THE INFLUENCE OF ADRENORECEPTOR ACTIVITY ON CRYPT CELL PROLIFERATION IN THE RAT JEJUNUM

The influence of adrenergic stimulation, adrenergic blockade and sympathectomy on crypt cell cycle time and mitotic time in rat jejunum was studied. Alpha adrenergic stimulation by noradrenaline was found to shorten both cell cycle and mitotic times, whereas beta adrenergic stimulation by adrenaline or isoprenaline was found to prolong both cell cycle and mitotic times. Conversely, alpha adrenergic blockade by phentolamine prolonged cell cycle time and beta adrenergic blockade by propranolol or practolol shortened cell cycle time but not mitotic time. Both chemical and surgical sympathectomy inhibited crypt cell proliferation. Chemically sympathectomized animals manifested supersensitivity to exogenous noradrenaline.     

Effect on renal function and renin secretion of noradrenaline infused into the renal artery.

Effect of noradrenaline on renal function and renin secretion was studied during infusion into the renal artery of anaesthetized dogs. Experiments were performed with or without alpha or beta receptor blockade. Noradrenaline infusion resulted in a significant elevation of renin secretion associated with marked vasoconstriction. Urine flow rate, the filtered and excreted amounts of sodium were diminished due to the decreased GFR. Alpha receptor blockade suppressed renin secretion in the presence of changes in renal haemodynamics. The simultaneous infusion of noradrenaline enhanced renin release without affecting renal haemodynamics or reducing Na-excretion. Following simultaneous inhibition of alpha and beta receptors renin secretion dropped markedly; there were no further changes in either renin secretion or renal haemodynamics upon the simultaneous administration of noradrenaline. Based on the present findings it is suggested that renin secretion is controlled by both alpha and beta receptors. Beta receptor simulation exerts a direct action, whereas alpha stimulation appears to be mediated in part by indirect mechanisms such as renal haemodynamics.     

Effects of adrenergic blockade on plasma catecholamine levels during adrenaline infusion.

Alpha and beta adrenergic blocking drugs were administered, either singly or in combination, prior to a 3hr adrenaline infusion (2 microgram kg body wt-1 min-1)), Animals were premediated with either phenoxybenzamine (1 mg kg body wt-1 min-1). Phenoxybenzamine did not affect circulating adrenaline levels, but propranolol, either alone or in combination with phenoxybenzamine, resulted in a significant reduction in plasma adrenaline levels when compared with the control unblocked situation of adrenaline infusion without premedication. The results provide a possible explanation for the protective effect of combined adrenergic blockade in shock situations.     

Adrenergic regulation of adipocyte metabolism

Adipocytes can be readily isolated from intact adipose tissue. In adipocytes from hamster and human white adipose tissue it is possible to demonstrate beta, alpha 1, and alpha 2 adrenoceptors. Alpha 2 adrenoceptor activation inhibits while beta adrenoceptor activation stimulates cyclic AMP accumulation and lipolysis. The effects of catecholamines on cyclic AMP accumulation are mediated through regulation of adenylate cyclase activity, which is activated through beta adrenoceptors and inhibited through alpha 2 adrenoceptors. Activation of alpha 1 adrenergic receptors has been shown to be associated with elevations of cytosol calcium and increased turnover of phosphatidylinositol. In white adipocytes, the only known alpha 1 adrenergic effects are inhibition of glycogen synthase and stimulation of glycogen phosphorylase via mechanisms distinct from those by which cyclic AMP produces similar end effects. In brown adipocytes, alpha 1 adrenoceptor activation stimulates respiration. Thyroid hormones primarily regulate the sensitivity of adipocytes to beta-adrenergic amines while having little effect on alpha adrenoceptor sensitivity.     

Alpha and beta adrenergic sensitivity in trained and untrained albino rats.

