Inhibitory Effect Of Propranolol Research Articles

The effects of propranolol on the biology and Notch signaling pathway of human umbilical vein endothelial cells.

Propranolol is the first choice for treating infantile hemangioma (IH). How propranolol works in IH remains unclear. Infantile hemangioma endothelial cells (HemECs) express Notch1, Jagged, Hey1, and other molecules in the Notch pathway, suggesting that Notch pathway-related molecules play an important role in affecting vascular endothelial cell proliferation. Whether propranolol can affect the Notch signaling pathway in IH treatment is unclear. We performed this study to observe the effect of propranolol on the expression of Notch signaling pathway molecules in human umbilical vein endothelial cells (HUVECs) and to explore the therapeutic mechanism of propranolol on IH. HUVECs cultured in vitro were exposed to 60, 120, 240, 360, or 480 µM propranolol. The morphological changes of the HUVECs were observed under an inverted microscope. HUVECs proliferation was detected with Cell Counting Kit-8 (CCK-8). The effects of propranolol on HUVECs apoptosis were detected by flow cytometry. The role of Notch in propranolol inhibition of HUVEC proliferation was analyzed with real-time polymerase chain reaction (PCR) and western blotting. Propranolol reduced HUVECs numbers and altered their morphology. The inhibitory effect of propranolol on cell proliferation was dependent on the reaction time and drug concentration. Propranolol upregulated Jagged1, Notch1, and Hey1 expression and downregulated delta-like ligand4 (DLL4) expression. Propranolol may play a role in IH treatment by increasing Jagged1 expression in endothelial cells, activating the Notch pathway and inducing the upregulation of the downstream target gene HEY1.

Effects of propranolol on in vitro cultured hemangioma endothelial cells and their mechanisms

Objective To evaluate effects of propranolol on the proliferation and apoptosis of in vitro cultured hemangioma endothelial cells (HemEC) , and to explore their molecular mechanisms. Methods Hemangioma tissues were resected from 7 children with proliferative hemangioma, and used for in vitro culture of HemEC. Meanwhile, cultured human umbilical vein endothelial cells (HUVEC) served as controls. The 2 kinds of cells were treated with propranolol at different concentrations of 0, 25, 50, 75, 100, 125 and 150 μmol/L for 24, 48 and 72 hours separately. Methyl thiazolyl tetrazolium (MTT) assay was performed to evaluate cellular proliferative activity, and flow cytometry to determine the apoptosis rate. Some cultured HemEC were divided into 2 groups to be treated with 100 μmol/L propranolol-containing culture medium (propranolol group) and culture medium alone (blank control group) , respectively, for 18 hours. Total RNA in the 2 groups was extracted separately. Differentially expressed genes in HemEC between the above 2 groups were identified by DNA microarray technology, and verified by real-time quantitative PCR. Results The treatment with 25 μmol/L propranolol for 24 and 48 hours caused a slight proliferation of HemEC (P 1.5-fold changes) were screened out by DNA microarray technology, including 128 up-regulated genes and 58 down-regulated genes. Real-time quantitative PCR showed that the mRNA expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) and fatty acid binding protein 3 (FABP3) in the propranolol group were (9.88 ± 2.19) and (21.90 ± 8.18) times that in the blank control group respectively (t = 7.028, 4.427 respectively, P < 0.05) . Conclusions Propranolol at high concentrations can inhibit the proliferation of HemEC and HUVEC, and its inhibitory effect on HemEC is stronger than that on HUVEC. The inhibitory effect of propranolol on HemEC may be related to the inhibition of HemEC proliferation and promotion of HemEC apoptosis. Key words: Hemangioma; Propranolol; Cell proliferation; Apoptosis; Gene expression profiling; Oligonucleotide array sequence analysis

Predictive validity of endpoints used in electrophysiological modelling of migraine in the trigeminovascular system

