Plasma histamine and catecholamine levels during hypotension induced by morphine and compound 48/80

Histamine receptors are present in adrenergic terminals, and histamine is reported to inhibit release of the neurotransmitter norepinephrine (NE) at certain neuroeffector junctions. However, a physiological role for histamine in modifying adrenergic neurotransmission has not been established. To examine the interaction of elevated plasma histamine and catecholamine release, two compounds that release histamine, morphine (3 mg/kg), and compound 48/80 (0.5 mg/kg), were administered intravenously (i.v.). Plasma norepinephrine (NE) levels were used to monitor sympathetic nervous system activity, and plasma epinephrine (Epi) levels were used to monitor adrenal activity. Both morphine and compound 48/80 caused an immediate and marked increase in plasma histamine. Simultaneous with this increase, a marked decrease in mean arterial pressure occurred. Plasma NE levels increased in animals administered compound 48/80, but in morphine-treated animals, plasma NE levels did not change from pretreatment values. Plasma Epi levels increased in both groups, but the magnitude and duration of the responses differed. The results indicate that elevated plasma catecholamines can increase in response to histamine-induced hypotension but this effect can be suppressed by the central actions of morphine.     

Pindolol increases plasma norepinephrine concentration by stimulation of beta 2-adrenoceptors in conscious spontaneously hypertensive rats.

The beta-adrenoceptor antagonist pindolol [10-1,000 micrograms/kg subcutaneously (s.c.)] caused dose-related decreases in mean arterial pressure (MAP) and increased heart rate (HR) in conscious spontaneously hypertensive rats (SHR). The lowest dose of pindolol (10 micrograms/kg) decreased MAP by 25 mm Hg (-16%) without affecting plasma norepinephrine (NE) or plasma renin concentration (PRC). However, higher doses of pindolol elicited dose-related increases in plasma NE concentration and PRC. Plasma epinephrine concentration was not altered by pindolol. The selective beta 2-adrenoceptor antagonist ICI 118,551 (3 mg/kg, s.c.) prevented the tachycardia but not the increase in PRC caused by 100 micrograms/kg pindolol. Treatment with ICI 118,551 completely eliminated the 45% increase in plasma NE elicited by 100 micrograms/kg of pindolol even though the decrease in MAP caused by this dose of pindolol was the same in the presence (-33 mm Hg) and absence (-34 mm Hg) of beta 2-adrenoceptor blockade. These results indicate that the vasodepressor action of pindolol in SHR does not result from an agonistic effect at postjunctional beta 2-adrenoceptors in the vasculature. In addition, the increases in plasma NE concentration produced by pindolol result from stimulation of beta 2-adrenoceptors. These beta 2-adrenoceptors may be located prejunctionally on sympathetic neurons.     

Effects of diet-induced hypokalaemia on the antiarrhythmic and electrophysiological actions of prolonged oral treatment with either amiodarone or disopyramide in the anaesthetised rat

The potential antiarrhythmic and electrophysiological effects of prolonged oral dosing with amiodarone (20 mg/kg/day) or disopyramide (25 or 50 mg/kg b.i.d.) were compared in normokalaemic (NK) and diet-induced hypokalaemic (HK) anaesthetised rats. In NK rats, amiodarone reduced the number of electrical deaths consequent upon coronary artery ligation and prolonged action potential duration (APD50) of papillary muscle. Disopyramide conferred marked protection against arrhythmias in NK animals, prolonged APD50, reduced the maximum rate of depolarisation, and induced bradycardia. Hypokalaemia inhibited both the antiarrhythmic efficacy and these electrophysiological actions of amiodarone and disopyramide. However, prolongation of APD90 by both drugs was little affected by hypokalaemia. Amiodarone prolonged QTc both in NK and HK rats, whilst disopyramide only prolonged QTc in NK rats and only at the higher dose. It is concluded that reduced antiarrhythmic efficacy of the two drugs by hypokalaemia may be due to altered electrophysiological responses. QTc prolongation per se appears to be associated with antiarrhythmic, not arrhythmogenic, actions in this experimental model.     

