Neurogenic histaminergic vasodilation in canine skeletal muscle: mediation by alpha 2-adrenoceptor stimulation.

This study examines the neurogenic effect of alpha 2-adrenoceptor stimulation on skeletal muscle vascular resistance and its relation to the level of background sympathetic activity. The isolated, separately perfused, neurally intact canine gracilis muscle preparation was used since it permits deliberate and quantifiable alterations in background sympathetic activity, as measured by skeletal muscle vascular resistance. Systemic intravenous UK-14304, a highly selective alpha 2-adrenoceptor agonist, produced a precipitous, neurogenic vasodilation that lowered vascular resistance below the subsequently denervated resistance, thus indicating that an active vasodilation was involved. The overall magnitude of the vasodilation was much greater in animals that had been hemorrhaged to elevate background sympathetic activity than in animals that had been transfused to lower background activity. The neurogenic vasodilation was unaffected by baroreceptor and cardiopulmonary receptor denervation and by prior cholinergic-receptor blockade of the gracilis muscle. Prior H1- and H2-histaminergic-receptor blockade, on the other hand, eliminated the active vasodilation but not a vasodilation down to the subsequently denervated resistance. Prior alpha 1-adrenoceptor blockade lowered resistance down to the subsequently denervated resistance and greatly attenuated the active vasodilation. The present study demonstrates that withdrawal of sympathetic activity by alpha 2-adrenoceptor stimulation produces an active vasodilation resulting from histamine release in skeletal muscle as well as a passive vasodilation resulting from lysis of peripheral vasoconstrictor tone.

Characterization of adrenergic control of the Leydig cell steroidogenesis: identification of both stimulatory and inhibitory components

Percoll-purified Leydig cells were studied in vitro in order to evaluate the effect of adrenaline on testosterone (T) secretion. Adrenaline enhanced the basal and potentiated the hCG-induced T release. A similar effect was also obtained with the ß2-agonist, salbutamol. Although phenyleprine, an alfa1-agonist, did not alter the basal T secretion, it enhanced hCG-mediated T secretion. Para-aminoclonidine, an alfa2-agonist, decreased the basal T release without altering the HCG-stimulated T release. These data demonstrate that either inhibitory or stimulatory effects on T release can be obtained and that they depend on the adrenoreceptor subtype involved

Ativaçäo e bloqueio da lipólise in vitro no tecido adiposo de pombos / Activation and blockade of lipolysis \"in vitro\" on pigeon adipose tissue

Säo estudadas in vitro as açöes de diferentes concentraçöes de adrenalina, noradrenalina ou teofilina sobre a lipólise no tecido adiposo de pombos. Relata-se, ainda, a açäo do propranolol e da fentolamina sobre aquelas respostas lipolíticas. Os resultados mostram que doses elevadas de adrenalina ou noradrenalina ocaciosam declínio da lipólise no tecido adiposo de pombos, e que säo necessárias altas concentraçöes de teofilina para que a resposta lipolítica a esta droga se manifeste. Verificou-se que níveis elevados daqueles bloqueadores adrenérgicos, inibem a resposta lipolítica do tecido adiposo daquela ave, possivelmente também em algum passo posterior à formaçäo do AMP cíclico

Physiological and pharmacological aspects of adrenergic receptor classification.

The questions raised are: what is the physiological or pharmacological basis for the differentiation into beta 1- and beta 2-, and alpha 1- and alpha 2-adrenergic receptors?; and do the neurotransmitter norepinephrine and the hormone epinephrine differ in their receptors? On the basis of a preference of beta 2- and alpha 2-adrenergic receptors for epinephrine, the hormone, and of beta 1-and alpha 1-receptors for norepinephrine, the neurotransmitter, it was postulated that the alpha 2- and beta 2-receptors are predominantly epinephrinergic in nature and located extrajunctionally and presynaptically whereas the alpha 1- and beta 1-receptors are predominantly norepinephrinergic in nature and located postsynaptically in the sympathetic terminal junction. The alpha 2- and beta 2-character of the presynaptic receptors matches that of the corresponding extrajunctional receptors. This indicates that a circulating catecholamine, namely epinephrine, is involved in the regulation of adrenergic transmitter release.

Effects of beta-adrenoceptor agonists and antagonists on thyroid hormone secretion.

