Changes in the vascular beta-adrenoceptor-activated signalling pathway in 2Kidney-1Clip hypertensive rats.

1. beta-Adrenoceptor (beta-AR)-mediated vasodilation, which plays an important physiological role in the regulation of vascular tone, is decreased in two-kidney, one clip (2K-1C) renal hypertension. In this study, downstream pathways related to vascular beta-AR activation were evaluated in 2K-1C rats. 2. Relaxation responses to isoprenaline, forskolin and 8-Br-cAMP were diminished in aortas without endothelium from 2K-1C when compared to those in normotensive two kidney (2K). Basal adenosine-3',5'-monophosphate (cAMP), as well as isoprenaline-induced increase in cAMP levels, was not different between 2K and 2K-1C aortas. 3. Contractile responses to caffeine, after depletion and reloading of intracellular Ca(2+) stores, were greater in 2K-1C than in 2K. The presence of isoprenaline during the Ca(2+)-reloading period abolished the differences between groups by increasing caffeine contraction in 2K without changing this response in 2K-1C aortas. Inhibition of the sarcolemmal Ca(2+)ATPase with thapsigargin markedly attenuated isoprenaline vasodilation in both 2K and 2K-1C and abolished the differences between groups. 4. Blockade of ATP-sensitive K(+) channels (K(ATP)) channels with glibenclamide significantly decreased isoprenaline vasodilation in 2K-1C without affecting this response in 2K. Both vascular gene and protein expression of protein kinase A (PKA), as well as phosphoserine-containing proteins, were increased in 2K-1C vs 2K rats. 5. In conclusion, decreased isoprenaline vasodilation in 2K-1C hypertensive rats is related to impaired modulation of the sarcolemmal Ca(2+)ATPase activity. Moreover, K(ATP) channels may play a compensatory role on isoprenaline-induced relaxation in renal hypertension. Both Ca(2+)ATPase and K(ATP) channel functional alterations, associated with decreased beta-AR vasodilation, are paralleled by an upregulation of protein kinase A (PKA) and phosphoserine proteins expression.

Anterior hypothalamic beta-adrenergic activity in the maintenance of hypertension in aortic coarctated rats.

The aim of this work was to demonstrate an alteration of the anterior hypothalamic catecholaminergic system in aortic coarctated (ACo) rats by the perfusion of beta-adrenergic antagonist and the microinfusion of beta-adrenergic agonist. Wistar urethane-chloralose anesthetized rats were used. The carotid artery was cannulated for blood pressure recording and changes in blood pressure were measured. A concentric microdialysis probe was inserted in the anterior hypothalamus. Metoprolol (a beta(1)-adrenoceptor antagonist) perfusion (6 microg ml(-1)) reduced the mean arterial pressure (MAP) in the ACo rats but not in sham operated (SO) animals. The anterior hypothalamic infusion of non-specific beta-adrenergic agonist isoproterenol induced a dose-dependent decrease of blood pressure in both experimental groups, but the depressor response was significantly lower in ACo rats. The pretreatment with atenolol, a selective beta(1)-adrenoceptor antagonist, increased the depressor effect of isoproterenol in ACo rats, but not in SO rats. On the other hand, the hypotensive action of isoproterenol was significantly diminished after the administration of non-specific beta-adrenoceptor antagonist propranolol in SO and ACo rats. The anterior hypothalamic infusion of clenbuterol, a selective beta(2)-adrenergic agonist, induced a dose-dependent decrease of blood pressure in both experimental groups. The depressor response to clenbuterol (1 nmol) was significantly lower in ACo rats than in SO rats. In summary, this study provides the evidence that there is a beta(1)-adrenergic compromise in anaesthetized ACo rats and this compromise may be involved in the maintenance of hypertension. On the other hand, this study also suggests the existence of pressor beta(1)-adrenoceptors in the anterior hypothalamic area of ACo rats but not in SO rats. We also found a diminished depressor beta(2)-adrenergic activity in ACo rats.