Alpha and beta-adrenoceptors in hypertension. I. Cardiac and renal alpha 1-, beta 1-, and beta 2-adrenoceptors in rat models of acquired hypertension

To determine whether adrenoceptor changes in genetic hypertension occur primary or secondary to blood pressure elevation, we measured cardiac and renal alpha 1- (by [125I]Be 2254 binding) and beta 1- and beta 2-adrenoceptors (by (-)-[125I]iodocyanopindolol binding) densities in various rat models of acquired hypertension (Dahl S rats on a high-sodium diet, 1-clip-1-kidney (1C-1K) renal hypertensive and DOCA-salt hypertensive rats) in comparison with genetically identical age-matched untreated rats. In addition, alpha 1-adrenoceptors were assessed in spontaneously hypertensive rats (SHR) and in SHR treated with the immunosuppressant cyclosporin A. In heart, no clear pattern of changes in alpha 1- or beta 1- and beta 2-adrenoceptors was obtained. In kidney, however, beta 1- and beta 2-adrenoceptors were increased in all models of hypertension, and a good correlation between renal beta-adrenoceptors and systolic blood pressure was found. In contrast, renal alpha 1-adrenoceptors were only increased in SHR but not in any form of acquired hypertension. Thus, renal beta-adrenoceptor increases probably occur secondary to blood pressure elevation, whereas alpha 1-adrenoceptor increases appear to be associated with genetic hypertension. Because renal alpha-adrenoceptors are linked to tubular sodium reabsorption, we suggest that an increase in renal alpha 1- (and alpha 2)-adrenoceptors may be a very early step in the development of genetic hypertension.     

Blockade of beta1- and beta2-adrenoceptors delays wound contraction and re-epithelialization in rats

1. The participation of sympathetic efferent fibres in wound healing is not well understood. The aim of the present study was to investigate the effects of beta(1)- and beta(2)-adrenoceptor blockade on rat excisional cutaneous wound healing. 2. Male rats were treated orally with propranolol dissolved in drinking water (50 mg/kg per day), whereas the control group received drinking water without propranolol. Propranolol was administered daily until rats were killed. A full-thickness excisional lesion was performed. The lesion area was measured to evaluate wound contraction. After rats had been killed, lesion and adjacent normal skin were formol fixed and paraffin embedded. Sections were stained with haematoxylin-eosin, Sirius red or Toluidine blue and immunostained for a-smooth muscle actin or proliferating cell nuclear antigen. 3. Propranolol-treated rats presented delayed wound contraction and epidermal healing and decreased hydroxyproline levels, collagen density and neo-epidermis thickness. Blockade of beta(1)- and beta(2)-adrenoceptors increased epidermal and connective tissue cell proliferation, polymorphonuclear leucocyte migration, myofibroblast density and mast cell migration. The volume density of blood vessels was increased and vessels were more dilated in propranolol-treated animals. 4. Thus, we conclude that beta(1)- and beta(2)-adrenoceptor blockade impairs cutaneous wound healing. This information should be considered by physicians during the treatment of patients who present with hypertension and problems in the healing process (such as venous ulcers).     

Different responses to beta-adrenoceptor blocking drugs of the blood pressure and heart rate in the urethane-anesthetized dog and rat

I.v. propranolol (Prop) produced sustained pressor responses in rats but not in dogs under urethane anesthesia. In the dogs there was a progressive reduction in systolic blood pressure (SBP) in accordance with a significant heart rate (HR) reduction. Even at the i.v. dose (5 mg/kg) where vasoconstrictor response to i.v. norepinephrine (NE) is changed to the vasodilator one in rats, phenoxybenzamine could not completely suppress the NE-induced vasoconstriction in dogs. In pithed dogs, unlike pithed rats, i.v. Prop augmented neither sympathetic nerve stimulation- nor i.v. epinephrine (Epi)-induced pressor responses. Urethane anesthesia brought much higher concentrations in plasma Epi and NE in the dog than in the rat. In comparison with their respective values under the conscious state, SBP and HR of the dog were higher and those of the rat were lower under urethane anesthesia. As in urethane-anesthetized dogs, i.v. Prop elicited remarkable HR reduction accompanied by progressive hypotension in coronary-ligated rats with high sympathetic activity. Thus the reason for the absence of pressor response to beta-receptor blockage in the dog may be due to less functional significance of beta 2-adrenoceptor-mediated vasodilation in determining the peripheral vascular tone; and also, the possibility that there may be the involvement of an inverse influence of urethane on the cardiovascular regulatory system in terms of enhancing sympathetic nervous activity in the dog and a decreasing one in the rat can not be ruled out.     

