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

Myocardial ischemia/reperfusion (I/R) injury is partly mediated by thrombin. In support, the functional inhibition of thrombin has been shown to decrease infarct size after I/R. Several cellular responses to thrombin are mediated by a G-protein coupled protease-activated receptor 1 (PAR1).However, the role of PAR1 in myocardial I/R injury has not been well characterized. Therefore, we hypothesized that PAR1 inhibition will reduce the amount of myocardial I/R injury. After we detected the presence of PAR1 mRNA and protein in the rat heart by RT-PCR and immunoblot analysis,we assessed the potential protective role of SCH 79797, a selective PAR1 antagonist, in two rat models of myocardial I/R injury. SCH 79797 treatment immediately before or during ischemia reduced myocardial necrosis following I/R in the intact rat heart. This response was dose-dependent with the optimal dose being 25 microg/kg IV. Likewise, SCH 79797 treatment before ischemia in the isolated heart model reduced infarct size and increased ventricular recovery following I/R in the isolated heart model with an optimal concentration of 1 microM. This reduction was abolished by a PAR1 selective agonist. SCH 79797-induced resistance to myocardial ischemia was abolished by wortmannin, an inhibitor of PI3 kinase; L-NMA, a NOS inhibitor; and glibenclamide, a nonselective K(ATP) channel blocker. PAR1 activating peptide,wortmannin, L-NMA and glibenclamide alone had no effect on functional recovery or infarct size. A single treatment of SCH 79797 administered prior to or during ischemia confers immediate cardioprotection suggesting a potential therapeutic role of PAR1 antagonist in the treatment of injury resulting from myocardial ischemia and reperfusion.
 ...
PMID:SCH 79797, a selective PAR1 antagonist, limits myocardial ischemia/reperfusion injury in rat hearts. 1746 33

This commentary on the review by DA Saint in the current issue of the British Journal of Pharmacology focuses on the pathological role of late I(Na) in the heart, the evidence supporting inhibition of late I(Na) as a therapeutic target in ischaemic heart disease, and the therapeutic applications and challenges for development of new late I(Na) inhibitors. Recent reports from a large clinical outcome trial (MERLIN) of ranolazine, a drug known to inhibit late I(Na), indicated that it was safe and reduced recurrent ischaemia and arrhythmic activity. In combination with other results indicating that inhibition of late I(Na) reduces ischaemia, myocardial Ca(2+) overload, and electrical and mechanical dysfunction when late I(Na) is increased, the new clinical trial results suggest that reduction of cardiac late I(Na) is safe and therapeutically beneficial.
 ...
PMID:Inhibition of late sodium current to reduce electrical and mechanical dysfunction of ischaemic myocardium. 1807 3

Platelets are now regarded as playing a dominant role in cardiovascular medicine since our recent understanding of acute coronary syndrome as an atherothrombotic process. This development has led to the widespread use of antiplatelet agents, such as aspirin, thienopyridines and glycoprotein-IIb/IIIa receptor blockers, for the prevention of ischemic heart disease. Nevertheless, recent evidence suggests that not all patients receive appropriate antiplatelet therapy because there may be resistance or a variable response to the drug used or because of an increased risk of hemorrhage. Moreover, the reported lack of efficacy of the combination of clopidogrel and aspirin when used for primary prevention has raised concerns about the general concept that greater inhibition implies greater efficacy. At present, research efforts are focused on improving current antiplatelet treatment with the aim of increasing efficacy and safety. Alternative ADP-receptor antagonists (e.g., prasugrel, cangrelor and AZD6140) and thrombin-receptor antagonists (e.g., E5555 and SCH 530348) are being developed. They may provide faster, more potent and more stable platelet inhibition. In addition, new insights into platelet structure and into the mechanisms underlying thrombus formation could lead to the discovery of new therapeutic targets. This article reviews what is known about the pathophysiological role of platelets in the atherothrombotic process, considers the current state of the art in antiplatelet therapy, and provides a commentary on new therapeutic approaches.
 ...
PMID:Coronary atherothrombotic disease: progress in antiplatelet therapy. 1846 54