Efecto del isofluorano sobre la respuesta inotrópica al isoproterenol en el corazón aislado de conejo / Effect of isofluorane on the inotropic response to isoproterenol in the isolated rabbit heart

Los anestésicos volátiles provocan depresión de la función sistólica, sensibilizan al miocardio frente a la acción de las catecolaminas y también pueden alterar la respuesta miocárdica a la estimulación ß-adrenérgica, aunque con discrepancias según el agente empleado. El objetivo del presente trabajo ha sido evaluar si la presencia de isofluorano modifica la respuesta inotrópica al isoproterenol. Se utilizaron 11 corazones aislados de conejo, perfundidos según la técnica modificada de Langendorff. Fueron calculadas: la presión desarrollada ventricular izquierda (PDVI) y la máxima velocidad de ascenso de la presión en función del tiempo (+ dP/dt max). Se realizaron dos grupos experimentales: Grupo 1 (G1, n=6), donde se evaluó la respuesta a isoproterenol, en dosis de 10 elevado a -8 y 10 elevado a -7 mM; Grupo 2 (G2, n=5), isofluorano 1 vol por ciento durante 10 minutos, previo a isoproterenol 10 elevado a -8 y 10 elevado a -7 mM. En el G1: la PDVI se incrementó 128.5 ñ 2.4 y 137.1 ñ 4,4 por ciento y la + dP/dt max 169.0 ñ 14.1 y 182.6 ñ 22.2 por ciento. En el G2: el isofluorano disminuyó la PDVI 5 por ciento y la +dP/dt 8 por ciento, mientras que el isoproterenol incrementó la PDVI 157.8 ñ 4.0 (P<0.05) y 169.6 ñ 6.3 por ciento (P<0.05) y la + dP/dt max 220.19 ñ 27.6 y 262.3 ñ 27.9 por ciento (p<0.05). La presencia de isofluorano modificó la respuesta inotrópica positiva al isoproterenol en un modelo experimental con estricto control de variables y similitudes con el corazón humano. (AU)

Lead (Pb2+) and cadmium (Cd2+) inhibit the dipsogenic action of central beta-adrenergic stimulation by isoproterenol.

We have previously demonstrated that acute third ventricle injections of both Pb2+ and Cd2+ impair the dipsogenic response elicited by three different situations: dehydration and central cholinergic or angiotensinergic stimulation. beta-Adrenergic activation is part of the multifactorial integrated systems operating in drinking behavior control in the central nervous system. In the present study acute third ventricle injections of Pb2+ (3, 30 and 300 pmol/rat) or Cd2+ (0.3, 3 and 30 pmol/ rat) blocked the dipsogenic response induced by third ventricle injections of isoproterenol (ISO; 160 nmol/rat) in a dose-dependent manner. Normohydrated animals receiving ISO + NaAc (sodium acetate) or saline (controls) displayed a high water intake after 120 min (ISO+saline = 5.78 +/- 0.54 ml/100 g; ISO+NaAc = 6.00 +/- 0.6 ml/100 g). After the same period, animals receiving ISO but pretreated with PbAc at the highest dose employed (300 pmol/rat) drank 0.78 +/- 0.23 ml/100 g while those receiving ISO and pretreated with the highest dose of CdCl2 (30 pmol/rat) presented a water intake of 0.7 +/- 0.30 ml/100 g. Third ventricle injections of CdCl2 (3 nmol/rat) or PbAc (3 nmol/rat) did not modify food intake in rats deprived of food for 24 h. Thus, general central nervous system depression explaining the antidipsogenic action of the metals can be safely excluded. It is concluded that both Pb2+ and Cd2+ inhibit water intake induced by central beta-adrenergic stimulation.

Effect of policosanol on isoprenaline-induced myocardial necrosis in rats.