Pressor response induced by clenbuterol treatment in immobilized normotensive rats

Short-term treatment with clenbuterol [0.6 mg/kg-1 subcutaneously (s.c.) daily] produces a pressor effect in stressed rats after a period of immobilization (40 min). The stress applied markedly increases the plasma concentrations of norepinephrine (NE) and epinephrine. After bilateral adrenal demedullation, the increased levels of catecholamines and the hypertensive response obtained after clenbuterol treatment in the stressed animals were reduced to the values of the control rats. Clenbuterol treatment produced desensitization of the beta 2-adrenoceptor-mediated effect and thus reduced the vasodilator response induced by isoproterenol and increased the vasoconstriction produced by epinephrine but not that caused by NE. This desensitization may be responsible for the hypertensive response after clenbuterol treatment in stressed animals which is attenuated after adrenal demedullation. In conclusion, our results provide evidence that clenbuterol treatment induces pressor effect in normotensive animals under stress.     

Contrasting cardiovascular responses from intrathecal administration of epinephrine and norepinephrine in conscious rats: role of alpha 1- and alpha 2-adrenoceptors.

In conscious rats, intrathecal (i.t.) administration of norepinephrine (NE) produced pressor responses, whereas i.t. epinephrine (Epi) caused depressor responses at low doses (0.1-1 microgram) and pressor responses at a higher dose (10 micrograms). Epi administered i.t. produced bradycardia; however, NE caused tachycardia at low doses and bradycardia at high doses. The cardiovascular responses were dissimilar to those observed after intravenous (i.v.) administration of these doses of NE and Epi. When [3H]NE or [3H]Epi (1.0 microgram, 10 mCi) was injected i.t., minimal radioactivity was detected in peripheral blood (PB) samples, indicating that the effects of i.t.-injected catecholamines on blood pressure (BP) and heart rate (HR) are due to stimulation of central spinal adrenoceptors and not to peripheral effects after leakage. Pretreatment with i.t. administration of the alpha 1-antagonist prazosin (1.0 microgram) attenuated pressor responses and tachycardia produced by i.t. NE (1.0 microgram), whereas i.t. pretreatment with the alpha 2-antagonist yohimbine (10 micrograms) counteracted depressor responses and bradycardia produced by i.t. Epi. Therefore, these spinally released catecholamines appear to produce opposite cardiovascular effects whereby sympathetic preganglionic neurons are excited by NE through spinal alpha 1-adrenoceptors and are inhibited by Epi through spinal alpha 2-adrenoceptors.     

Pressor response to beta 1- and beta 2-blockers in conscious rats treated with phentolamine

The purpose of this study was to examine the conditions whereby beta-blockers cause a pressor response in conscious, unrestrained rats: (1) whether beta-blockers cause a pressor response in rats subjected to, or not subjected to, nonselective alpha-blockade with phentolamine; (2) whether the pressor response to beta-blockers is due to the blockade of vasodilator beta 2-adrenoceptors, and (3) whether it is due to an acute increase in the release of adrenaline (A) and noradrenaline (NA). In the first series of experiments cumulative dose-response curves for propranolol, atenolol and ICI 118,551, nonselective beta-, beta 1- and beta 2-selective antagonists, respectively, were constructed in rats subjected to a continuous intravenous infusion of phentolamine. The administration of each of the beta-antagonists caused a significant dose-dependent increase in mean arterial pressure (MAP). The ED50 values for the increase in MAP were found to be 3.6 +/- 0.8, 10 +/- 2.6 and 4.6 +/- 0.8 micrograms/kg for propranolol, atenolol and ICI 118,551, respectively. In the second series of experiments, a single bolus injection of a selective or nonselective beta-antagonist or saline vehicle was given to rats subjected to a continuous intravenous infusion of phentolamine. Plasma levels of A and NA were determined in the control condition, during the infusion of phentolamine and again after the injection of a beta-antagonist. The infusion of phentolamine significantly decreased MAP and increased plasma levels of A and NA.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of beta 1- and beta 1 + beta 2-antagonists on training-induced myocardial hypertrophy and enzyme adaptation