The trigeminovascular system has a pivotal role in the pathomechanism of migraine. The aim of the present study was to further develop existing models of migraine making them more suitable for testing the effects of compounds with presumed antimigraine activity in anaesthetised rats. Simultaneous recording of ongoing activity of spontaneously active neurons in the trigeminocervical complex as well as their discharges evoked by electrical stimulation of the dura mater via activation of A- and C-sensory fibres were carried out. Effects of sumatriptan, propranolol and topiramate were evaluated prior to and after application of a mixture containing inflammatory mediators on the dura. Propranolol (10mg/kg s.c) and topiramate (30mg/kg s.c.) resulted in a tendency to decrease the level of both spontaneous and evoked activity, while sumatriptan (1mg/kg s.c.) did not exhibit any effect on recorded parameters. Application of an inflammatory soup to the dura mater boosted up spontaneous activity, which could be significantly attenuated by propranolol and topiramate but not by sumatriptan. In addition, all compounds prevented the delayed increase of spontaneous firing. In contrast to the ongoing activity, evoked responses were not augmented by inflammatory mediators. Nevertheless, inhibitory effect of propranolol and topiramate was evident when considering A- or C-fibre responses. Findings do not support the view that electrically evoked responses are useful for the measurement of trigeminal sensitization. It is proposed however, that inhibition of enhanced firing (immediate and/or delayed) evoked by inflammatory mediators as an endpoint have higher predictive validity regarding the clinical effectiveness of compounds.

Inhibitory effect of propranolol on the vasoconstrictor response to sympathetic nerve stimulation.

Inhibitory effect of propranolol on the vasoconstrictor response to sympathetic nerve stimulation.

In Vitro Sensitivity of Leukemia Cells to Propranolol

BackgroundPropranolol, as a beta-adrenergic blocker is used for treatment of a large number of cardiovascular diseases such as hypertension and arrhythmias. The inhibitory effects of propranolol on tumor cells growth and also its cytotoxicity on cancerous cells have been revealed by several studies. In this study the sensitivity of a number of human leukemic cell lines to propranolol was evaluated in vitro.MethodsTwo human leukemic T cells (Molt-4 and Jurkat) and a monocyte (U937) cell line were used in this study. The cells were cultured in complete RPMI medium and then incubated with different concentrations of propranolol (0.0004 -0.4 mM) in the presence or absence of phytoheamagglutinin (20 μg/ml) for 12, 24 and 48 hours. The cytotoxic effect of the drug was then assessed by trypan blue dye exclusion and also 3-(4,5-dimethyl thiazol-2,5-diphenyltetrazoliumbromide) (MTT) reduction methods.ResultsPropranolol induced a significant dose dependent cytotoxic effect at ≥ 0.2 mM concentration on all three human cell lines (Molt-4, Jurkat and U937) used in this study, after 12 hours incubation onwards, compared to untreated control cells.ConclusionsOur results demonstrated that leukemic cell lines used in this study were sensitive to propranolol at ≥ 0.2 mM concentration of the drug. These results suggest that propranolol may have potential implication in chemoprevention of lymphoproliferative disorders along with its chronic long-term usage in cardiac problems.KeywordsPropranolol; Leukemia; Cell lines; Sensitivity