Policosanol is a mixture of higher aliphatic primary alcohols isolated from sugar cane (Saccharum officinarum L.) and octacosanol represents its main component. This study was conducted to examine the effects of policosanol on myocardial necrosis induced by subcutaneous injection of isoprenaline in rats. A significant reduction (P < 0.01) of infarct size, polymorphonuclear cells and mast cells was observed in animals treated with policosanol at 5 or 25 mg kg-1, while animals receiving only acetysalicylic acid pretreatment showed a significant decrease in the infarct area (P < 0.05). No significant differences in polymorphonuclear and mast cells were obtained when compared with positive control data. It is concluded that policosanol delays the evolution of infarction, showing a protective effect on the myocardial necrosis induced by isoprenaline in this experimental model.

The antiadrenergic effects of hypermagnesemia: an experimental study

The circulatory effects of norepinephrine (4 * g/kg) and phenylephrine (20 */kg) were determined in anesthetized dogs withnormal plasma magnesium and with induced hypermagnesemia. Norepinephrine caused a 24% increased in heart rate by 103% increase in the systemic vascular, resistance index in normomagnesemic dogs, while with hypermagnesemia the variations were of 13% and 1%, respectively. Isoproterenol increased heart rate by 485 and 185 in dogs with normo- and hypermagnesemia, respectively.Phenylephrine increased the systemic vascular resistance index (74%) only in the normomagnesemic state.The effects of all the drugs were significantly defferent (P<0.01), without and with the simultaneous administration of magnesium sulfate (plasma magnesium, 1.3ñ0.2mEq/l and 6.8ñ1.1 mEq/l, respectively).We conclude that acute induced hypermagnesemia antagonizes the circulatory effects of adrenergic stimulation, a fact that may explain its antiarrhythmic and hemodynamic effects during acute myocardial ischemia

The antiadrenergic effects of hypermagnesemia: an experimental study.

The circulatory effects of norepinephrine (4 micrograms/kg), isoproterenol (10 micrograms/kg) and phenylephrine (20 micrograms/kg) were determined in anesthetized dogs with normal plasma magnesium and with induced hypermagnesemia. Norepinephrine caused a 24% increase in heart rate and a 103% increase in the systemic vascular resistance index in normomagnesemic dogs, while with hypermagnesemia the variations were of 13% and 1%, respectively. Isoproterenol increased heart rate by 48% and 18% in dogs with normo- and hypermagnesemia, respectively. Phenylephrine increased the systemic vascular resistance index (74%) only in the normomagnesemic state. The effects of all the drugs were significantly different (P less than 0.01), without and with the simultaneous administration of magnesium sulfate (plasma magnesium, 1.3 +/- 0.2 mEq/l and 6.8 +/- 1.1 mEq/l, respectively). We conclude that acute induced hypermagnesemia antagonizes the circulatory effects of adrenergic stimulation, a fact that may explain its antiarrhythmic and hemodynamic effects during acute myocardial ischemia.

Effects of footshock stress on the sensitivity of the isolated rat pacemaker to catecholamines.

The effect of repeated footshock on the sensitivity of the isolated rat pacemaker to the chronotropic effect of catecholamines was studied. Footshock stress caused subsensitivity to noradrenaline and supersensitivity to isoprenaline. The subsensitivity to the neurotransmitter was abolished by cocaine, whereas supersensitivity to isoprenaline was unchanged after blockade of the extraneuronal uptake. The pA2 value of metoprolol was increased by repeated footshock. Butoxamine reversed the supersensitivity to isoprenaline and the alteration of the pA2 value. Repeated footshock stress appears to cause prejunctional subsensitivity to noradrenaline and to increase the function of postjunctional beta 2-adrenoceptors.