The effects of beta 1- and beta 1 + beta 2-antagonists on the myocardial adaptation to exercise training were investigated in male Sprague-Dawley rats randomly divided into trained (treadmill, 1 hr/day, 5 days/week for 10 weeks at 27 m/min, 15% grade) without drug (TC), sedentary without drug (SC), trained treated with atenolol (TA) (10 mg/kg body wt, i.p.), trained treated with propranolol (TP, 30 mg/kg body wt, i.p.), and sedentary propranolol. Doses of both beta-antagonists were titrated to decrease the exercise heart rate by 25% compared to the controls. The heart weight and heart/body weight ratio were significantly greater in TC (1.28 +/- 0.07 g (P less than 0.01); 296 +/- 12 mg/100 g body wt (P less than 0.05) respectively) than in SC (1.09 +/- 0.04 g and 268 +/- 11 mg/100 g body wt), or in TP and TA. Myocardial mitochondrial protein was unchanged by training or beta-blockade. Citrate synthase and beta-hydroxyacyl CoA dehydrogenase activities were not altered. Carnitine palmitoyltransferase activity was increased in SP compared to SC. Training increased hexokinase activity only in TC (5.22 +/- 0.12 vs 4.26 +/- 0.23 mumol/min/g wet wt, P less than 0.01). Lactate dehydrogenase activity increased significantly (P less than 0.01) in both TC (383 +/- 14 mumol/min/g wet wt) and TA (372 +/- 14 mumol/min/g wet wt) compared to SC (276 +/- 14 mumol/min/g wet wt), but not in TP versus SP. These data indicate that (1) beta-adrenergic blockade prevents training-induced cardiac hypertrophy; (2) beta-antagonists have little effect on the myocardial oxidative capacity; and (3) while the training induction of myocardial hexokinase is inhibited by both beta 1- and beta 1 + beta 2-antagonists, myocardium may increase its ability to utilize lactate during exercise with training despite beta 1-blockade.     

Cardiac 3,4-dihydroxyphenylethylene glycol (DHPG) and catecholamine levels in a rat model of left ventricular failure

Cardiac norepinephrine (NE), dopamine (DA), epinephrine (Epi), and dihydroxyphenylethylene glycol (DHPG) (a major neuronal metabolite of NE) content were measured in rats with cardiac failure resulting from left ventricular myocardial infarction (LVMI) induced by coronary ligation. The ratio of DHPG/NE was significantly higher in both the right ventricle and interventricular septum of rats with LVMI compared with controls, reflecting a tendency for cardiac DHPG content to rise and NE content to fall during cardiac failure. Cardiac DA and Epi content did not significantly differ between rats with LVMI and controls. Elevated DHPG/NE ratios apparently reflected the increase in NE turnover that accompanies elevated sympathetic activity in heart failure more precisely than changes in NE levels or DHPG levels alone. Furthermore, DHPG/NE ratios are not influenced by increases in cardiac weight due to cardiac hypertrophy. The DHPG/NE ratios may be a useful index of cardiac sympathetic activity for future studies of the effects of drug treatment of cardiac failure in this animal model.     

Epinephrine-induced pulmonary oedema in rats is inhibited by corticotropin-releasing factor.

In various animal models of injury to skin, mucous membranes, muscle and brain, corticotropin-releasing factor (CRF) attenuated vascular leakage in the injured tissues. Here, the effects of CRF on a rat model of pulmonary oedema were examined. Male albino rats (220-290 g) received saline or CRF s.c., 30 min before pentobarbital anaesthesia, 60 mg/kg i.p., and 1 h before 1-epinephrine bitartrate (Epi), 30 micrograms/kg i.v. Within 30 min after Epi all (n = 27) saline-pretreated rats were dead from pulmonary oedema, but animals receiving human/rat CRF at doses of 7 to 57 micrograms/kg s.c. (n = 25) were all alive. Body wt, wet and dry wt of lungs were used to calculate an oedema index. This index increased from 3.6 +/- 0.1 to 9.6 +/- 0.3 after Epi but was inhibited by 87% after CRF 28 micrograms/kg s.c. The ED50 of CRF for reducing pulmonary oedema was 3.2 (1.3-7.4) micrograms/kg s.c. Mean arterial pressure increased from 119 +/- 4 to 167 +/- 2 mmHg after Epi 10 micrograms/kg i.v., but was not different (118 +/- 3 to 169 +/- 4 mmHg) after CRF pretreatment, 6 micrograms/kg s.c., a dose which reduced lung oedema. Pharmacokinetic estimates suggest that plasma levels of CRF sufficient to attenuate lung oedema in rats approximate those seen in pregnant women at delivery, raising the possibility that endogenous CRF may protect the maternal organism during parturition.     