The effects on the blood pressure and heart rate responses of different adrenergic stimulants (norepinephrine, sympathomim, epinephrine and isoproterenol) and blocking agents (phenoxybenzamine and propranolol) were studied in control (N=55) and exercising (N=52) albino rats under anaesthesia. The test rats exercised by regular swimming for 10-14 weeks. Alpha stimulation and beta blocking produced smaller responses while alpha blocking and beta stimulation were followed by greater changes after training as compared with the control animals. The assumption of a modified adrenergic receptor sensitivity could not be substantiated by the results; the observations indicate rather a complex change in the autonomous regulation following regular physical exercise.     

Influence of alpha and beta adrenergic receptors blockade on the adrenolytic effect of muscular work

The changes in the response of adrenergic receptors alpha and beta in the blood vessels in the working muscles in a hindlimb in cats were studied after intra-arterial administration of noradrenaline, isoprenaline and during electric stimulation of the sympathetic trunk. The experiments were carried out during alpha-adrenergic receptors blockade with dihydroergotamine (0.3 mg/kg) beta-adrenergic receptors blockade with propranolol (1 mg/kg) and blockade of acetylcholine M receptors with atropine (0.5 mg/kg). The investigations were performed at rest, during exercise (electric stimulation of the sciatic nerve) and after the exercise. The following results deserve attention: 1) beta-adrenergic receptors blockade reduced significantly the alpha-adrenolytic effect of exercise restoring the ability of blood vessel to constriction in response to noradrenaline; 2) the vasodilator effect of isoprenaline evident in resting state and maintained to some extent during exercise was abolished completely by preceding alpha-adrenergic blockade. The changes in the reactivity of resistance vessels in working skeletal muscles to noradrenaline, with abolition of its vasoconstrictor effect, have been shown by Rein [7] and others authors [2, 5]. Similarly, it is well known that the resistance vessels contain two types of adrenergic receptors alpha and beta, and that the response of the vessels to stimulation of these receptors are different [1]. In view of the recently published observations of Jarhult and Lundvall suggesting that the beta-adrenergic receptors play an important physiological role [6] in the arterial part of the microcirculation [6] and in view of the hypothesis put forward by Kunos and Szentivanyj that alpha and beta receptors can be transformed depending on the intensity of tissue metabolism [8] it seemed worth while to study more systematically the changes of the reactivity of alpha and beta adrenergic receptors in the vascular bed of the skeletal muscles during and after muscle exercise.     

alpha- and betaCaMKII. Inverse regulation by neuronal activity and opposing effects on synaptic strength

We show that alpha and betaCaMKII are inversely regulated by activity in hippocampal neurons in culture: the alpha/beta ratio shifts toward alpha during increased activity and beta during decreased activity. The swing in ratio is approximately 5-fold and may help tune the CaMKII holoenzyme to changing intensities of Ca(2+) signaling. The regulation of CaMKII levels uses distinguishable pathways, one responsive to NMDA receptor blockade that controls alphaCaMKII alone, the other responsive to AMPA receptor blockade and involving betaCaMKII and possibly further downstream effects of betaCaMKII on alphaCaMKII. Overexpression of alphaCaMKII or betaCaMKII resulted in opposing effects on unitary synaptic strength as well as mEPSC frequency that could account in part for activity-dependent effects observed with chronic blockade of AMPA receptors. Regulation of CaMKII subunit composition may be important for both activity-dependent synaptic homeostasis and plasticity.     