Cambio de sensibilidad de receptores B-adrenérgicos cardiovasculares luego de la desnervación sinoaórtica en rata / Changes of sensibility of cardiovascular beta adrenergic receptors after sinoaortic denervation in rats

Mediante la desaferentación sinoaórtica (DSA) se obtiene un adecuado modelo de hipertensión neurógena en el que ocurren cambios del tono simpático que determinan una hipertensión considerada lábil. Se estudió la respuesta de los receptores beta cardiovasculares luego de la DSA por estimulación con el agonista beta adrenérgico isoproterenol en ratas despiertas. La DSA no afectó significativamente la hipotensión desarrollada por el isoproterenol a las pocas horas o a los 7 días de la operación en presencia o no de hexametonio. En cambio, el aumento de frecuencia cardíaca producido por isoproterenol a las pocas horas de la DSA es significativamente menor que en los animales sham; a la semana la respuesta es similar a la de las seudooperadas. El pretratamiento con hexametonio previene el efecto observado a las pocas horas de la operación y no modifica la respuesta cronotrópica del isoproterenol a los 7 días. Se postula que la menor respuesta al agonista beta adrenérgico en ratas con DSA en las primeras horas postoperatorias se debería a una subsensibilidad de los receptores beta adrenérgicos miocárdicos causada por el aumento del tono simático y adrenal, ya que el bloqueo del mismo con hexametonio previene el efecto. La DSA subsensibilizaría, los receptores beta adrenérgicos cardíacos, sin afectar los vasculares

Cambio de sensibilidad de receptores B-adrenérgicos cardiovasculares luego de la desnervación sinoaórtica en rata / Changes of sensibility of cardiovascular beta adrenergic receptors after sinoaortic denervation in rats

Mediante la desaferentación sinoaórtica (DSA) se obtiene un adecuado modelo de hipertensión neurógena en el que ocurren cambios del tono simpático que determinan una hipertensión considerada lábil. Se estudió la respuesta de los receptores beta cardiovasculares luego de la DSA por estimulación con el agonista beta adrenérgico isoproterenol en ratas despiertas. La DSA no afectó significativamente la hipotensión desarrollada por el isoproterenol a las pocas horas o a los 7 días de la operación en presencia o no de hexametonio. En cambio, el aumento de frecuencia cardíaca producido por isoproterenol a las pocas horas de la DSA es significativamente menor que en los animales sham; a la semana la respuesta es similar a la de las seudooperadas. El pretratamiento con hexametonio previene el efecto observado a las pocas horas de la operación y no modifica la respuesta cronotrópica del isoproterenol a los 7 días. Se postula que la menor respuesta al agonista beta adrenérgico en ratas con DSA en las primeras horas postoperatorias se debería a una subsensibilidad de los receptores beta adrenérgicos miocárdicos causada por el aumento del tono simático y adrenal, ya que el bloqueo del mismo con hexametonio previene el efecto. La DSA subsensibilizaría, los receptores beta adrenérgicos cardíacos, sin afectar los vasculares (AU)

Effect of the frequency of stimulation on the blocker action of propranolol in isolated rat left atria.

The beta-blocking activity of propranolol was studied on the positive inotropic effect of norepinephrine, epinephrine, isoproterenol, dopamine and ethylephrine, in the left atrium driven at different rates. Dose of the antagonist of 10(-8) and 10(-7) M did not block the norepinephrine dose-response curve at 1 and 2.8 Hz, but a shift to the right was observed at 1.6 Hz. Although epinephrine showed a significant increase in its pD2 (p less than 0.001) at the lower stimulation frequency, the blockade increased progressively the higher the rates. On the other hand, propranolol antagonized isoproterenol at all the frequencies tested, in spite of an increase in the maxima at 2.8 Hz. This latter behavior was also true for dopamine and ethylephrine. Both sympathomimetic amines were blocked by propranolol at 1 and 1.6 Hz. The complex effect of propranolol on Ca2+ movements and its effects on cAMP and ATPase seem to be superimposed to the beta-blocking activity. Thus, the various actions on the sympathomimetic amines change according to the agonist considered and the stimulation frequency employed.