Kininogen and prekallikrein increases in the blood of streptozotocin-diabetic rats are normalized by insulin in vivo and in vitro

Twelve days following treatment with 50 mg/kg streptozotocin (STZ), male rats were diabetic, with a three-fold increase in blood glucose (P<0.001) and increased plasma bradykinin (BK) kininogen reserves of [high-(HK)- and low- (LK)-molecular-weight kininogens,+162%, P<0.01 and +63%, P=0.05, respectively], as determined by bioassay of BK released by trypsin from these precursors under standardized conditions. Administration of a single dose (10 U/kg i.v.) of regular insulin decreased plasma HK and LK to near non-diabetic values. Within 24 h these values had returned to levels characteristic of uncorrected diabetes. Prekallikrein (PK), the precursor of plasma kallikrein, an enzyme which releases BK from HK, was increased by 63.4% (P<0.05) in STZ-diabetes, but dropped to near normal levels following insulin treatment. Incubation of whole blood of normal or diabetic rats with 0.02-0.2 mU/ml regular insulin for 10 min at 37 C, decreased HK (P<0.01) and PK (P<0.05) and led to the appearance (P<0.05) of Arg-Pro-Pro-Gly-Phe, a partially stable product of BK metabolism, detected in the incubation media by an enzyme-linked immunosorbent assay (ELISA). Incubation of cell-free plasma insulin had no effect on these parameters, suggesting that blood cells, possibly neutrophils, are required by insulin for the activation of plasma PK to kallikrein leading to BK release. Insulin may be a factor modulating BK formation; its reduction in diabetes may explain increases of plasma kininogen and PK observed in this condition.     

Chronic effects of metoprolol on myocardial beta-adrenergic receptors in doxorubicin-induced cardiac damage in rats.

This study was designed to clarify whether chronic administration of metoprolol had any influence on cardiac beta-adrenergic receptors (BAR) in doxorubicin (DOX)-induced cardiac damage. DOX was injected through the tail vein into rats (3 mg/kg/week, n = 22) for 5 weeks. One week after the final injection, the rats were randomly divided into two groups, M (with metoprolol, 10 mg/kg/day subcutaneously, s.c.; n = 11) and D (without metoprolol; n = 11). After 3-week infusion, plasma norepinephrine (NE) levels and BAR density [[125I]iodocyanopindolol (ICYP) binding on crude membranes] were measured. Left and right ventricular end-diastolic pressure (LVEDP, RVEDP) and myocardial NE levels were also measured, and the results were compared with those from an age-matched control group (C n = 11). Decreased BAR density and increased plasma NE levels were evident in group D, indicating downregulation. In group M, BAR density and plasma NE levels were similar to those in group C. The myocardial NE levels were decreased in group D, but were higher in group M than in group D. The LVEDP and RVEDP were increased in group D, but were almost normal in group M. These results suggest that metoprolol is a promising drug for treatment of DOX-induced cardiac damage.     

Independent regulation of beta 1- and beta 2-adrenoceptors.

1 The down-regulation of beta-adrenoceptors has been postulated as a biochemical marker of antidepressant efficacy. Here we demonstrate that chronic treatment with desipramine down-regulates beta 1-adrenoceptors in rat cerebral cortex and that beta-adrenoceptor subtypes can be independently regulated by treatment with different beta-adrenoceptor agonists. 2 Desipramine, (+/-)-clenbuterol, prenalterol, corwin (20 mg kg-1 daily) and corwin (10 mg kg-1 daily) were administered to male, Sprague-Dawley rats, over eight days, by means of osmotic Alzet pumps placed subcutaneously and removed 24 h before analysis. Control rats received vehicle only. The beta 1- and beta 2-adrenoceptor populations were measured in cerebral cortex by a modified (-)-[125I]-pindolol receptor binding assay. 3 The conventional antidepressant, desipramine, preferentially down-regulated beta 1-adrenoceptors whereas the non-selective beta-adrenoceptor agonist (+/-)-clenbuterol preferentially down-regulated beta 2-adrenoceptors. The beta 1-selective partial agonist, prenalterol, up-regulated beta 1-adrenoceptors perhaps acting more as an antagonist than as an agonist. Finally, neither dose of corwin had any significant effect on beta-adrenoceptor number.     