Chronic kidney disease and elevated serum C-reactive protein (CRP) have been suggested as clinical risk factors for cardiac attacks. The present study investigated postmortem blood urea nitrogen (BUN), creatinine (Cr) and CRP levels in the peripheral blood of sudden cardiac death cases. Adult autopsy cases of ischemic heart diseases (n=153, >20 years of age), including acute myocardial infarction (AMI, n=71), recurrent myocardial infarction (RMI, n=47), acute ischemic heart disease without infarction (AIHD, n=27) and chronic ischemic heart disease (CIHD, n=8), were examined and compared with chronic congestive heart disease (CHD, n=24), spontaneous cerebral hemorrhage (SCH, n=17) and mechanical asphyxiation (n=32). BUN was slightly higher for RMI and CHD, although Cr was slightly higher for SCH. CRP was higher for AMI than for AIHD. The correlation between BUN and Cr levels was significant for AMI, AIHD and CHD, but insignificant for RMI and CIHD. Heart weight was larger for all heart diseases and SCH than for asphyxiation, and was larger for RMI and CHD but lower for AIHD and CIHD among them. Body mass index (BMI) was slightly higher for AMI, RMI, AIHD and CHD, remaining within the reference interval in most cases, but was lower for CIHD. These findings suggest different risk factors or etiologies, including active atherosclerosis, latent renal failure, dehydration and cardiac hypertrophy, for sudden deaths due to these heart diseases.
 ...
PMID:Potential risk factors for sudden cardiac death: an analysis of medicolegal autopsy cases. 1925 62

Major steps have been made in the treatment of ischemic heart disease from the discovery of nitrates as antianginal medication to the techniques of percutaneous angioplasty. This incredible therapeutic progress has resulted in a reduced incidence of ischemic heart disease and related mortality and morbidity. However, statistical and epidemiological data indicate that in ischemic heart disease, despite the achievement of great success, there is a necessity for a further step toward treatment, considering the fact that the characteristics of this population are changing (increased prevalence of subendocardial infarction compared with classic transmural infarction, especially in the elderly population). Furthermore, the need for alternative therapeutic approaches to traditional ones is recognized. Ranolazine is a selective inhibitor of Na channels that prevents pathological extension of late Na current developing in the ischemic myocardial cell. This current is responsible for calcium overload, with consequent impairment of diastolic relaxation. Ranolazine reduces Na overload induced by calcium and improves diastolic relaxation and coronary subendocardial flow, without affecting hemodynamic parameters such as blood pressure, heart rate, or inotropic state of the heart, avoiding undesirable side effects. Efficacy of ranolazine has been evaluated in several trials, using clinical and instrumental endpoints (MARISA and CARISA) or, more recently, using endpoints such as mortality and reinfarction (ERICA and MERLIN-TIMI 36). Ivabradine acts through the inhibition of late Na current (also known as If), which controls the spontaneous diastolic depolarization of sinus node cells. The partial inhibition of these channels reduces the frequency of sinus node action potential initiation, resulting in decreased heart rate without effects on contractility, atrio-ventricular conduction, or repolarization. The BEAUTIFUL trial has tested whether the effect of ivabradine in lowering heart rate is able to reduce mortality and cardiovascular morbidity in patients with coronary artery disease and left ventricular systolic dysfunction. The most significant results were obtained in the subgroup of patients with life-limiting exertional angina. In this group, ivabradine significantly reduced the primary endpoint, a composite of cardiovascular death, hospitalization for fatal and nonfatal acute myocardial infarction (AMI) or heart failure, by 24%, and hospitalizations for AMI by 42%. In the subgroup of patients with baseline heart rate >70 bpm, hospitalizations for AMI and revascularization were reduced by 73% and 59%, respectively.
 ...
PMID:[New pharmacological approaches to ischemic heart disease]. 2309 76