Effects of intravenous ethanol on basal bile-pancreatic secretion in nonalcoholic and alcohol-fed rats.

In nonalcoholic (NA) and alcohol-fed rats (AF), intravenous-ethanol-induced percentage changes in bile-pancreatic-secretion (BPS) were evaluated, with and without gastric juice diversion (GJD) and with and without BPS duodenal recirculation (DR). Even with GJD, ethanol elicited a slight increase in BPS. These changes were greater in AF animals even when performed without GJD. When intravenous ethanol was given under conditions of GJD and DR, there were marked differences between the NA and AF animals in the ethanol-elicited post-plateau percentage changes of BPS. NA animals evidenced no significant difference from controls. But in the AF rats, ethanol triggered a marked and significant increase of flow, protein concentration, and output that became progressively greater in successive collection periods. It is postulated that without DR, and the resulting lack of negative duodeno-pancreatic reflexes (DPR), there occurs a change in reactivity to intravenous ethanol of the hypothalamic-bulbar nuclei (HBN) and in the mechanisms that modulate the flow of cholinergic impulses through the intrapancreatic ganglia (IPG). The postulated consequence is predominance (slight in NA rats receiving intravenous ethanol, greater in AF rats) in discharge of positive impulses from HBN and flowing unimpeded through the IPG to the "pancreon" units. In the NA animal with DR, ethanol may enhance BPS values, but in the AF rats, impairment of the negative DPR elicited by chronic alcohol intoxication might, after an acute intravenous ethanol injection, favor the discharge of positive impulses from the HBN flowing unimpeded through the IPG. In the AF rats also, ethanol would activate the nonnicotinic receptors of the neurons of the "antral," "duodenal," and "celiac" autonomic brains.(ABSTRACT TRUNCATED AT 250 WORDS)

Physiological role of alpha-adrenoceptors in salivary secretion.

The submaxillary gland (SM) of rat is innervated by both branches of the autonomic nervous system. Secretion is mediated by the activation of both muscarinic-cholinergic and alpha/beta adrenergic receptors. Studies of the relative affinity of pharmacological agonists and antagonists have warranted a subclassification of alpha adrenoceptors into types alpha 1 and alpha 2. Our studies involve an analysis of the physiologic role of both types of alpha adrenoceptors in salivary secretion. Dose response curves (DRC) to noradrenaline (NA) following administration of alpha adrenoceptor antagonists, i.e. prazosin (alpha 1 antagonist), yohimbine (alpha 2 antagonist) and phentolamine (alpha 1-alpha 2 antagonist) were constructed. Our results demonstrate that prazosin is 100 times more effective than yohimbine in blocking NA-induced salivary secretion. The alpha 2 agonist clonidine (10 micrograms/Kg) blocked the DRCs to methacholine, noradrenaline and substance P-but failed to modify the DRC to isoproterenol. Our results reveal that the subtypes of alpha adrenergic receptors play antagonistic roles in salivary secretion. Alpha 1 stimulation elicits profuse salivary secretion whereas alpha 2 stimulation inhibits salivary secretion induced by 3 different types of agonists, i.e. alpha 1, muscarinic-cholinergic and neurokininergic without affecting beta receptor mediated responses.

Physiological role of alpha-adrenoceptors in salivary secretion

The submaxillary gland (SM) of rat is innervated by both branches of the autonomic nervous system. Secretion is mediated by the activation of both muscarinic-cholinergic and alpha/beta adrenergic receptors. Studies of the relative affinity of pharmacological agonists and antagonists have warranted a subclassification of alpha adrenoceptors into types alpha 1 and alpha 2. Our studies involve an analysis of the physiologic role of both types of alpha adrenoceptors in salivary secretion. Dose response curves (DRC) to noradrenaline (NA) following administration of alpha adrenoceptor antagonists, i.e. prazosin (alpha 1 antagonist), yohimbine (alpha 2 antagonist) and phentolamine (alpha 1-alpha 2 antagonist) were constructed. Our results demonstrate that prazosin is 100 times more effective than yohimbine in blocking NA-induced salivary secretion. The alpha 2 agonist clonidine (10 micrograms/Kg) blocked the DRCs to methacholine, noradrenaline and substance P-but failed to modify the DRC to isoproterenol. Our results reveal that the subtypes of alpha adrenergic receptors play antagonistic roles in salivary secretion. Alpha 1 stimulation elicits profuse salivary secretion whereas alpha 2 stimulation inhibits salivary secretion induced by 3 different types of agonists, i.e. alpha 1, muscarinic-cholinergic and neurokininergic without affecting beta receptor mediated responses.

