Depletion Of Catecholamine Stores Research Articles

A role for adrenoceptors in the regulation of pleural neutrophilia induced by LPS

The role of catecholamines in regulating pleural neutrophilia evoked by intrathoracic (i.t.) injection of lipopolysaccharide (LPS) was investigated in Wistar rats by means of surgical adrenalectomy, depletion of catecholamine stores or adrenoceptor blockade. Treatment of animals with a single dose of LPS evoked a dramatic increase in the number of pleural neutrophils concomitant with an increase in the number of these cells in blood at 4 h. Although blood neutrophilia was drastically reduced when catecholamine stores were depleted with intraperitoneal (i.p.) injection of reserpine, pleural neutrophilia was not modified. However, the i.t. injection of reserpine reduced the increase in pleural neutrophils after LPS stimulation. Adrenalectomy failed to inhibit the increase in neutrophil counts in the blood or pleural cavity after LPS challenge. Pretreatment with intravenous (i.v.) injection of prazosin, an α 1/α 2B antagonist, reduced LPS-induced blood but not pleural neutrophilia. On the other hand, although pleural neutrophilia was not affected by systemic pretreatment with the α 2-adrenoceptor antagonist, yohimbine, the local treatment (i.t. injection) with this antagonist markedly reduced the increase in pleural neutrophil counts observed after stimulation by LPS. In contrast, pleural neutrophilia induced by i.t injection of formyl-methionyl-leucyl-phenylalanine (fMLP) was not modified by local treatment with yohimbine. Taken together, our results suggest that catecholamines, through activation of α 1 and α 2-adrenoceptors, play a role in the regulation of blood and pleural neutrophilia observed during the inflammatory response evoked by LPS in the pleural cavity.

In vitro effects of dantrolene on rat myocardium.

Dantrolene is the only known effective treatment for malignant hyperthermia. However, its effects on myocardial contraction and relaxation remain debatable. The effects of dantrolene (10(-5)-10(-3) M) on the contractility of rat left ventricular papillary muscles were investigated in vitro (Krebs-Henseleit solution, 29 degrees C, pH 7.40, 2.5 and 0.5 mM Ca2+, stimulation frequency 12 pulses/min). The authors studied contraction, relaxation, contraction-relaxation coupling under high and low load, energetics, and postrest potentiation. The effects of dantrolene after depletion of catecholamine stores with reserpine also were studied. Dantrolene induced a moderate concentration-dependent negative inotropic effect at a low calcium concentration (active force at 10(-4) M: 86 +/- 14% of control values, P < 0.05), but not at a high calcium concentration. Dantrolene did not significantly modify the curvature of the force-velocity relation, suggesting that it did not modify myocardial energetics. Dantrolene induced no significant lusitropic effect under low load, suggesting that it did not modify calcium uptake by the sarcoplasmic reticulum. Dantrolene did not significantly modify postrest potentiation and postrest potentiation recovery, suggesting that it did not modify maximum capacity of calcium release by the sarcoplasmic reticulum nor its postrest resetting capacity. Reserpine did not modify the myocardial effects of dantrolene. In rat myocardium, dantrolene did not modify any of the sarcoplasmic reticulum functions tested (uptake, release, postrest recovery). Dantrolene induced a moderate negative inotropic effect, probably mediated by a decrease in transarcolemmal calcium entry, and this negative inotropic effect was blunted by an increase in calcium concentration.

Cyclosporine A-induced hypertension in SHR and WKY: role of the sympatho-adrenal system.

1. Cyclosporine A induced a highly significant additional increase in blood pressure in spontaneously hypertensive rats (SHR) and elevated clearly the blood pressure in the genetically related normotensive controls, Wistar-Kyoto (WKY) rats, after both single (i.v.) and long-term administration (oral). 2. Acceleration of rise in blood pressure by cyclosporine is caused by sympatho-adrenal activation. Evidence for this mechanism of action came from the following pharmacological interventions: After chemical sympathectomy with 6-hydroxydopamine increase in blood pressure by cyclosporine was significantly reduced. Depletion of catecholamine stores by reserpine also diminished significantly the cyclosporine induced hypertension. Selective alpha1-adrenergic receptor blockade by prazosin blunted acute hypertension induced by cyclosporine. 3. Norepinephrine concentrations in the spleen of both WKY and SHR were reduced by long-term administration of cyclosporine. In the kidneys of WKY rats the level of norepinephrine was decreased but increased in the kidneys of SHR after long-term administration of cyclosporine. 4. Also the immunosuppressive agent FK506 with a macrolide-like structure induced acute hypertension in normotensive rats. The hypertensive effect was blunted by the vasoselective calcium channel blocker felodipine. 5. It is concluded that immunosuppressive agents like cyclosporine or FK506 activate the sympatho-adrenal system in normotensive and genetically hypertensive rats, thereby inducing hypertension. The mechanism of action may contribute to the hypertension seen in patients treated with cyclosporine after transplantation of heart, kidney or liver.