Interaction of alpha and beta adrenergic stimulation on aortic ornithine decarboxylase activity

The interaction between beta and alpha adrenergic agonists on regulation of cockerel aortic ornithine decarboxylase (ODC) activity was examined. The beta adrenergic agonist isoproterenol both reduced basal aortic ODC activity and prevented induction of the decarboxylase by the alpha adrenergic agonist methoxamine. 3-Isobutyl-1- methylxanthine (IBMX) similarly reduced basal ODC activity and blocked induction of the enzyme by methoxamine. When given ten minutes before or after methoxamine, isoproterenol prevented aortic ODC induction, but not large sustained increases in blood pressure evoked by the alpha adrenergic agonist. In contrast, when injected three hours after methoxamine, isoproterenol had no effect on already elevated levels of enzyme activity. Addition of isoproterenol (10(-7)M), IBMX (1 mM) or dibutyryl cAMP (2.5 mM) to isolated aortic segments cultured in minimal salts-glucose media evoked decreases in basal levels of ODC activity resembling those observed in the intact animal. These results suggest that the balance between alpha and beta adrenergic stimulation may be an important feature of the regulation of polyamine biosynthesis in artery wall cells.     

Prejunctional beta 1-adrenoceptors inhibit cholinergic transmission in canine bronchi

The aim of the present study was to determine in canine bronchi the effects produced by norepinephrine (released from adrenergic nerve terminals) on cholinergic neurotransmission. Electrical stimulation of canine bronchi activates cholinergic and adrenergic nerve fibers. The adrenergic neuronal blocker, bretylium tosylate, inhibited the increase in [3H]norepinephrine overflow evoked by electrical stimulation but did not prevent that caused by the indirect sympathomimetic tyramine. During blockade of the exocytotic release of norepinephrine with bretylium, the pharmacological displacement of the sympathetic neurotransmitter by tyramine significantly decreased the contractions evoked by electrical stimulation but did not affect contractions caused by exogenous acetylcholine. Metoprolol, a beta 1-adrenergic antagonist, abolished and propranolol significantly reduced the effect of tyramine during electrical stimulation. alpha 2-Adrenergic blockade, beta 2-adrenergic blockade, or removal of the epithelium did not significantly affect the response to tyramine. These results suggest that norepinephrine when released from sympathetic nerve endings can activate prejunctional inhibitory beta 1-adrenoceptors to depress cholinergic neurotransmission in the bronchial wall.     

Calcium handling in vasoconstriction to stimulation of alpha 1- and alpha 2-adrenoceptors

Vasoconstriction to stimulation of postsynaptic alpha 1- and alpha 2-adrenoceptors involves different mechanisms of Ca2+ mobilization. Alpha 2-adrenoceptor-mediated vasoconstriction in vivo as well as in vitro is invariably and effectively antagonized by Ca2+ channel blockers, such as nifedipine or verapamil, and is therefore primarily carried by influx of extracellular Ca2+. On the other hand, alpha 1-adrenoceptor stimulation has been linked to both influx of extracellular Ca2+ and release of Ca2+ from intracellular stores. The sensitivity of alpha 1-adrenoceptor-mediated vasoconstriction to blockade by Ca2+ channel antagonists depends on how much both mechanisms of Ca2+ mobilization contribute to the contraction process, and varies between vascular tissues and alpha 1-adrenoceptor agonists. The experimental evidence for the differential utilization of Ca2+ in vasoconstriction to alpha 1- and alpha 2-adrenoceptor stimulation is reviewed.     

Antiabortifacient action of dibenzyloxyindanpropionic acid in mice

To evaluate the details of the adrenergic stimulation of urinary prostaglandins in man, ten normal volunteers were given various agonists and antagonists. The effect of 4 hour IV infusions of norepinephrine (NE), NE + phentolamine (PHT), NE + phenoxybenzamine (PHB), NE + prazosin (PZ), isoproterenol (ISO), and PHT alone on urinary PGE2 and PGI2 (6 keto PGF1 alpha) were determined. PGE2 and 6 keto PGF1 alpha were measured by radioimmunoassay from 4 hour urine samples. NE stimulated both PGE2 (196 +/- 40 to 370 +/- 84 ng/4 hrs/g creatinine and 6 keto PGF1 alpha (184 +/- 30 to 326 +/- 36), both p less than 0.01. In contrast, ISO had no effect on either PGE2 or 6 keto PGF1 alpha excretion. Alpha blockade with PHT. PHB, or PZ inhibited the NE induced systemic pressor effect. However, the effect of the alpha blockers on the NE induced stimulation of PGE2 and 6 keto PGF1 alpha varied. PHT did not alter the NE stimulated PGE2 or 6 keto PGF1 alpha release (370 +/- 84 vs. 381 +/- 80) PGE2 and (326 +/- 50 vs. 315 +/- 40) 6 keto PGF1 alpha both p greater than 0.2). PHT alone stimulated only 6 keto PGF1 alpha. PHB and the specific alpha 1 antagonist PZ similarly eliminated the NE induced prostaglandin release. These results suggest that adrenergically mediated urinary prostaglandin release in man is via an alpha receptor with alpha 1 characteristics.     