Cardiovascular effects of tyramine: Adrenergic and cholinergic interactions

The cardiovascular effects of tyramine, and its interactions with propranolol, atenolol, phentolamine, prazosin, yohimbine and atropine, have been investigated in anesthetized rats in vivo and in vitro. Tyramine (i.v.) increased both the mean arterial blood pressure and heart rate. Phentolamine, prazosin or a combination of prazosin and yohimbine caused an inhibition of the hypertensive effect of tyramine, but propranolol, atenolol and/or atropine had no effect. Propranolol added to rats receiving atropine depressed the chronotropic effect of tyramine. However, in non-atropinized animals, the positive chronotropic effect of tyramine was paradoxically enhanced by propranolol, and further enhanced by atropine. A similar result was found with atenolol pre-treated animals. Phentolamine did not alter the effects of propranolol and atropine on heart rate. Prazosin depressed the positive chronotropic effects of tyramine, and this effect was re-stored by pre-treatment of the animals with both prazosin and yohimbine. In the isolated atria, propranolol – in contrast to the in vivo results – inhibited the chronotropic effect of tyramine. Atropine potentiated the positive inotropic effect of isoproterenol and tyramine. Tyramine produced a concentration-dependent contraction of isolated thoracic aortic rings, and this was potentiated by N G-nitro- l-arginine, or by removal of the endothelium, but inhibited by phentolamine. The in vivo and in vitro effects of tyramine were not seen in rats which had been treated with reserpine. We conclude that the positive inotropic and chronotropic effects of tyramine in the rat are due to indirect release of transmitter. The results suggest that the paradoxical enhancement by propranolol and atenolol of the chronotropic effect in vivo could be due to tyramine causing increased vagal activity, such that an inhibitory effect of propranolol can only be revealed in animals treated with atropine.

Central and peripheral components of the pressor effect of anandamide in urethane‐anaesthetized rats

1. We wanted to search for the mechanism(s) responsible for the brief pressor response induced by anandamide in urethane-anaesthetized rats. 2. The anandamide-induced pressor effect was not modified by the antagonists of cannabinoid CB(1) and vanilloid TRPV(1) receptors, SR 141716A (3 micromol kg(-1)) and capsazepine (1 micromol kg(-1)), respectively, by bilateral vagotomy and by pithing. Replacement of urethane by pentobarbitone virtually abolished the pressor effect of anandamide, both in pithed and vagotomized and in 'intact' rats (i.e. not treated in this manner). 3. The pressor effect of anandamide was reduced by the nonselective TRPV family inhibitor ruthenium red (3 micromol kg(-1)) and by the blocker of L-type calcium channels nifedipine (1 micromol kg(-1)), both in pithed urethane-anaesthetized rats and in 'intact' urethane-anaesthetized rats. The nonselective beta-adrenoceptor antagonist propranolol (0.1 or 0.3 micromol kg(-1)) and the nonselective NMDA receptor antagonist MK-801 (1 micromol kg(-1)) diminished the anandamide-induced vasopressor response in 'intact' but not in pithed rats. The inhibitory effect of propranolol in 'intact' rats was mimicked by the beta(2)-adrenoceptor antagonist ICI 118551 (1 micromol kg(-1)), but not by the beta(1)-adrenoceptor antagonist CGP 20712 (1 micromol kg(-1)). 4. The present study revealed that two mechanisms may be responsible for the anandamide-induced pressor response in urethane-anaesthetized rats. The first involves the central nervous system (probably the medulla oblongata) and is sensitive to propranolol and MK-801. The second, which is located peripherally (most probably in blood vessels), is sensitive to nifedipine, ruthenium red and pentobarbitone and, hence, probably represents a Ca(2+)-dependent mode of action.

The inhibitory effect of propranolol on ATP-sensitive potassium channels in neonatal rat heart.

1. Whole cell and single channel recordings of ATP-sensitive K+ current (I(K,ATP)) were carried out in ventricular myocytes isolated from neonatal rat hearts. 2. (+/-)-Propranolol, a commonly used beta-blocker, inhibited the whole cell I(K,ATP) in a concentration-dependent manner with a half-maximal concentration (IC50) of 6.7 +/- 1.4 microM, whereas it blocked the inward rectifier K+ current (I(K,I)) only at much higher concentrations (IC50 = 102.4 +/- 20.2 microM). The inhibition was time- and voltage-independent. 3. In the outside-out patch configuration, (+/-)-propranolol inhibited I(K,ATP) (IC50 = 9.8 +/- 2.9 microM) by decreasing the open probability of the channel without inducing additional noise in the open-channel current or a decrease of single channel conductance. The single channel current of I(K,I) was also blocked by (+/-)-propranolol in the same way as I(K,ATP). 4. (+)-Propranolol, an optic isomer having no beta-blocking effect, inhibited I(K,ATP) (IC50 = 5.8 +/- 1.0 microM), whilst atenolol, a selective beta1-blocker had no effect. Neither GDPbetaS (1 mM) nor GTPgammaS (200 microM) included in the pipette solution modulated the inhibitory effect of (+/-)-propranolol. 5. We concluded that the inhibitory effect of (+/-)-propranolol was not via the beta-adrenergic signal transduction pathway, but by direct inhibition of I(K,ATP) channels.