The effects of various beta-adrenoceptor agents on radioiodine release from the thyroid were studied in mice pretreated with 125I and thyroxine. The non-selective beta-adrenoceptor agonist isopropylnoradrenaline and the selective beta 2-adrenoceptor agonist terbutaline both, and with the same efficacy, enhanced radioiodine release, whereas the selective beta 1-adrenoceptor agonist prenalterol had no such effect. The non-selective beta-adrenoceptor antagonist L-propranolol and the selective beta 2-adrenoceptor antagonist ICI 118,551 both abolished the radioiodine release induced by isopropylnoradrenaline or by terbutaline. The selective beta 1-adrenoceptor antagonist metoprolol inhibited the radioiodine response to isopropylnoradrenaline, but not that to terbutaline. Neither of the beta-adrenoceptor antagonists influenced the radioiodine release induced by TSH. It is concluded that the beta-adrenoceptors involved in the regulation of thyroid hormone secretion are mainly of the beta 2-subtype, and, further, that beta-adrenoceptor agonists and TSH exert their thyroid hormone secretory effects through different mechanisms.

Modulation by beta-adrenoreceptors of spontaneous contractions of rat urinary bladder.

1 Propranolol (0.1 mg/kg i.v.) but not metoprolol (0.2 mg/kg i.v.) pretreatment increased the spontaneous motility triggered by progressive filling of rat urinary bladder without a concomitant effect on bladder capacity, except at high filling volumes. Compared to controls, the spontaneous motility of urinary bladder in propranolol pretreated rats displayed a higher frequency, indicating the existence of a tonic sympathetic inhibition. 2 beta-adrenoreceptor stimulation by isoprenaline (0.1-10 microgram/kg i.v.) or terbutaline (0.1-1 mg/kg i.v.) in vivo produced a dose dependent inhibition of bladder spontaneous motility which was antagonized by propranolol (0.1 mg/kg i.v.) but not by metoprolol (0.2 mg/kg i.v.). Propranolol (0.2 mg/kg i.v.) pretreatment did not antagonize the inhibition of bladder motility produced by intravenous papaverine (0.5 mg/kg). 3 Propranolol (0.1 mg/kg i.v.) significantly antagonized the isoprenaline-induced tachycardia (beta 1 mediated) and fall in diastolic blood pressure (beta 2 mediated) while metoprolol (0.2 mg/kg i.v.) antagonism was confined to beta 1 mediated responses. 4 Isoprenaline (0.25-1.5 microM) inhibited in a concentration dependent manner field stimulation induced contractions of rat detrusor muscle strips as did tetrodotoxin (0.5 microM). Hexamethonium (50 microM) had no inhibitory effect. 5 Our in vivo findings support the view that beta 2-adrenoreceptors are responsible for modulating bladder motility mainly by suppressing the onset of spontaneous contractions.

Positive chronotropic responses produced by alpha-adrenoreceptors in the pithed rat.

1 Phenylephrine (1-100 microgram/kg, intravenously) produced dose-dependent increases in heart rate and blood pressure in the pithed rat. 2 The positive chronotropic response to phenylephrine (10 microgram/kg) was reduced in a dose-dependent manner by propranolol (0.01-0.3 mg/kg), but higher doses of propranolol (up to 3 mg/kg) did not reduce the response by more than about 50%. The residual response was virtually abolished by phentolamine (0.3 mg/kg) or prazosin (3 microgram/kg). Labetalol (3 mg/kg) which has both alpha- and beta-blocking activity, also abolished the positive chronotropic response. 3 The pressor response to phenylephrine (1-30 microgram/kg) was enhanced by propranolol (1 mg/kg) and abolished by phentolamine (1 mg/kg) and prazosin (30 microgram/kg). Labetalol (3 mg/kg) reduced the response to phenylephrine by 73%. 4 Propranolol (0.3 mg/kg) completely blocked the chronotropic and vasodepressor effects of isoprenaline (0.1 microgram/kg). 5 It is concluded that phenylephrine acts on both alpha 1- and beta 1-adrenoreceptors to produce an increase in heart rate, on alpha 1-adrenoreceptors to produce vasoconstriction and on beta 2-adrenoreceptors to produce vasodilation. This latter effect is usually masked by the predominant vasoconstrictor action.

Quantitative pharmacological characterization of beta-receptors and two types of alpha-receptors mediating sympathomimetic smooth muscle response in the human Fallopian tube at various cyclic stages.