Characterization of adrenergic receptors on proximal tubular basolateral membranes

Alpha adrenergic receptors are identified on basolateral plasma membranes derived from proximal tubular epithelial cells. The density of alpha 2 receptors was over two-fold greater than alpha 1 receptors. The basolateral membranes were devoid of beta receptors. These results support previous demonstrations of alpha adrenergic receptors in rat renal cortex and concur with studies which suggest a limited presence of beta receptors on rat proximal tubules.     

Fatty acid synthesis in the fetal lung: relationship to surfactant lipids

The aims of this study were to investigate the control of fatty acid synthesis and its relationship to surfactant production in the fetal lung during alteration of hormonal and substrate conditions. Lung explants from 18 day fetuses (term = 22 days) which were cultured 2 days in the presence of 10 mM lactate showed parallel acceleration of de novo fatty acid synthesis (3H2O incorporation) and [14C]choline incorporation into disaturated phosphatidylcholine (DSPC) compared to culture of explants in glucose. Both the cultured and fresh explants were resistant to the classical short term (4 h) cAMP inhibition of fatty acid synthesis with 3 mM dibutyryl cAMP or 0.5 mM aminophylline. In the cultured explants short term cAMP elevation increased DSPC production, and long term (2 day) cAMP elevation caused a further increase in DSPC synthesis and also stimulated fatty acid synthesis. In cultured explants from 17 day fetuses, dexamethasone (0.1 microM) caused a synergistic increase with aminophylline in both fatty acid synthesis and DSPC production whereas, in explants from 18 day fetuses, dexamethasone inhibited both processes and reduced the level of stimulation of DSPC and fatty acid synthesis seen with aminophylline alone. Dexamethasone also reduced the stimulation of both DSPC and fatty acid synthesis produced in the culture of 18 day explants with bacitracin (0.5 mg/ml), whereas the combination of bacitracin and aminophylline resulted in a synergistic increase in DSPC production. Culture with glucagon (0.1 microM) also stimulated DSPC synthesis but at physiological levels insulin had no effect on either DSPC or fatty acid synthesis. These data show that lung fatty acid synthesis exhibits unique features of fatty acid synthesis regulation compared to other lipogenic tissues and also suggest a link between de novo fatty acid synthesis and surfactant production during the critical period of accelerated lung maturation.     

Hepatic potassium movements induced by sympathomimetic amines before and after adrenergic blockade.

The hepatic K+-mobilizing effects of phenylephrine and isoproterenol were studied in dogs equipped with chronic indwelling portal vein catheters. Animals anesthetized with sodium pentobarbital, received intraportal injections of these sympathomimetic amines, alone or in combination, before and after alpha, or beta, or combined adrenergic blockade. Hepatic K+ movements were assessed by measuring systemic arterial and hepatic venous K+ levels. It was concluded that adrenergic blockade exerted no significant influence on the ability of these agents to provoke the initial release and subsequent uptake of K+ by the liver.     