Physiological role of alpha-adrenoceptors in salivary secretion.

The submaxillary gland (SM) of rat is innervated by both branches of the autonomic nervous system. Secretion is mediated by the activation of both muscarinic-cholinergic and alpha/beta adrenergic receptors. Studies of the relative affinity of pharmacological agonists and antagonists have warranted a subclassification of alpha adrenoceptors into types alpha 1 and alpha 2. Our studies involve an analysis of the physiologic role of both types of alpha adrenoceptors in salivary secretion. Dose response curves (DRC) to noradrenaline (NA) following administration of alpha adrenoceptor antagonists, i.e. prazosin (alpha 1 antagonist), yohimbine (alpha 2 antagonist) and phentolamine (alpha 1-alpha 2 antagonist) were constructed. Our results demonstrate that prazosin is 100 times more effective than yohimbine in blocking NA-induced salivary secretion. The alpha 2 agonist clonidine (10 micrograms/Kg) blocked the DRCs to methacholine, noradrenaline and substance P-but failed to modify the DRC to isoproterenol. Our results reveal that the subtypes of alpha adrenergic receptors play antagonistic roles in salivary secretion. Alpha 1 stimulation elicits profuse salivary secretion whereas alpha 2 stimulation inhibits salivary secretion induced by 3 different types of agonists, i.e. alpha 1, muscarinic-cholinergic and neurokininergic without affecting beta receptor mediated responses.

Potassium-evoked efflux of [3H]purines from the rat submaxillary gland.

1. Normal, atrophied and denervated submaxillary glands were incubated with [3H]adenine for 1 h. The accumulation of [3H]adenine, expressed as microCi/g tissue, did not differ significantly when the sympathetically denervated glands were compared with the control group. The radioactivity retained in both control and denervated tissues was also similar. 2. In atrophied glands 3H-accumulation as well as 3H-retention were 2-fold higher than these obtained in controls per unit weight, but 30% lower when expressed per gland. 3. The spontaneous efflux of radioactivity, expressed as fractional release, from normal, atrophied and denervated glands prelabelled with [3H]adenine was similar. 4. The outflow of radioactivity was enhanced by exposure of the tissues to 60 mM K+ during 2.5 min. 5. In all three groups, the purine release induced by K+ was the same. 6. Phentolamine 3.1 microM enhanced the K+-induced release of [3H]purine compounds in control and atrophied glands but not in denervated glands. 7. Propranolol 0.3 microM produced no changes among the three experimental groups. 8. Atropine 1 microM and phentolamine 3.1 microM plus atropine 1 microM did not modify the release of tritiated purine compounds in control and denervated glands. 9. Our results cannot discriminate between neuronal or non-neuronal elements as the source of purines released by depolarization but suggest that classical pharmacological tools such as phentolamine and atropine may affect purine metabolism in a complex fashion.