Central propranolol and pindolol, but not atenolol nor metoprolol, inhibit sexual behavior in male rats

Are the anti-sexual effects of propranolol and pindolol due to actions within the brain? To answer this, these agents were administered directly into the brain ventricular system (ICV). Additionally, atenolol and metoprolol were evaluated to see whether differential delivery to the brain contributed to the observed lack of effect of systemically administered β 1-adrenoceptor antagonists. ICV administration of pindolol (45 or 90 μg) was followed by a suppression of copulation. At 45 μg, inhibition was limited to performance aspects of copulation, whereas at 90 μg, decrements in motivational and performance aspects of copulation were evident. ICV administration of propranolol also suppressed copulatory behavior. At 45 μg, no significant effects were observed, whereas at 90 μg decrements in motivational and performance aspects of copulation were evident. In contrast, ICV administration of the β 1-adrenoceptor antagonists, atenolol and metoprolol, was not associated with any major modifications in copulatory behavior. We suggest that the inhibitory effects of propranolol and pindolol may involve interactions with 5-HT 1A receptors in the CNS. Alternatively, it may be that the adverse effects of pindolol and propranolol are due to the simultaneous blockade of both β 1- and β 2-adrenoceptors.

The inhibitory effects of propranolol on genital reflexes in male rats

We have previously reported that propranolol adversely affects sexual behavior in male rats. To elucidate whether the effects of propranolol might involve decrements in ability, we examined two components of sexual function ex copula — ejaculatory reflex capacity and erectile reflexes. In the first study, we examined the effects of various doses of (±)-propranolol (1.25-10 mg/kg) administered subcutaneously. Marked inhibition was observed, evidenced by increases in the latency to ex copula ejaculation and to initial erection and decrements in the number of seminal emissions and in the number of erectile reflexes. Analyses of dose-response relationships indicated that the degree of inhibition increased with increasing dose. In the second study, we evaluated the stereo-selectivity of the responses. Both (+)- and (−)-propranolol (1.25 mg/kg) significantly inhibited ejaculatory reflex potential, and although (+)- and (−)-propranolol significantly inhibited erectile reflexes, (−)-propranolol had a greater effect. The data are interpreted to indicate that a) propranolol-induced sexual dysfunction involves both motivational and ability aspects; and b) propranolol-induced inhibition of genital reflexes may be due, at least in part, to mechanisms other than β-adrenoceptor blockade.

Relationship between Potassium Concentration and Inhibitory Effects of β-Adrenergic Blockers on Myocardial Na+, K+-ATPase

The inhibitory effects of Propranolol, Carazolol and metoprolol on the Mg2+-dependent ATP hydrolytic action of myocardial Na+, K+ -ATPase were tested in guinea-pig heart preparations in media containing different K+ concentrations, in order to investigate their potential relevance to the cardiac effects of these agents. All 3 drugs exhibited concentration-dependent inhibitory actions on enzyme activity at potassium ion concentrations of 2.5, 5 and 10 mmol/L; IC50 (concentrations producing 50% inhibition) values at these concentrations were 0.53 ± 0.06, 0.72 ± 0.04 and 1.90 ± 0.25 mmol/L for Carazolol, 0.79 ± 0.04, 0.86 ± 0.07 and 0.96 ± 0.09 mmol/L for metoprolol, and 0.98 ± 0.04, 1.55 ± 0.11 and 3.65 ± 0.37 mmol/L for Propranolol. Thus, reducing the K+ concentration from the physiological level of 5 mmol/L to 2.5 mmol/L produced a significant increase in the inhibitory potencies of these drugs, while increasing the K+ concentration to 10 mmol/L resulted in a decrease in inhibitory potencies. This relationship between K+ concentration and inhibitory effects of β-adrenergic receptor antagonists may have some relevance to the proarrhythmic effects of these drugs.