The dissociation constants for adrenoceptor-antagonist complexes (KB) were determined in vitro in circular and longitudinal smooth musculature from the ampullary and isthmic regions of the human Fallopian tube. High extracellular potassium concentrations were used to eliminate the spontaneous contractile activity. Neuronal and extraneuronal amine uptake mechanisms were blocked. The parallel shift of the log dose-response curves was secured in Arunlakshana-Schild plots. KB for the beta-receptor, mediating sympathomimetic relaxation, were determined during alpha-receptor blockade: the values for propranolol were the same (approximately 10(-6) M) in all preparations and at all cyclic stages, as determined from plasma estradiol and progesterone levels. KB for the complex between the alpha-receptor (mediating contraction) and phentolamine were determined during beta-receptor blockade. The values were the same in all types of smooth musculature, but varied with cyclic stage: they were around 7 x 10(-8) M when plasma estradiol and progesterone were both minimum, and around 2 x 10(-7) M when these steroid levels were moderate to high, suggesting that the properties of the contractile receptors of the human Fallopian tube are modified during the menstrual cycle.

Possible mechanism of stimulation of gastrin secretion by exogenous serotonin in rats.

The effect of 6-hydroxydopamine, propranolol, phentolamine, alpha-methyl-tyrosine and alpha-methyl-tyrosine plus propranolol on serotonin-stimulated gastrin secretion in rats has been examined. Gastrin secretion in response to administration of serotonin alone (10 mg/kg i.p.) was significantly reduced in rats pretreated with 6-hydroxydopamine or with propranolol. These results suggest that the effect of exogenous serotonin on gastrin secretion can be described as sympathomimetic and indirect. The serotonin-stimulated gastrin secretion was significantly enhanced by previous administration of phentolamine. Pretreatment with alpha-methyl-tyrosine also elevated serotonin-stimulated gastrin secretion, indicating that in the presence of diminished concentrations of the catecholamines, the influence of exogenous serotonin on secretion by G cells is increased. This enhancement in the serum gastrin levels was also reduced to a significant extent by simultaneous administration of propranolol, which suggested the activation of G-cell beta-adrenergic receptors after serotonin administration.

Alpha-adrenergic vasoconstriction in arterial and arteriolar sections of the canine coronary circulation.

Using a method which allowed the in-situ measurement of segmental coronary vascular resistances, the reaction of arterial and arteriolar sections of the coronary vascular system to alpha-receptor stimulation was studied i anaesthetized dogs. The left coronary artery was cannulated, and the perfusion pressure was kept constant. Allowance was made for extravascular and metabolic influences of alpha-stimulation on coronary vascular resistances. On an average, submaximal alpha-stimulation with xylometazoline increased the arterial resistance by about 60% and the arteriolar resistance by about 90%. The cannulation of the left coronary artery increased the sympathetic reactivity of the arterioles. Moreover, xylometazoline increased the extravascular component of the coronary vascular resistance by about 4%. Thus it can be assumed that under normal in-vivo conditions alpha-receptor vasoconstriction might be less different in coronary arteries and arterioles. Since the arterial resistance ranges from 20% to 50% of total coronary resistance, a sympathetic vasoconstriction of this vascular section might lead even to a critical limitation of coronary blood flow. On the other hand, a predominant constriction in arterioles leads to an increase in peripheral coronary pressure, i.e. to a "reverse coronary steal phenomenon".

Alpha-adrenoceptor-mediated modulation of 5-hydroxytryptamine release from rat brain cortex slices.

Slices of rat brain cortex preincubated with 3H-5-hydroxytryptamine were superfused with physiological salt solution and stimulated electrically, or they were superfused with Ca2+-free solution containing 25 mM K+ and stimulated by introduction of 1.3 mM CaCl2 for 2 min. 1. The electrically evoked 3H overflow was decreased by noradrenaline and increased by phentolamine in a concentration-dependent manner. 2. Phentolamine caused a parallel shift to the right of the concentration-response curve of noradrenaline for its inhibitory effect on impulse-evoked 3H overflow; by contrast, it left the inhibitory effect of unlabelled 5-hydroxytryptamine on the electrically evoked 3H overflow unaffected. 3. Propranolol did not alter the inhibitory effect of noradrenaline on impulse-induced 3H overflow. 4. The increasing effect of phentolamine on the electrically evoked 3H overflow was not modified by paroxetine. 5. Cocaine (at a concentration which almost completely blocks the uptake of 3H-noradrenaline but only partially that of 3H-5-hydroxytryptamine into cortex slices) decreased impulse-evoked 3H overflow. This effect was abolished by phentolamine. 6. In the presence of tetrodotoxin throughout superfusion, the Ca2+-evoked 3H-overflow from slices superfused with Ca2+-free solution was inhibited by noradrenaline and increased by phentolamine. These findings suggest that the terminal serotoninergic fibers of rat brain cortex possess alpha-adrenoceptors, activation of which by exogenous or endogenous noradrenaline leads to inhibition of the release of 5-hydroxytryptamine.

