beta-adrenergic receptors in rat liver: effects of adrenalectomy.

Abstract

The response of rat liver adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] to catecholamines is enhanced after adrenalectomy. To ). An increase in the sensitivity of adrenergically innervated organs to catecholamines has also been observed after denervation (4-7). This increase has been associated with both pre-and postsynaptic changes.f3-Adrenergic receptor-mediated responses to catecholamines involve the activation of adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] which catalyzes the formation of adenosine 3':5'-cyclic monophosphate (cAMP) (8). An increase in hormone-sensitive adenylate cyclase activity and a concomitant increase in the concentration of cAMP after exposure to appropriate hormones have been seen in surgically denervated dog heart (5) and rat pineal organ (9). An increased production of cAMP in response to catecholamines has also been observed after administration of 6-hydroxydopamine (7) or reserpine (10).Chronic exposure to acetylcholine leads to a decrease in the sensitivity of skeletal muscle to cholinergic agonists (11). Deguchi and Axelrod have shown that the sensitivity of the pineal to catecholamines is decreased after administration of isoproterenol to rats (9). This decrease has been correlated with a reduction in the number of fl-adrenergic receptors in the pineal organ (12). Furthermore, administration of isoproterenol to frogs or incubation of frog erythrocytes with isoproterenol leads to a desensitization to catecholamines, which is mediated through a decrease in receptor density (13,14).Adenylate cyclase-linked receptors for catecholamines exist in the liver where they affect carbohydrate metabolism. Administration of catecholamines leads to an increase in intracellular cAMP levels and to an increase in the rate of gluconeogenesis and glycogenolysis (15). In cat and dog liver, fl-adrenergic receptors appear to be predominantly involved in regulating these processes. However, the pharmacological specificity of adrenergic receptors in rat liver is controversial (15). It is likely that both a and fl-adrenergic receptors mediate the specific effects of catecholamines on glucose metabolism in rat liver but the exact contribution of the two types of receptors is in question (see 15). Glucocorticoids play a "permissive" role in regulating cAMP-mediated effects of hormones in liver and other organs (16,17). In adrenalectomized (Adx) rats, the stimulation of gluconeogenesis and glycogenolysis in response to catecholamines is markedly reduced (16). However, the production of cAMP in response to catecholamines is increased in Adx animals (16,18,19).Since changes in the catecholamine-sensitive adenylate cyclase occur in the absence of glucocorticoids, it was of interest to determine the number and properties of fl-adrenergic receptors in liver from normal and Adx animals.[125I]Iodohydroxybenzylpindolol (IHYP), a potent fl-receptor antagonist, has been used as the ligand in a binding assay for fl-adrenergic receptors of rat liver. The increase ...

Modeling receptor/gene-mediated effects of corticosteroids on hepatic tyrosine aminotransferase dynamics in rats: dual regulation by endogenous and exogenous corticosteroids

“…Rats were weighed, anesthetized with ketamine/xylazine, and sacrificed by aortic exsanguinations at 0.25, 0.5, 0.75, 1, 2, 4, 5,6,7,8,12,24,36,48,60,72,84 and 96 h (n = 3 per time point). Six rats injected with IM saline and sacrificed at 12 and 24 h (n = 3 per time point) served as controls.…”

“…(5) (6) where A, C and D are the amount, concentration and dose in the corresponding compartments designated by the subscripts P and T representing plasma and tissue (distribution) compartments; k el is the first-order elimination rate constant from the central compartment, Vc is the central volume of distribution, k 12 and k 21 are the first-order intercompartmental distribution rate constants, F r and (1 -F r ) are the fractions of dose absorbed through two absorption pathways described by two first-order rate constants, k a1 and k a2 . The overall IM bioavailability (F) was determined by simultaneously fitting plasma MPL concentrations after 50mg/kg IV and IM dosing.…”

“…Part of DR(N) may either recycle back (R f ) to the cytosol or may degrade with a rate constant of (1 -R f ) ·k re . The equations describing this chain of events are: (10) (11) (12) The receptor density was determined in two groups of control animals sacrificed at 12 and 24 h, and the initial condition for Eq. 10 was fixed to the mean values from those two groups (476 fmol/g).…”

“…Due to absence of endogenous CST, studies in adeenalectomized ADX rats facilitates assessment of various pharmacodynamic/toxicodynamic endpoints governed by synthetic CS without confounding factors such as non-stationary baselines of biomarkers. Although the practical advantages in using this model are substantial, adrenalectomy may lead to undesirable physiological changes such as increased sensitivity of hepatic cAMP in response to catecholamines [12], decrease in body weight [13], delay in onset of puberty in female rats, changes in expression of various neuropeptide genes [14], and-most importantly-multi-factorial changes in the gluconeogenic pathway [15]. Despite the complexities that may be involved in using normal rats, they are more physiologically relevant especially when evaluating the interrelationships between carbohydrate, protein, and lipid metabolism.…”

Effects of fasting on hepatic catecholamine receptors

“…Glycogenolytic activation via the fl-receptor is negligible in these animals. The characteristics of catecholamine activation of these processes have been reported to be altered in adrenalectomized [5,6] and hypothyroid rats [7][8][9]. In these animals, a decrease in a-adrenergic action concomitant with an increase in fl-adrenergic action was observed [5,6,8,9].…”