Stimulation of insulin secretion and improvement of glucose tolerance in rat and dog by the P2y-purinoceptor agonist, adenosine-5'-O-(2-thiodiphosphate).

1. In vivo effect of a P2y-purinoceptor agonist, adenosine-5'-O-(2-thiodiphosphate) (ADP beta S), on insulin secretion and glycaemia were studied both in rats and dogs. 2. In anaesthetized rats, i.v. administered ADP beta S (0.2 mg kg-1) produced an insulin response dependent on the nutritional state of the animals, since we observed only a transient increase in overnight-fasted rats and a sustained insulin secretion followed by a reduction in plasma glucose levels in fed rats. During an i.v. glucose tolerance test, ADP beta S enhanced insulin release and thus increased the glucose disappearance rate. 3. In anaesthetized fasted dogs, i.v. administered ADP beta S (0.1 mg kg-1) increased pancreaticoduodenal insulin output and slightly decreased blood glucose levels. 4. In conscious fasted dogs, orally administered ADP beta S (0.1 mg kg-1) transiently increased insulinemia and punctually reduced glycaemia. Furthermore, during an oral glucose tolerance test, orally administered ADP beta S at the same dose markedly enhanced insulin secretion and consequently reduced the hyperglycaemia. 5. In conclusion, the P2y-agonist, ADP beta S, is a potent insulin secretagogue in vivo, improves glucose tolerance and is effective after oral administration. Thus, the P2y-purinoceptors of the beta cell may be a target for new antidiabetic drugs.     

Resveratrol enhances insulin secretion by blocking K(ATP) and K(V) channels of beta cells

The present study investigated the effect of resveratrol on the electrophysiology and insulin secretion of pancreatic beta cells, and examined resveratrol-induced alterations in insulin levels and plasma glucose of normal and streptozotocin-induced diabetic rats. Whole-cell voltage clamp study in the MIN6 cell, a mouse beta cell line, revealed that resveratrol significantly inhibited ATP-sensitive K(+) current at 3 micromol/l, and voltage-gated K(+) currents at 30 micromol/l. Ca(2+)-activated K(+) current was activated by resveratrol at 100 micromol/l. In MIN6 cells stained with membrane potential dye DiBAC(4)(5), resveratrol markedly depolarized membrane potential at the concentrations of 3-100 micromol/l. Insulin secretion was increased in the presence of resveratrol in MIN6, Hit-T15, and RIN-m5F cells. Resveratrol (3 mg/kg, i.p.) increased insulin secretion associated with a lowering in plasma glucose in normal rats, but not in streptozotocin-diabetic rats within the initial 60 min. In conclusion, resveratrol can act as an insulin-secretagogue through I(KATP) and I(KV) inhibition which can contribute to plasma glucose lowering effect in normal rats.     

Antidiuresis induced by beta1- and beta2-adrenergic agonists in ethanol-anesthetized rats.

The beta1- and beta2-components in antidiuresis and sodium retention induced by beta-adrenergic agonists were analysed in ethanol-anesthetized, water-diuretic rats. Intravenous infusions of isoprenaline, salbutamol and carbuterol did not affect insulin clearance but increased plasma renin concentration to the same same extent. Propranolol completely blocked the decreases in urine volume (V) and urinary sodium excretion (UNaV) induced by isoprenaline; practolol (beta1-blocker) inhibited only the decrease in UNaV and butaxamine (beta2-blocker) inhibited only the decrease in V. The ratios of doses of beta-agonists which decreased UNaV and by 50% (ED50 UNaV decrease/ED50 V decrease) were 0.34, 0.68, 1.56 and 2.36 for isoprenaline, tretoquinol, salbutamol and carbuterol, respectively. This increasing order of the ratios coincided with the order reported for the preponderance of the beta2- over beta1-component of these agonists. These results indicate that the decrease in UNaV induced by beta-agonists is related to beta1 stimulation, while the decrease in V is related to beta2 stimulation.     