Differential effects of propranolol on responses to receptor-dependent and receptor-independent stimuli in human neutrophils

Recent evidence suggests that the hydrolysis of phosphatidylcholine (PC) by phospholipase D (PLD) may mediate superoxide anion (O 2 −) production in human neutrophils. To define the role of the PC-specific PLD products phosphatidic acid (PA) and diacylglycerol (DAG) in O 2 − production in response to agonists which activate the PLD pathway, we blocked the metabolism of PA to DAG with propranolol, an inhibitor of PA phosphohydrolase. Propranolol (150 μM) enhanced the production of O 2 − in response to the receptor agonists n-formyl-methionyl-leucyl-phenylalanine (FMLP, 292 ± 94% of controls), platelet-activating factor (PAF, 932 ± 215%) and leukotriene B 4 (LTB 4, 1305 ± 475%). In the presence of propranolol, total O 2 − production in response to PAF and LTB 4, which are potent priming stimuli but very weak direct agonists, was similar to that obtained with FMLP. In contrast, responses to receptor-independent agonists phorbol myristate acetate (PMA) and ionomycin were inhibited (81 ± 8% and 87 ± 5% inhibition, respectively). The effects of propranolol were demonstrable in the absence of cellular calcium and were shared by both stereoisomers of the drug. These data are consistent with the hypothesis that PA produced through the hydrolysis of PC by PLD is an important mediator of O 2 − production in response to receptor-dependent agonists. However, the inhibitory effects of propranolol on receptor-independent stimuli suggest that PA generated through the PLD pathway plays a different role in the signal transduction mechanisms of these agonists or that propranolol may have additional effects beyond inhibition of PA phosphohydrolase.

Propranolol inhibits O2-sensitive chemoreceptor activity in trout gills

The effects of propranolol on the activity of O2-sensitive chemoreceptors innervated by cranial nerve IX were studied using an isolated, perfused first gill arch preparation from rainbow trout (Onchyrhyncos mykiss). Perfusing the gill with hypoxic perfusate resulted in an increase in chemoreceptor activity. Propranolol (100-200 nmol) added to the perfusate inhibited O2-receptor discharge during both normoxia and hypoxia and attenuated the response to bolus injections of NaCN (25 micrograms). These results suggest that a beta-adrenergic mechanism is involved in O2 chemoreception. They further suggest that the inhibitory effects of propranolol on branchial, O2-sensitive chemoreceptors may contribute to the attenuated hypoxic ventilatory reflex observed in intact fish after propranolol injections.

Beta-adrenergic agonists stimulate the synthesis of noncontractile but not contractile proteins in cultured myocytes isolated from adult rat heart.