The alpha 4 beta 1 (very late antigen (VLA)-4, CD49d/CD29) and alpha 5 beta 1 (VLA-5, CD49e/CD29) integrins mediate beta 2 (CD11/CD18) integrin-independent neutrophil recruitment to endotoxin-induced lung inflammation

The beta(2) integrin cell adhesion molecules (CAM) mediate polymorphonuclear leukocyte (PMNL) emigration in most inflamed tissues, but, in the lung, other yet to be identified CAMs appear to be involved. In Lewis rats, the intratracheal injection of Escherichia coli-LPS induced acute (6-h) PMNL accumulation in the lung parenchyma (280 x 10(6) by myeloperoxidase assay; PBS control = 35 x 10(6)) and bronchoalveolar lavage fluid (BALF = 27 x 10(6); PBS = 0.1 x 10(6)). Parenchymal accumulation was not inhibited by a blocking Ab to beta(2) integrins and only minimally inhibited (20.5%; p < 0.05) in BALF. We examined the role of alpha(4)beta(1) and alpha(5)beta(1) integrins and of selectins in this PMNL recruitment. Treatment with mAbs to alpha(4)beta(1) or alpha(5)beta(1), even in combination, had no effect on PMNL accumulation induced by intratracheal LPS. However, anti-alpha(4) combined with anti-beta(2) mAbs inhibited PMNL recruitment to the parenchyma by 56% (p < 0.001) and to BALF by 58% (p < 0.01). The addition of anti-alpha(5) mAb to beta(2) plus alpha(4) blockade inhibited PMNL accumulation further (by 79%; p < 0.05). In contrast, blockade of L-, P-, and E-selectins in combination or together with beta(2), alpha(4), and alpha(5) integrins had no effect. LPS-induced BALF protein accumulation was not inhibited by treatment with anti-beta(2) plus alpha(4) mAbs, but was prevented when alpha(5)beta(1) was also blocked. Thus, while selectins appear to play no role, alpha(4)beta(1) and alpha(5)beta(1) function as major alternate CAMs to the beta(2) integrins in mediating PMNL migration to lung and to pulmonary vascular and epithelial permeability.     

Basic properties of beta adrenergic receptors mediating melanosome dispersion of melanophores in a cyprinid fish, Zacco temmincki

In melanophores of a cyprinid fish, Zacco temmincki, receptor mechanisms of melanosome dispersion induced by catecholamines were examined. While possessing a melanosome-aggregating action in higher concentrations, isoproterenol and epinephrine in lower concentrations acted to disperse melanosomes. Norepinephrine, epinine and dopamine altered their action from melanosome aggregation to melanosome dispersion after alpha adrenergic blockade. The catecholamine-induced melanosome dispersion was inhibited by beta adrenergic blocking agents. Mediation of dispersion is regulated through beta adrenergic receptors. The beta adrenergic responses were unaffected by mersalyl, a sulfhydryl inhibitor. A prospective substance acting in dispersing melanosomes appears to be adrenaline, but not noradrenaline.     

Age-related changes in the control of hepatic cyclic AMP levels by alpha 1- and beta 2-adrenergic receptors in male rats

Hepatocytes from juvenile male rats (80-110 g) showed a 12-fold elevation of cAMP in response to epinephrine, which was mediated by beta 2-adrenergic receptors. In these cells, either alpha 1- or beta 2-adrenergic stimulation alone activated phosphorylase and glucose release although the alpha 1-phosphorylase response was 10-fold more sensitive to epinephrine and resulted in more rapid (by 10-20 s) activation of the enzyme. This suggests that the beta 2-adrenergic response is functionally unimportant for glycogenolysis, even in juvenile rats. beta 2-Adrenergic stimulation did, however, produce an increase in the rate of gluconeogenesis from [U-14C] lactate in these cells. Aging in the male rat was associated with attenuation of the beta 2-adrenergic cAMP response coupled with the emergence of an alpha 1-receptor-mediated accumulation of cAMP. The order of potency displayed by the alpha 1-adrenergic/cAMP system to adrenergic agonists and antagonists was identical with that of the alpha 1-adrenergic/Ca2+ system. These data suggest that, in maturity, hepatic alpha 1-receptors become linked to 2 separate transduction mechanisms, namely Ca2+ mobilization and cAMP generation. Calcium depletion of hepatocytes from adult, but not juvenile, male rats increased the alpha 1-component of the cAMP response to epinephrine, but under these conditions, alpha 1-activation of phosphorylase occurred more slowly than in calcium-replete cells. Blockade of alpha 2-adrenergic receptors did not significantly modify catecholamine effects on hepatocyte cAMP or phosphorylase a levels in male rats at any age studied, suggesting a lack of functional significance for these receptors in the regulation of glycogenolysis.     