Métodos no invasivos para evaluación del bloqueo beta-adrenergico / Non invasive methods for evaluation of beta adrenergic blockade

Con el objetivo de evaluar el grado de bloqueo ß-adrenérgico en 22 pacientes con cardiopatía isquémica, se estudiaron las respuestas cardíacas cronotrópica e inotrópica por medio de 3 manibras no invasivas: respiración única profunda, postura de pie y manibra de Valsalva. Además se investigó la secreción de amilasa de la glándula parótida como respuesta a la estimulación intraoral, ya que esta actividad enzimática es ß1-mediada de la misma manera que lo son los parámetros cardíacos citados. Los resultados obtenidos se compararon con los valores de 21 sujetos sanos jóvenes y mayores de 50 años, así como con los de 11 pacientes con cardiopatía isquémica sin tratamiento. En los pacientes jóvenes tratados con betabloqueantes se encontró que la respuesta cronotrópica estaba reducida un 60% cuando se comparó con el subgrupo cano de igual edad, pero sólo un 20% con respecto a pacientes no tratados. En los pacientes mayores de 50 años tratados con betabloqueantes, la respuesta cronotrópica fue tan sólo un 20% menor que la del subgrupo control correspondiente y sin diferencias estadísticamente significativas cuando se comparó con los pacientes sin tratamiento de igual edad. La respuesta inotrópica mostró un decrecimiento mayor aún en los pacientes jóvenes betabloqueados (75%), con respecto al subgrupo control sano y 64% cuando se comparó con el subgrupo de pacientes no tratados. En los pacientes mayores de 50 años que recibían betabloqueantes se obtuvo una reducción de la respuesta inotrópica del 53% con respecto alsubgrupo control, pero la diferencia fue nula cuando se comparó con los pacientes de igual edad si tratamiento. Esta disimilitud de respuesta según edad y cardiopatía previa obtenida con las 3 maiobras, no se presentó al estudiar la amilasa parotídea con la que se obtuvo una reducción de 50%, tanto en jóvenes como en mayores de 50 años tratados con betabloqueantes, cuando se compararon con los subgrupos control o con los datos de pacientes sin tratamiento. Esto puede atribuirse a la relativa simplicidad del arco reflejo responsable de la secreción de amilasa parotídea cuando se compara con la complejidad de las respuestas integradas cardiopulmonares. Los 3 tests empleados permiten conocer aspectos del bloqueo ß-adrenérgico hasta ahora no suficientemente jerarquizados, y pueden proponerse para estudios de seguimiento longitudinal

Métodos no invasivos para evaluación del bloqueo beta-adrenergico / Non invasive methods for evaluation of beta adrenergic blockade

Con el objetivo de evaluar el grado de bloqueo ß-adrenérgico en 22 pacientes con cardiopatía isquémica, se estudiaron las respuestas cardíacas cronotrópica e inotrópica por medio de 3 manibras no invasivas: respiración única profunda, postura de pie y manibra de Valsalva. Además se investigó la secreción de amilasa de la glándula parótida como respuesta a la estimulación intraoral, ya que esta actividad enzimática es ß1-mediada de la misma manera que lo son los parámetros cardíacos citados. Los resultados obtenidos se compararon con los valores de 21 sujetos sanos jóvenes y mayores de 50 años, así como con los de 11 pacientes con cardiopatía isquémica sin tratamiento. En los pacientes jóvenes tratados con betabloqueantes se encontró que la respuesta cronotrópica estaba reducida un 60% cuando se comparó con el subgrupo cano de igual edad, pero sólo un 20% con respecto a pacientes no tratados. En los pacientes mayores de 50 años tratados con betabloqueantes, la respuesta cronotrópica fue tan sólo un 20% menor que la del subgrupo control correspondiente y sin diferencias estadísticamente significativas cuando se comparó con los pacientes sin tratamiento de igual edad. La respuesta inotrópica mostró un decrecimiento mayor aún en los pacientes jóvenes betabloqueados (75%), con respecto al subgrupo control sano y 64% cuando se comparó con el subgrupo de pacientes no tratados. En los pacientes mayores de 50 años que recibían betabloqueantes se obtuvo una reducción de la respuesta inotrópica del 53% con respecto alsubgrupo control, pero la diferencia fue nula cuando se comparó con los pacientes de igual edad si tratamiento. Esta disimilitud de respuesta según edad y cardiopatía previa obtenida con las 3 maiobras, no se presentó al estudiar la amilasa parotídea con la que se obtuvo una reducción de 50%, tanto en jóvenes como en mayores de 50 años tratados con betabloqueantes, cuando se compararon con los subgrupos control o con los datos de pacientes sin tratamiento. Esto puede atribuirse a la relativa simplicidad del arco reflejo responsable de la secreción de amilasa parotídea cuando se compara con la complejidad de las respuestas integradas cardiopulmonares. Los 3 tests empleados permiten conocer aspectos del bloqueo ß-adrenérgico hasta ahora no suficientemente jerarquizados, y pueden proponerse para estudios de seguimiento longitudinal (AU)