The effect of catecholamines on adult myocardial protein synthetic activity was studied by use of an experimental model of isolated adult rat cardiac myocytes maintained in culture for 1-6 days. During this period, the majority of myocytes retained their rod-shaped morphology, but the cell number decreased progressively (50% of the initial density after 2 days in culture). Between day 1 and day 3 in culture, the specific synthetic activities of total proteins and of electrophoretically purified myosin heavy chain and actin ([14C] phenylalanine incorporation into protein, in disintegrations per minute per microgram protein) decreased (-19%,-32%, and -73%, respectively). Addition of isoproterenol or norepinephrine (10 nM) from the onset of the culture for 3 days increased the specific activity of both total and noncontractile proteins (greater than 20%) but had no effect on the specific activity of myosin heavy chain and actin when compared with 3-day cultured control cells. beta-Adrenergic receptors are specifically required to mediate this increase in total protein synthesis. This finding was demonstrated by the inhibitory effects of propranolol; neither prazosin nor yohimbine showed any effect. The pattern of synthesized protein during adrenergic stimulation was qualitatively evaluated by use of [35S]methionine incorporation and gel electrophoresis. The general pattern of labeled proteins did not differ significantly from that of control cells; this occurrence suggests that isoproterenol harmoniously stimulates the synthesis of noncontractile proteins. These findings demonstrate that low doses of beta-adrenergic agonists have an anabolic effect on adult cardiac quiescent myocytes that do not affect the major contractile proteins. Regulation of myofibrillar protein synthesis may be more dependent on myocyte contractile activity.

Nonspecific effects of propranolol on the photogenic cells of Porichthys isolated photophores

1. 1. The effects of the β-adrenergic antagonist propranolol have been tested on various types of light responses (KCN-, DNP-, IAA-, and epinephrine-induced luminescences) of luminous organs isolated from the epipelagic fish, Porichthys. 2. 2. All light emissions were markedly inhibited by propranolol. 3. 3. Stereoisomeric forms of propranolol ( d- and dl-propranolol) showed similar effects on the photophores. 4. 4. It is concluded that the inhibitory effect of propranolol is not mediated through β-adrenergic receptors blockade, but rather results from nonspecific interactions of this drug at the photogenic cells level. 5. 5. Furthermore, the results suggest that β-adrenergic processes are not involved in the triggering mechanism of photocytes luminescence stimulated by epinephrine.

Dietary Fat and the β-Adrenergic-Mediated Chronotropic Response in the Rat

We have investigated the effect of dietary fat on isoproterenol-stimulated and propranolol-inhibited heart rate in the rat. In the first experiment, weanling male Sprague-Dawley rats were fed diets containing 10% butter (10B), 10% corn oil (10C) or 9% butter/1% corn oil (10M) for 4 wk. Heart rate was determined in response to increasing i.v. doses of isoproterenol. The percent stimulation at the highest dose of isoproterenol (100 microM) was found to be significantly higher (P less than 0.05) in the 10C-fed group than either the 10B- and 10M-fed groups. A similar study investigated the effect of propranolol inhibition of heart rate in low-fat (10C and 10B) as well as high-fat (25C) corn oil- and high-fat (25B) butter-fed animals. Heart rate was elevated with a constant i.v. infusion of isoproterenol and the inhibitory effect of propranolol was determined. The ED50 was found not to depend on the level of fat, but was found to be significantly lower in the corn oil-fed animals than in those red butter fat (P less than 0.05). Thus, animals appear to be more sensitive to these beta-adrenergic agonists/antagonists when fed a diet containing corn oil rather than butter fat as the lipid source.

Possible activation of intracellular ?-adrenoceptors by extraneuronally accumulated isoprenaline in perfused rat heart