Antenatal steroids, postnatal surfactant, and pulmonary function in premature rabbits

Antenatal corticosteroids reduce the incidence of the respiratory distress syndrome and improve pulmonary mechanics at least in part by mechanisms other than surfactant stimulation. We measured several aspects of pulmonary function in rabbits to better understand the mechanisms involved. Seven does were given intramuscular betamethasone and six were given vehicle on days 25 and 26 of gestation. Delivery was on day 27 (term = 31). Half of the fetuses from each litter were given rabbit surfactant before the first breath. All fetuses were then ventilated at a consistent tidal volume for 1 h. Pulmonary function tests included static and dynamic compliance, expiratory time constant, stress relaxation, total lung resistance, and total lung conductance. Steroid or surfactant treatment increased dynamic compliance, and the effects of both together were greater than either alone. Static compliance was affected more by surfactant than steroids, whereas lung resistance and conductance were affected more by steroids. The differences in action of the two therapies help account for the increased dynamic compliance seen with combination therapy.     

Serotonergic and noradrenergic receptors in the rat brain: modulation by chronic exposure to ovarian hormones

Noradrenergic (alpha 1 and beta) and serotonergic (5HT1 and 5HT2) receptors were assayed in the brains of ovariectomized female rats treated for 2 weeks with estrogen, progesterone or a combination of both hormones. Estrogen treatment resulted in a decrease in the number of 5HT1 and beta adrenergic receptors, with a concomitant increase in 5HT2 receptors. Progesterone alone caused a smaller increase in 5HT2 receptors, a similar decrease in 5HT1 and had no significant effect on noradrenergic receptors. When given with estrogen, progesterone blocked the estrogen effect on 5HT2 receptors but did not inhibit the estrogen-mediated decrease in 5HT1 and beta adrenergic receptors. alpha 1 adrenergic receptors were not affected by any of the hormone treatment paradigms. beta adrenergic and 5HT2 receptors are often implicated in antidepressant action, and the modulation of these two receptor types by ovarian hormones might be relevant to hormone-linked affective changes such as premenstrual tension and post-partum depression.     

The effect of alpha and beta adrenergic receptor stimulation on the adenylate cyclase activity of human adipocytes.

The effects of the mixed agonist epinephrine and the beta agonist isoproterenol, each alone and in combination with the alpha adrenergic blocker phentolamine and the beta blocker propranolol on the adenylate cyclase activity of human adipocyte membrane fragments were determined in a calcium free buffer. Neither phentolamine (10 muM) nor propranolol (32 muM) affected basal adenylate cyclase activity. Epinephrine (10 muM) stimulated adenylate cyclase activity and this effect was slightly enhanced by phentolamine. The combination of epinephrine plus propranolol depressed adenylate cyclase below the basal level. Isoproterenol (10 muM) markedly stimulated adenylate cyclase; the addition of phentolamine caused an equivocal further increase while the addition of propranolol depressed adenylate cyclase activity to, but not below, the basal level. These findings are consistent with the hypothesis that human adipocytes have both alpha and beta adrenergic receptors and that these receptors are associated with the cell membrane adenylate cyclase system.