Adrenergic

Abstract: Since the classification of beta-adrenergic receptors (beta-ARs) into beta 1 and beta 2 subtypes, additional beta-ARs have been implicated in the control of various metabolic processes by catecholamines. A human gene has been isolated that encodes a third beta-AR, here referred to as the "beta 3-adrenergic receptor." Exposure of eukaryotic cells transfected with this gene to adrenaline or noradrenaline promotes the accumulation of adenosine 3',5'-monophosphate; only 2 of 11 classical beta-AR blockers efficiently inhibited this effect, whereas two others behaved as beta 3-AR agonists. The potency order of beta-AR agonists for the beta 3-AR correlates with their rank order for stimulating various metabolic processes in tissues where atypical adrenergic sites are thought to exist. In particular, novel beta-AR agonists having high thermogenic, antiobesity, and antidiabetic activities in animal models are among the most potent stimulators of the beta 3-AR.

Abstract: We studied the effects of cigarette smoking, sham smoking and smoking during adrenergic blockade in 10 subjects to determine whether smoking released the sympathetic neurotransmitter norepinephrine, as well as the adrenomedullary hormone epinephrine, and whether smoking-associated hemodynamic and metabolic changes were mediated through adrenergic mechanisms. Smoking-associated increments in mean (±S.E.M.) plasma norepinephrine (227±23 to 324±39 pg per milliliter, P<0.01) and epinephrine (44±4 to 113±27 pg per milliliter, P<0.05) were demonstrated. Smoking-associated increments in pulse rate, blood pressure, blood glycerol and blood lactate/pyruvate ratio were prevented by adrenergic blockade; increments in plasma growth hormone and cortisol were not. Since significant smoking-associated increments, in pulse rate, blood pressure and blood lactate/pyruvate ratio, preceded measurable increments in plasma catecholamine concentrations, but were adrenergically mediated, these changes should be attribut...

Abstract: The medical treatment of chronic heart failure has undergone a remarkable transition in the past 10 years. The approach has changed from a short-term hemodynamic/pharmacological paradigm to a more long-term, reparative strategy that aims to favorably alter the biological properties of the failing heart.1 This is dramatically illustrated by the recent success in treating mild-to-moderate chronic heart failure with β-adrenergic blocking agents. This review describes how a treatment that began as a contraindication1 2 3 became an established treatment of chronic heart failure. The failing human heart is adrenergically activated,4 5 6 which helps to maintain cardiac performance over the short term by increasing contractility and heart rate. In contrast, in the resting state there is no adrenergic support of normally functioning human left ventricles.6 Multiple lines of evidence7 8 9 indicate that it is the increase in cardiac adrenergic drive rather than an increase in circulating norepinephrine that is both initially supportive and then ultimately damaging to the failing human heart. As shown in Table 1⇓, there are 3 adrenergic receptors (β1, β2, and α1) in human cardiac myocytes coupled to a positive inotropic response and cell growth.10 11 12 β-Adrenergic receptors are coupled via the “stimulatory” G protein Gs to the effector enzyme adenylyl cyclase, which converts the substrate MgATP to cAMP. cAMP is a positively inotropic and chronotropic second messenger and is strongly growth promoting. In nonfailing human left or right ventricles, the β1/β2 ratio is 70 to 80/30 to 20, but in failing human ventricles, 35% to 40% of the total number of β-receptors are β2 because of selective downregulation in the β1 subtype.10 11 α1 Receptors are coupled via a different G protein (G …

Abstract: The role of the glucocorticoid receptor (GR) in glucocorticoid physiology and during development was investigated by generation of GR-deficient mice by gene targeting. GR -/- mice die within a few hours after birth because of respiratory failure. The lungs at birth are severely atelectatic, and development is impaired from day 15.5 p.c. Newborn livers have a reduced capacity to activate genes for key gluconeogenic enzymes. Feedback regulation via the hypothalamic-pituitary-adrenal axis is severely impaired resulting in elevated levels of plasma adrenocorticotrophic hormone (15-fold) and plasma corticosterone (2.5-fold). Accordingly, adrenal glands are enlarged because of hypertrophy of the cortex, resulting in increased expression of key cortical steroid biosynthetic enzymes, such as side-chain cleavage enzyme, steroid 11 beta-hydroxylase, and aldosterone synthase. Adrenal glands lack a central medulla and synthesize no adrenaline. They contain no adrenergic chromaffin cells and only scattered noradrenergic chromaffin cells even when analyzed from the earliest stages of medulla development. These results suggest that the adrenal medulla may be formed from two different cell populations: adrenergic-specific cells that require glucocorticoids for proliferation and/or survival, and a smaller noradrenergic population that differentiates normally in the absence of glucocorticoid signaling.