Two rat hearts were perfused in series by a modified Loewi's method. The recipient heart was perfused with the perfusate collected from the donor heart. 1. After perfusion with 3H-isoprenaline in the presence of tropolone, an inhibitor of catechol-O-methyltransferase, the donor heart was washed out with amine-free medium containing tropolone and corticosterone. The heart rate of the recipient heart increased after the change to the perfusate from the donor heart during the wash-out. After wash-out the heart rate of the donor heart (which had accumulated 43.4 pmol.g-1 3H-isoprenaline) was higher than that of the recipient heart (which had accumulated 0.44 pmol.g-1 3H-isoprenaline), and the rates of efflux of 3H-isoprenaline from both hearts were similar. 2. After perfusion with 3H-isoprenaline and corticosterone in the absence of tropolone, the enhanced heart rate of the donor heart decreased during wash-out with amine-free medium in the presence of corticosterone. The heart rate of the recipient heart increased after the medium change to the perfusate from the donor heart, and the heart rates in both hearts were similar after wash-out. Only small amounts of 3H-isoprenaline remained in both hearts after wash-out, and the rates of efflux of 3H-isoprenaline from both hearts were similar. 3. After perfusion with 3H-isoprenaline in the presence of tropolone, the effects of propranolol and atenolol on the heart rate during wash-out with amine-free medium containing tropolone and corticosterone were compared. The inhibitory effect of propranolol on the heart rate was significantly greater than that of atenolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibitory effect of propranolol on accumulation of non-esterified fatty acids inthe dog myocardium during ischemia

Inhibitory effect of propranolol on accumulation of non-esterified fatty acids inthe dog myocardium during ischemia

Inhibitory Action of Propranolol on the Contractions Induced by Nerve Stimulations or Calcium in the Smooth Muscle of Rat Vas Deferens

Inhibitory effects of propranolol on the contractions to various treatments were investigated in the epididymal half of the rat vas deferens. Reportedly, 10−5~3×10−4 M propranolol inhibited 150 mM K-induced contractions dose-dependently; 3×10−4 M propranolol abolished the contractions. The present results showed that propranolol at concentrations up to 10−4 M did not inhibit the maximal contractions to 10−3 M norepinephrine (NE) or 10−2 M methacholine (MCh). Propranolol at 3×10−4 M slightly inhibited contractions to NE and MCh by 11% and 12%, respectively. In contrast, propranolol inhibited twitch components of the contractions induced by nerve stimulations at similar doses to those reported for high K contractions. Propranolol also inhibited contractions to Ca in high K-containing solution and shifted the dose-response curve to the right. Propranolol did not affect the depolarizations by high K measured by microelectrodes. Propranolol at concentrations of 10−5~3×10−5 M diminished the magnitude of spikes dose-dependently. Spikes were rarely observed in the presence of 10−4 M propranolol in spite of generation of e.j.p.s with amplitudes that would be sufficient to induce spikes in the absence of propranolol. These results suggest that propranolol inhibits contractions by decreasing Ca-influx through the potential-operated Ca-channels in the smooth muscle cells of rat vas deferens.

Dual effect of adrenaline on noradrenaline release in the pithed rabbit.

We examined the effects of adrenaline on the noradrenaline release rate and plasma catecholamine levels in the pithed rabbit with electrically stimulated sympathetic outflow (3 Hz). Adrenaline (0.06 micrograms/kg/min) increased the rate of noradrenaline release into the plasma. This increase was prevented by propranolol (0.2 mg/kg + 0.1 mg/kg/h) and probably involves activation of presynaptic beta-adrenoceptors. A higher dose of adrenaline (1.0 micrograms/kg/min) significantly reduced the noradrenaline release rate. The reduction was "reversed" to a facilitatory effect by phenoxybenzamine (4 mg/kg). Propranolol alone slightly inhibited the noradrenaline release rate. After pretreatment with desipramine (1.0 mg/kg + 0.2 mg/kg/h), the inhibitory effect of propranolol on noradrenaline release was more pronounced and blood pressure was also lowered. However, in rabbits pretreated with captopril (1 mg/kg) in addition to desipramine, the sympathoinhibitory effect of propranolol was not observed. These results suggest that adrenaline can activate either presynaptic beta-adrenoceptors to increase noradrenaline release or, in higher doses, presynaptic alpha-adrenoceptors to inhibit noradrenaline release in vivo. The decrease in the noradrenaline release rate produced by propranolol alone may not be due to blockade of facilitatory presynaptic beta-adrenoceptors, but rather to depression of renin secretion. This would decrease angiotensin II formation and hence decrease the presynaptic release-enhancing effect of angiotensin II.