a 6 g/d reduction and tripled with a 9 g/d reduction. Reducing salt intake by 9 g/d (eg, from 12 to 3 g/d) would reduce strokes by approximately one third and IHD by one quarter, and this would prevent approximately 20 500 stroke deaths and 31 400 IHD deaths a year in the United Kingdom. The current recommendations to reduce salt intake from 9 to 12 g/d to 5 to 6 g/d will have a major effect on blood pressure and cardiovascular disease but are not ideal. A further reduction to 3 g/d will have a much greater effect and should now become the long-term target for population salt intake worldwide.
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PMID:How far should salt intake be reduced? 1461 Jan

A large number of association studies revealed the importance of gene polymorphisms in renin-angiotensin system(RAS) in the pathogenesis of hypertension. Among these many polymorphisms of RAS genes, M235T or G-6A polymorphism of angiotensinogen gene increases the risk for salt sensitivity, lacunar infarction, non-dipper type of blood pressure variation, etc. and plasma angiotensinogen level. On the other hand, homozygous deletion polymorphism of angiotensin converting enzyme gene(ACE DD) increases the risk for male hypertension, ischemic heart disease and renal disease via increase of plasma and tissue ACE levels, and shows poor response to medication. Gene targeting experiments in mice enable us to examine whether quantitative changes in gene expression in RAS affect blood pressure, resulted that a simple computer simulation concerning RAS and the kallikrein-kinin system(KKS) emphasize the importance of interaction between RAS and KKS. This mini-review also describes the effect of renin or AT1 receptor gene polymorphisms, and the role of RAS genes in the correlation between inflammation and atherosclerosis.
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PMID:[Genes in rennin-angiotensin system]. 1473 43

Over 70 years ago, potassium was found to have a natriuretic effect and was used in patients with heart failure. However, it took many years for its role in the control of blood pressure to be recognized. Recently, epidemiological and clinical studies in man and experimental studies in animals have shown that increasing potassium intake towers blood pressure and that communities with a high potassium intake tend to have lower population blood pressures. Several studies have shown an interaction between salt intake and potassium intake. However, the recent DASH-Sodium (Dietary Approaches to Stop Hypertension) study demonstrates an additive effect of a low salt and high potassium diet on blood pressure. Increasing potassium intake may have other beneficial effects, for example, reducing the risk of stroke and preventing the development of renal disease independent of its effect on blood pressure. A high potassium intake reduces calcium excretion and could play an important role in the management of hypercalciuria and kidney stone formation, as well as bone demineralization. Potassium intake may also play an important role in carbohydrate intolerance. A reduced serum potassium increases the risk of lethal ventricular arrhythmias in those at risk, i.e. patients with ischemic heart disease, heart failure or left ventricular hypertrophy, and increasing potassium intake may prevent this. In this article, we address the evidence for the important role of potassium intake in regulating blood pressure and other beneficial effects of potassium which may be independent of and additional to its effect on blood pressure.
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PMID:Potassium: more beneficial effects. 1501 47


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