Influence of age on the beta 1- and beta 2-adrenergic receptors in rat liver.

The influence of maturation and aging on beta receptors in rat liver was studied. Competition binding experiments with the nonselective beta-antagonist propranolol and the subtype selective antagonists ICI 118,551 (beta 2) ICI 89,406 (beta 1), and CGP 20,712A (beta 1) revealed the presence of a mixed beta 1 and beta 2 receptor population in crude plasma membrane preparations from livers of newborn, mature, and senescent rats. The percentage of beta 1 receptors was lowest in livers from newborn rats and was increased in livers from mature and senescent rats. This increase is caused by a decrease in beta 2 receptor density on maturation, although the beta 1 receptor density is nearly constant throughout the life span of the rat. Isoproterenol-stimulated adenylate cyclase activity was inhibited in livers from senescent rats by propranolol and ICI 118,551 and to a lesser extent by ICI 89,406 and CGP 20,712A. The isoproterenol-stimulated glucose output in hepatocytes from senescent rats was inhibited concentration dependently by propranolol, ICI 118,551, ICi 89,406, and CGP 20,712A. From these results we conclude that beta 1 and beta 2 receptors are present in livers from rats of the three age groups and that the beta 1 to beta 2 receptor ratio is increased in livers from mature and senescent rats compared with newborn rats. Both beta receptor subtypes are linked to the cAMP second messenger system in newborn and senescent rats; beta 1 and beta 2 receptors are equally involved in the regulation of glycogenolysis in hepatocytes from senescent rats.     

Effect of oral administration of zanapezil (TAK-147) for 21 days on acetylcholine and monoamines levels in the ventral hippocampus of freely moving rats

Zanapezil (TAK-147 (3-[1benzylpiperdin-4-yl]-1-(2,3,4,5-tetrahydro-1 H-1-benzazepin-8-yl) propan-1-one fumarate)) is a selective acetylcholine (ACh) esterase inhibitor under investigation as a drug for Alzheimer's disease (AD) treatment. In this study, the effects of TAK-147 at 2 mg kg(-1) p.o. for 21 days, compared to donepezil (E2020), on the levels of ACh, catecolamines and indoleamines were investigated in the ventral hippocampus (VH) of freely moving rats by microdialysis-high-performance liquid chromatography. The results revealed that the VH contains 92.05+/-21.97 fmol 20 microl(-1) ACh and the following monoamines levels (pg 30 microl(-1)), norepinephrine (NE) 1.92+/-0.39, epinephrine (Epi) 1.91+/-0.183, 3-methoxy-4-hydroxyphenylglycol (MHPG) 11.53+/-3.22, normetanephrine 3.26+/-0.61, dopamine (DA) 0.77+/-0.23, 3,4-dihydroxyphenylacetic acid (DOPAC) 3.37+/-1.01, homovanillic acid (4-hydroxy-3-methoxyphenylacetic acid; HVA) 4.04+/-0.93, 3-methoxytyramine 0.64+/-0.13, serotonin (5-HT) 0.73+/-0.16 and 5-hydroxyindoleacetic acid (5-HIAA) 313.15+/-18.42. On the 21st day and prior to the last dose, TAK-147 increased ACh, Epi, DA and 5-HT, whereas E2020 increased MHPG, Epi and DA. Following the last dose, TAK-147 increased NE, whereas E2020 increased NE, ACh and 5-HT in addition to their effects prior to the last dose. TAK-147 decreased HVA : DA ratio, but only marginally decreased DOPAC : DA and 5-HIAA : 5-HT ratios. On the other hand, E2020 decreased ratios of HVA : DA, DOPAC : DA (prior to the last dose), and 5-HIAA : 5-HT (90-180 min after the last dose). Both drugs decreased MHPG : NE only at 180 min after the last dose. The results also showed that TAK-147 increased Epi : NE ratio prior to and for 120 min following the last dose, whereas E2020 increased the ratio only before the last dose. The present results show that TAK-147 at a subthreshold dose could differentially increase ACh and 5-HT, compared to MHPG increased by E2020. The last dose of each drug could extend their effects to other monoamines. The increase of the monoamines levels, in addition to that on the ACh, and decrease of their oxidation could be of value in the treatment of the AD, other dementic diseases and the cohort neurological disorders depending on the type of the monoamine underlying the disorder.