Involvement of D1 dopamine receptors in the nicotine-induced noradrenaline release from hypothalamic and preoptic noradrenaline nerve terminal systems

Nicotine (4 x 2 mg/kg, i.p.) was given every 30 min for 2 h to male rats. Some rats were pretreated with the D1 dopamine (DA) receptor antagonist SCH 23390 (1 mg/kg, i.p.) or with the D2 DA receptor antagonist raclopride (1 mg/kg, i.p.), 5 min before nicotine treatment. Hypothalamic and preoptic catecholamine levels were measured by quantitative histofluorimetry in discrete DA and noradrenaline nerve terminal systems. Nicotine treatment produced a depletion of catecholamine stores in noradrenaline and DA nerve terminals of the hypothalamus, the preoptic area and the median eminence, an action which was counteracted by SCH 23390 but not by raclopride. The results indicate that hypothalamic D1 DA receptors may regulate the sensitivity of the nicotinic cholinoceptors and increase their ability to release hypothalamic noradrenaline. A possible role of D1 DA receptor antagonists to reduce the ability of nicotine treatment to produce rapid increases in LH, prolactin and corticosterone secretion and tonic arousal is implicated.

The prenatal development of the organ of Zuckerkandl in rats

The effect of maternal glucocorticoid depletion upon the fetal development of the organ of Zuckerkandl (OZ) in rats was determined. Maternal hypophysectomy at 13d8h gestation resulted in a fifty percent decrease in plasma corticosterone levels at 18d8h when compared to both sham operated and unoperated controls. No differences in the volume of the OZ among the three groups of animals were found. The chromaffinity of the OZ was decreased in the hypophysectomized and sham operated groups suggesting a stress-induced depletion of catecholamine stores. The data suggests that the OZ participates in fetal sympathoadrenal activity and that its development is independent of maternal corticosterone titers.

Methyl O-(4-hydroxy-3-methoxycinnamoyl)reserpate〔CD-3400〕の末梢作用について ―特に平滑筋臓器に対する作用―

Effects of methyl O-(4-hydroxy-3-methoxycinnamoyl) reserpate (CD-3400), a new antihypertensive agent, on the peripheral nervous system in mice, rats and guinea pigs were investigated and compared with effects of reserpine and rescinnamine. Oral administration of CD-3400 in doses from 40 to 320 mg/kg revealed a miotic action and such was weaker than that seen with reserpine and rescinnamine. The intestinal propulsion in mice was accelerated by pretreatment with reserpine, but no so with CD-3400. In isolated guinea pig vas deferens, CD-3400 at a concentration of 1 X 10(-5) M inhibited on norepinephrine-induced contraction non-competitively. However, in insolated rat vas deferens pretreated with CD-3400 (1 mg/kg, i.p.) for 5 days, norepinephrine-induced contraction was potentiated and this effect was weaker than that seen with reserpine and rescinnamine. In isolated rat vas deferens pretreated with CD-3400 for 1, 2 and 5 days,, the contraction induced by tyramine (3 X 10(-5)M) was significantly inhibited. The effect was qualitively similar to those of reserpine and rescinnamine. The intravenous administration of these three rauwolfia alkaloids in doses of 1, 2 and 4 mg/kg had no effect on the spontaneous movement of rat uterus. In isolated rat uterus pretreated with CD-3400, no significant effect was observed on oxytocin- and isoproterenol-induced responses. The peripheral actions of CD-3400 are attributed to a deterioration in the function the sympathetic nerve resulting in depletion of catecholamine stores. Efect of CD-3400 were slightly weaker than those of reserpine and rescinnamine.

Livedo Reticularis during Amantadine Treatment

Livedo reticularis is a common side effect of treatment with amantadine for Parkinson's disease. Investigation of 40 such patients suggests that the livedo is a physiological response provoked by depletion of catecholamine stores in peripheral nerve terminals.