In vitro characterization of adrenergic receptors mediating extrusion of preformed sebum from preputial gland of rat.

Extrusion of preformed sebum from the preputial glands of rat after phenylephrine and adrenaline treatment, and its inhibition by alpha-receptor blocking agents under in vitro conditions, shows that secretory response of the glands is influenced by alpha-adrenergic receptors, and isoproterenol--a beta-agonist--is not effective in elicitation of exudation of secretion from the preputial gland.

Structure activity relationships between catecholamines and the alpha-adrenergic receptor responsible for the aggregation of human platelets by epinephrine.

PEA is a potent inhibitor (Ki approximately 13 microM) of human platelet aggregation induced by epinephrine. This led us to perform an SAR study of a congeneric series of compounds in an effort to identify the molecular components of epinephrine critical to its aggregating effect upon human platelets. Phenylethanolamine was similar to PEA in inhibitory potency. However, hydroxylation of the phenyl ring diminished the inhibitory effect (Ki tyramine approximately 87 microM; Ki octopamine approximately 88 microM). Dopamine, the weakest inhibitor (Ki approximately 150 microM), was a partial agonist capable of inducing platelet aggregation in some samples of PRP. The order of potency of catecholamines as aggregating agents was epinephrine greater than norepinephrine greater than Epinine greater than dopamine. Phenylephrine, the prototype alpha-agonist, did not induce aggregation but was a potent inhibitor (Ki approximately 12 microM) of the aggregation induced by epinephrine. Isoproterenol, the prototype beta-agonist, was neither an aggregant nor an inhibitor of epinephrine-induced platelet aggregation. These findings suggest that the binding of epinephrine to the alpha-adrenergic receptor responsible for platelet aggregation is accomplished by the N-methyl amino group whereas intrinsic aggregating activity is a function of the catechol moiety.

[The role of beta and alpha adrenergic receptors in the lipolytic effect of catecholamines on dog adipocytes (author's transl)]. / Intervention de récepteurs adrénergiques alpha et bêta dans l'effet des catécholamines sur la lipolyse d'adipocytes de chien.

Pharmacological properties of adrenergic receptors have been investigated in fat cells isolated from omental adipose tissue of the Dog. From the results, the following points can be stated. 1. Lipolysis is markedly enhanced by isoproterenol. This effect is competitively inhibited by propranolol (a beta-adrenoceptor blocking agent). (Fig 1). 2. The beta 2-sympathomimetic salbutamol is found to have only a slight effect on lipolysis rate (Fig. 2). 3. The epinephrine-induced lipolysis is potentiated by phentolamine (an alpha-adrenoceptor blocking agent) only on large sized adipose cells (mean fat cell size 96.7 +/- 5.3 micrometer; Fig. 5). 4. The isoproterenol-induced lipolysis is partially inhibited by phenylephrine (an alpha-adrenomimetic drug) (Table I). These findings show that beta 1 nature of the receptors involved in the adrenergic control of lipolysis in Dog adipose tissue. Moreover an antilipolytic effect of epinephrine, via alpha-adrenergic receptors, is observed, especially in large adipose cells.

The effect of practolol and butoxamine on aortic arch malformation in beta adrenoreceptor stimulated chick embryos.

An equimolar dose of the beta-1 adrenoreceptor antagonist practolol administered to embryonic chicks prevents the induction of aortic arch malformations by isoproterenol. Whereas 3.75 X 10(-9) mole isoproterenol in 5 microliter saline solution induced aortic arch anomalies in 39% of embryos injected at Hamburger-Hamilton developmental stage 26, pretreatment with practolol one to two minutes before catecholamine administration reduced the anomaly rate to to 4%. Practolol when injected alone did not influence survival rate nor did it cause cardiovascular malformations. Probably the most significant result of this study involves the prevention by practolol of aortic hypoplasia and interrupted aortic arch complexes, anomalies frequently induced by isoproterenol when administered at this stage of embryonic chick development. Butoxamine, a beta-2 adrenoreceptor antagonist, did not block the overall effect of isoproterenol nearly as effectively as did practolol. Results from the present study suggest that aortic arch anomalies may be induced in embryonic chicks via beta-1 adrenoreceptor stimulation. Beta-2 receptor stimulation does not appear to be as significantly involved.