Biomedical subjects

T R McMinn

Publications and source records attributed to T R McMinn.

3 recordsLinked to original sources

PubMed1995

Physiological effects of inverse agonists in transgenic mice with myocardial overexpression of the beta 2-adrenoceptor.

G-protein-coupled receptors are thought to have an inactive conformation (R), requiring an agonist-induced conformational change for receptor/G-protein coupling. But new evidence suggests a two-state model in which receptors are in equilibrium between the inactive conformation (R), and a spontaneously active conformation (R*) that can couple to G protein in the absence of ligand (Fig. 1). Classic agonists have a high affinity for R* and increase the concentration of R*, whereas inverse agonists have a high affinity for R and decrease the concentration of R*. Neutral competitive antagonists have equal affinity for R and R* and do not displace the equilibrium, but can competitively antagonize the effects both of agonists and of inverse agonists. The lack of suitable in vivo model systems has restricted the evidence for the existence of inverse agonists to computer simulations and in vitro systems. We have used a transgenic mouse model in which there is such marked myocardial overexpression of beta 2-adrenoceptors that a significant population of spontaneously activated receptor (R*) is present, inducing a maximal response without agonist. We show that the beta 2-adrenoceptor ligand ICI-118,551 functions as an inverse agonist, providing evidence supporting the existence of inverse agonists and validating the two-state model of G-protein-coupled receptor activation.

Adrenergic beta-Agonists↗

PubMed1995

Hereditary dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is a common and important cause of morbidity and mortality. Many factors can contribute to the development of this disorder, although most commonly the etiology is unexplained. However, recent studies in individuals with idiopathic DCM now reveal a heritable cause in 20-30% of individuals. Diverse modes of inheritance have been demonstrated, encompassing an autosomal dominant type (by far the most common), together with recessive and X-linked forms, and maternal inheritance through mitochondrial DNA. The hereditary forms of DCM (HDCM) predominantly affect the left ventricle, although inherited abnormalities affecting primarily the right ventricle also are described. HDCM may occur as a primary cardiomyopathy, or secondary to inherited systemic metabolic or neuromuscular disorders. The causative genes for primary HDCM of the autosomal dominant and recessive types have not yet been discovered, but the combination of family pedigree analysis and phenotyping by echocardiography, together with new genetic techniques, should now allow their identification. Knowledge of the gene or genes responsible for HDCM would improve diagnostic accuracy, facilitate genetic counseling, advance understanding of pathogenesis, and provide the starting point for new methods of treatment. Because of the frequently heritable nature of DCM, it is of great importance that a diligent search for all potentially affected family members be undertaken.

Cardiomyopathy, Dilated↗

PubMed1994

Enhanced myocardial function in transgenic mice overexpressing the beta 2-adrenergic receptor.

Transgenic mice were created with cardiac-specific overexpression of the beta 2-adrenergic receptor. This resulted in increased basal myocardial adenylyl cyclase activity, enhanced atrial contractility, and increased left ventricular function in vivo; these parameters at baseline in the transgenic animals were equal to those observed in control animals maximally stimulated with isoproterenol. These results illustrate a useful approach for studying the effect of gene expression on cardiac contractility. Because chronic heart failure in humans is accompanied by a reduction in the number of myocardial beta-adrenergic receptors and in inotropic responsiveness, these results suggest a potential gene therapy approach to this disease state.

Adenylyl Cyclases↗