Action of fenfluramine on monoamine stores of rat tissues.

1. Fenfluramine is an anorexogenic agent used clinically because it is devoid of central stimulatory effects.2. In rats, fenfluramine causes a depletion of 5-hydroxytryptamine (5-HT) from the telencephalon + diencephalon which lasts longer than one might have expected from the biological half life of fenfluramine. The depleting effects of fenfluramine do not extend to brainstem, stomach and heart stores of 5-HT.3. Fenfluramine causes an increase in the turnover rate of tel-diencephalic 5-HT but such an acceleration could not be detected in the 5-HT stores of the brainstem.4. It is inferred that the effects of fenfluramine on brain 5-hydroxytryptamine may be related to the accumulation of a fenfluramine metabolite in 5-HT neurones.5. High doses of fenfluramine cause a depletion of catecholamine stores in brain and heart but the time course of this depletion is shorter than the depletion of brain 5-HT.

The pharmacological basis of coronary and systemic vasodilator actions of diazepam (Valium).

1. The effects of alpha and beta-adrenoceptor blockade, depletion of catecholamine stores, vagotomy, atropine, and ganglionic blockade on diazepam-induced vasodilatation were investigated in forty-six anaesthetized dogs.2. Coronary blood flow was measured by timed collections of coronary venous efflux from fibrillating, decompressed ventricles; coronary and systemic vascular resistances were determined during total cardiopulmonary bypass under conditions of normothermia and constant aortic (coronary artery) pressure.3. No significant alteration in the vasodilatation produced by diazepam was observed following either vagotomy or alpha-adrenoceptor blockade; partial inhibition of vasodilatation occurred after beta-adrenoceptor blockade or catecholamine depletion, and nearly total inhibition was observed after small doses of atropine or ganglion-blocking agents.4. The results suggest that diazepam may act as a specific ganglion-stimulant, causing active sympathetic and cholinergic vasodilatation.

Contracture and catecholamines in mammalian myocardium.

Contractures induced by KCl are produced in cat ventricular muscle after depletion of catecholamine stores by previous treatment with reserpine or by selective blocking of adrenergic receptor sites with propranalol. Contractures are reproducible for 2 to 3 hours and are markedly depressed by the addition of epinephrine. The relaxation of contracture induced by epinephrine parallels the eftect of this compound of shortening the duration of the normal twitch. The failure of the normal mammalian myocardium to maintain tension in solutions of high KCI concentration appears to be related to the endogenous amounts of catecholamines in the tissue.

Work capacity and efficiency of the autotransplanted heart.

Total extrinsic denervation of the heart was accomplished in six animals by cardiac autotransplantation. The work capacity and efficiency were studied in the postoperative period, when there was depletion of catecholamine stores. The left ventricular oxygen consumption (VO 2 ) of these six cardiac autotransplants (average body weight, 13.6±0.6 kg) and six normal dogs (average body weight, 14.0±0.4 kg) were compared with a right-heart bypass at similar heart rates, mean arterial blood pressures, and systemic flows. The two groups of animals achieved comparable levels of stroke work (17.3 g-m) over the same range of filling pressures. Average maximum rates of left ventricular pressure development were also similar (autotransplants 2455±278 mm Hg/sec, versus 2267±209 mm Hg/sec for normal dogs). At VO 2 /100 g left ventricle, autotransplants averaged 9.54±0.97 cc/min and normal dogs 9.62±0.76 cc/min. However, left ventricular weights in the autotransplant group were significantly greater (110.9±6.2 g) than in the normal dogs (96.7±3.4 g), and represented a significantly greater percentage of body weight (8.2±0.5% versus sus 6.6±0.3%). Total left ventricular VO 2 was greater in autotransplants during performance of comparable levels of external work and at comparable degrees of contractility. No systematic difference in handling of glucose, lactate, or pyruvate was noted between the groups. Respiratory quotients were 1.0 or greater. The normal dogs showed no net change in circulating catecholamines across the coronary bed, whereas autotransplants always showed a net uptake of catecholamines. Myocardial mitochondria were enlarged in electron micrographs of the ventricular myocardium of the autotransplants. The totally extrinsically denervated cardiac autotransplant can achieve a level of performance similar to that of a normal heart, but is less efficient in doing so. Alterations in utilization of circulating catecholamines may aid the hemodynamic adaptation to the cardiac denervation.