Interaction between amphetamine and alpha 2-postsynaptic adrenoreceptors in the rat submaxillary gland.

1 The interaction between amphetamine and the alpha 2-adrenoreceptor agonists, clonidine and guanabenz, was studied in the submaxillary gland of anaesthetised rats. 2 Low doses of clonidine (10 micrograms/kg) and guanabenz (10 micrograms/kg) inhibited the secretory responses induced by methacholine and substance P, respectively. 3 Amphetamine (300 micrograms/kg) antagonized the inhibitory effects of both alpha 2-agonists. This dose of amphetamine alone did not show sialagogic effects. 4 Atropine (1 micrograms/kg) diminished the secretory responses to methacholine as much as clonidine (10 micrograms/kg). Amphetamine did not modify the blockade by atropine. 5 Guanabenz (10 micrograms/kg) markedly decreased the secretory responses to substance P, an effect that was also prevented by amphetamine. 6 Reserpine pretreatment (5 mg/kg, i.p., 18 h) did not alter the effect of amphetamine. 7 These results indicate that the interaction between amphetamine and alpha 2-adrenoreceptor agonists is unrelated to the indirect effect of this amine and suggest a direct interaction between the drug and postsynaptic inhibitory alpha 2-adrenoreceptors.

Sympathetic and parasympathetic nerves regulate postsynaptic alpha-2 adrenoceptor in salivary glands.

The effects of sympathetic denervation or parasympathetic decentralization on the inhibitory effects of postsynaptic alpha-2 adrenoceptors were studied in the submaxillary and the sublingual gland of the rat. Chronic sympathetic denervation enhanced by a factor of 10 the potency of clonidine to inhibit the secretory responses of the submaxillary gland to either norepinephrine or methacholine. In denervated glands, clonidine (1 microgram/kg), reduced markedly the response to norepinephrine, but potentiated this response in control glands. Blockade of postsynaptic alpha-2 adrenoceptors with idazoxan (3 micrograms/kg) enhanced the secretory responses of denervated glands to norepinephrine. Parasympathetic decentralization also potentiated the inhibitory effects of the alpha-2 agonists. In the submaxillary gland the potency of guanabenz to decrease the secretory response to methacholine was increased by a factor of 30. Supersensitivity to the inhibitory effects of clonidine was also observed in parasympathetically decentralized sublingual glands. Parasympathetic decentralization increased the maximum binding site of [3H]clonidine binding by about 50% in both the submaxillary and sublingual glands. No changes in KD were detected. This surgical procedure also increased the maximum binding site of [3H]prazosin binding in submaxillary glands. The present findings show clearly that interruption of either branch of the autonomic nervous system induces supersensitivity of the inhibitory response mediated through postsynaptic alpha-2 adrenoceptors. The enhanced inhibitory activity could mask alpha-1 adrenoceptor supersensitivity after postganglionic sympathetic denervation.

Blockade of postsynaptic alpha 2-adrenoceptors enhances responses to mixed alpha 1/alpha 2-agonists in rat submaxillary gland.

