Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardiac muscarinic receptor ligands suitable for positron emission tomography have previously been characterised. Attempts to develop radioligands of these receptors suitable for single-photon emission tomographic (SPET) imaging have not been successful due to high lung retention and high non-specific binding of previously investigated potential tracers. The purpose of this study was to evaluate the biodistribution and in vivo imaging characteristics of a new radiopharmaceutical, [123I]N-methyl-4-iododexetimide. Biodistribution studies performed in rats showed high cardiac uptake (2.4% ID/g) 10 min after injection with a heart to lung activity ratio of 5:1. Specificity and stereoselectivity of cardiac binding were demonstrated using blocking experiments in rats. Dynamic imaging studies in anaesthetised greyhounds demonstrated rapid and high myocardial uptake and low lung binding with stable heart to lung activity ratios of > 2.5:1 between 10 and 30 min, making SPECT imaging feasible. Administration of an excess of an unlabelled muscarinic antagonist, methyl-quinuclidinyl benzylate rapidly displaced myocardial activity to background levels and the pharmacologically inactive enantiomer, [123I]N-methyl-4-iodolevetimide, had no detectable cardiac uptake, indicating specific and stereoselective muscarinic receptor binding. SPET revealed higher activity in the inferior than in the anterior wall, this being consistent with previously described regional variation of cardiac parasympathetic innervation. [123I]N-methyl-4-iododexetimide shows promise as an imaging agent for muscarinic receptor distribution in the heart and may be helpful in evaluating diverse cardiac diseases associated with altered muscarinic receptor function, including heart failure and diabetic heart disease.
 ...
PMID:Iodine-123 N-methyl-4-iododexetimide: a new radioligand for single-photon emission tomographic imaging of myocardial muscarinic receptors. 760 65

Immunocytochemistry of muscarinic receptors on human heart biopsies from patients with heart disease was studied using rabbit antibodies against a synthetic peptide corresponding to amino acids 168-192 of the second extracellular loop of the human M2 muscarinic receptor. By using both light and electron microscopic immunocytochemistry techniques, muscarinic receptors were visualized on sarcolemma of human myocytes from patients with different heart diseases such as coronary heart disease and dilated cardiomyopathy in adults and congenital heart disease in children. The patchy distribution of immunoreactivity suggests a muscarinergic activity in vivo. These reactivities were abolished by preincubation of antibodies with antigenic peptide and were not shown in the absence of antibodies. Moreover, these antibodies were able to interfere with muscarinic ligand binding in myocardium from human dilated cardiomyopathy as shown by decreases in binding sites and antagonist affinity. These results demonstrate that the antibodies against the second extracellular loop of the human M2 muscarinic receptor can specifically recognize muscarinic receptors in human tissue and display pharmacological activity in human diseased myocardium, confirming their usefulness for the study of localization and function of muscarinergic activity in the human heart.
 ...
PMID:Localization of muscarinic receptors in human heart biopsies using rabbit anti-peptide antibodies. 852 36

This study investigated the role of the sorbitol pathway on the genetic up-regulation of the cardiac M(2) muscarinic receptor (M(2)-mAChR) in streptozotocin (STZ)-induced diabetic rats. Three-month-old male Wistar rats were divided into five groups: (1) normal controls; (2) rats rendered diabetic by streptozotocin; (3) rats fed with glucose; (4) rats injected with sorbitol; and (5) diabetic rats treated with ONO-2235, an aldose reductase inhibitor. The M(2) muscarinic receptor (M(2)-mAChR) protein and mRNA densities of the heart tissue were measured by Western immunoblotting and Northern blotting, respectively. The densities of M(2)-mAChR protein and mRNA in the heart were significantly increased in diabetic rats, and rats given either glucose or sorbitol. When diabetic rats were treated with ONO-2235, the increases in heart M(2)-mAChR protein and mRNA were significantly reduced. The findings suggest that hyperglycemia and the sorbitol pathway are involved in the pathogenesis of diabetic heart disease in STZ-induced diabetic rats. Aldose reductase inhibitors may be useful in the treatment and prevention of cardiac complication in diabetes.
 ...
PMID:The role of sorbitol pathway and treatment effect of aldose reductase inhibitor ONO2235 in the up-regulation of cardiac M2-muscarinic receptors in streptozotocin-induced diabetic rats. 1593 25

The role of autoimmunity in cardiovascular diseases has become one of the focal points of research studies. Autoimmune response and autoreactive autoantibodies have been found in dilated cardiomyopathy, heart failure, rheumatic fever, myocarditis, atherosclerosis, and other diseases. Autoantibodies may appear due to tissue injury and exposure of autoantigens, in addition to molecular mimicry and cross-reactivity with antigens found in infectious agents in predisposed individuals. In the early 1990s, autoantibodies reacting with the M2 muscarinic receptor were found in patients with dilated cardiomyopathy and subsequently, in patients with Chagas heart disease and arrhythmic disorders. Immunization of animals with the corresponding antigen triggered cardiac abnormalities also appearing in dilated cardiomyopathy of humans. It has been suggested that antibodies against M2 muscarinic receptors play a role in the pathogenesis of cardiac diseases and may also alter the electrophysiological properties of cardiac tissue. Herein, we review the current knowledge of antibodies against M2 muscarinic receptors and the possible use of a targeted therapy against these autoantibodies.
 ...
PMID:The diagnostic and clinical significance of anti-muscarinic receptor autoantibodies. 2120 92