alpha2-Adrenergic receptors (alpha2ARs) are essential components of the neural circuitry regulating cardiovascular function. The role of specific alpha2AR subtypes (alpha2a, alpha2b, and alpha2c) was characterized with hemodynamic measurements obtained from strains of genetically engineered mice deficient in either alpha2b or alpha2c receptors. Stimulation of alpha2b receptors in vascular smooth muscle produced hypertension and counteracted the clinically beneficial hypotensive effect of stimulating alpha2a receptors in the central nervous system. There were no hemodynamic effects produced by disruption of the alpha2c subtype. These results provide evidence for the clinical efficacy of more subtype-selective alpha2AR drugs.
-Adrenergic receptors (-ARs) are members of the superfamily of G-protein-coupled receptors that mediate the effects of catecholamines in the sympathetic nervous system. Three distinct -AR subtypes have been identified (1-AR, 2-AR, and 3-AR). In order to define further the role of the different -AR subtypes, we have used gene targeting to inactivate selectively the 2-AR gene in mice. Based on intercrosses of heterozygous knockout (2-AR ؉/؊) mice, there is no prenatal lethality associated with this mutation. Adult knockout mice (2-AR ؊/؊) appear grossly normal and are fertile. Their resting heart rate and blood pressure are normal, and they have a normal chronotropic response to the -AR agonist isoproterenol. The hypotensive response to isoproterenol, however, is significantly blunted compared with wild type mice. Despite this defect in vasodilation, 2-AR ؊/؊ mice can still exercise normally and actually have a greater total exercise capacity than wild type mice. At comparable workloads, 2-AR ؊/؊ mice had a lower respiratory exchange ratio than wild type mice suggesting a difference in energy metabolism. 2-AR ؊/؊ mice become hypertensive during exercise and exhibit a greater hypertensive response to epinephrine compared with wild type mice. In summary, the primary physiologic consequences of the 2-AR gene disruption are observed only during the stress of exercise and are the result of alterations in both vascular tone and energy metabolism.
At least three distinct beta-adrenergic recep-
Manipulations of the murine genome that alter cardiovascular function have created the need for methods to study cardiovascular physiology in genetically altered animals in vivo. We adapted chronic physiological measurement techniques to the nonanesthetized, nonrestrained murine model, established strain-specific cardiovascular and metabolic norms, and evaluated responses to anesthesia, exercise, and adrenergic stimulation. Anesthesia resulted in alterations in heart rate (HR), blood pressure (BP), and O2 consumption (V(O2)) and CO2 production (V(CO2)) for up to 6 h postoperatively. There were significant interstrain differences in resting values of HR and BP Graded treadmill exercise resulted in linear increases in HR, V(O2), V(CO2), and respiratory exchange ratio (RER) similar to those seen in larger species. Response to beta-adrenergic stimulation showed a classic sigmoidal dose-response curve; however, there was very little tachycardiac response to vagal blockade, indicating low resting vagal tone. This study demonstrates the feasibility of performing chronic cardiovascular measurements in nonanesthetized mice and stresses the importance of allowing for anesthetic recovery and strain variability. Murine cardiovascular responses to exercise can be reliably measured and are qualitatively similar to those in humans.
Cardiomyopathy is a major cause of morbidity and mortality. Ventricular conduction delay, as shown by prolonged deflections in the electrocardiogram caused by delayed ventricular contraction (wide QRS complex), is a common feature of cardiomyopathy and is associated with a poor prognosis. Although the G i-signaling pathway is up-regulated in certain cardiomyopathies, previous studies suggested this up-regulation was compensatory rather than a potential cause of the disease. Using the tetracycline transactivator system and a modified G i-coupled receptor (Ro1), we provide evidence that increased Gi signaling in mice can result in a lethal cardiomyopathy associated with a wide QRS complex arrhythmia. Induced expression of Ro1 in adult mice resulted in a >90% mortality rate at 16 wk, whereas suppression of Ro1 expression after 8 wk protected mice from further mortality and allowed partial improvement in systolic function. Results of DNA-array analysis of over 6,000 genes from hearts expressing Ro1 are consistent with hyperactive G i signaling. DNA-array analysis also identified known markers of cardiomyopathy and hundreds of previously unknown potential diagnostic markers and therapeutic targets for this syndrome. Our system allows cardiomyopathy to be induced and reversed in adult mice, providing an unprecedented opportunity to dissect the role of G i signaling in causing cardiac pathology.G proteins ͉ signal transduction ͉ gene expression ͉ genome ͉ bioinformatics I diopathic dilated cardiomyopathy (IDC) is a major cause of heart failure characterized by cardiac dilation and reduced systolic function. In the United States, about half of the cases of dilated cardiomyopathy are associated with myocarditis or coronary artery disease, and half are considered idiopathic (1-4). Ventricular conduction delay, as shown by a prolonged depolarization in the electrocardiogram (wide QRS complex), is associated with up to 70% of IDC cases (5) and is an independent risk factor for death among IDC patients (6, 7). Several lines of evidence implicate altered G i signaling in the development of cardiomyopathies such as IDC, but a direct relationship between G i signaling and cardiomyopathy has not been demonstrated in vivo. We recently created a system that utilizes a specifically designed G i -coupled receptor and inducible gene expression techniques to control G i signaling in the adult mouse heart (8).With over 2
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