The effects of selective blockade of alpha 2-adrenoceptors with idazoxan on salivary secretion elicited by several alpha-adrenoceptor agonists known to differ in their alpha 1/alpha 2 potency ratios were studied in the submaxillary gland. Doses of idazoxan ranging between 0.01 to 10 000 micrograms/kg did not produce secretion in anaesthetized rats. Idazoxan (3 micrograms/kg) effectively blocked the inhibitory action of clonidine, 10 micrograms/kg, on the responses to methacholine but did not change the sialagogic responses to either phenylephrine or isoprenaline. On the other hand, idazoxan enhanced the secretion elicited by other agonists known to have mixed alpha 1/alpha 2-agonistic properties. The degree of augmentation of the responses observed after alpha 2 blockade was: clonidine much greater than alpha-methyl-norepinephrine greater than norepinephrine. Guanabenz did not elicit secretory responses in either the presence or absence of idazoxan. These results argue that two components determine the magnitude of the sialagogic response induced by agonists with mixed alpha 1/alpha 2 activity: (a) an alpha 1-mediated secretory effect and (2) an alpha 2-mediated inhibitory effect, both being localized at postsynaptic level.

Effects of guanabenz and guanfacine on postsynaptic alpha 2-adrenoceptors in the rat submaxillary and parotid glands.

The effects of two alpha 2-agonists (guanfacine and guanabenz) on both the submaxillary and parotid gland of the rat were studied. Whereas guanfacine in doses ranging between 1,000 and 30,000 micrograms/kg i.v. produced an immediate and persistent secretion of saliva from the submaxillary gland, guanabenz in doses as high as 40,000 micrograms/kg did not induce measurable secretion either from the parotid or the submaxillary gland. Secretion elicited by guanfacine was not modified by yohimbine (300 micrograms/kg) but was abolished by prazosin (100 micrograms/kg). In both glands, low doses of either guanabenz (10 micrograms/kg) or guanfacine (100 micrograms/kg) markedly inhibited the secretory responses induced by noradrenaline, methacholine and substance P, but not that induced by isoprenaline. The inhibition caused by the alpha 2-agonists was greater for noradrenaline than for either methacholine or substance P. Blockade of alpha 2-adrenoceptors with yohimbine (300 micrograms/kg) did not modify the response to noradrenaline, methacholine or substance P in either gland. However, the same dose of yohimbine injected 5 min before the alpha 2-agonists prevented the inhibitory effects of guanfacine and guanabenz on the response induced by either one of the three sialagogic agents. Guanabenz (10 micrograms/kg) did not modify the increase in mean blood pressure observed after the different doses of noradrenaline employed to induce salivary secretion. Guanabenz (10 micrograms/kg) and guanfacine (100 micrograms/kg) did not change the time course of the secretion elicited by either noradrenaline, methacholine or substance P, since the degree of inhibition was of similar magnitude at all the periods of time analyzed.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in the vascular bed of submandibular glands after chronic autonomic denervation.

The effect of chronic sympathetic denervation (SCG) or parasympathetic decentralization (PSD) on the vascularization of the submaxillary gland (SM) of rat was studied in connection with morphological and functional changes. The resection of the superior cervical ganglion or the section of the chorda tympani was performed in adult male Wistar rats prior to the injection of Microfil MV Orange 3.25 cm3/kg. Once dissected, the glands were made transparent in increasing concentrations of methyl salicylate--alcohol. Three longitudinal sections were performed and the central one was projected in an automatic image analyzer (Kontron Zeiss), where vascular length and vascular volume were measured. Another group of animals was injected with Microfil after having received an injection of noradrenaline (10 g/kg) in SCG glands and methacholine in PSD glands. In SCG glands, vascular length underwent a 60% increase and the vascular volume increased from 0.26 +/- 0.15 cu mm/cu mm in controls to 0.54 +/- 0.15 cu mm/cu mm in SCG. The intravenous administration of noradrenaline prior to Microfil injection reverted the phenomenon. PSD caused a reduction of the vascular bed which resulted mainly in increased vascular volume. The administration of methacholine (10 g/kg) reverted the-response. It was concluded that SCG induced a loss of the existing vasoconstrictor tone, thus causing increase of vascular length and volume (passive vascular dilatation). Increased vascular volume after chronic PSD is compatible with vascular stasis and the absence of variations in vascular volume after the injection of methacholine would indicate that in the SM glands of rats there is no vascular dilatation tone.