Effect of ATP on radiation damage to DNA caused by prolonged irradiation

The influence of bradykinin and kallikrein on the action of norepinephrine, epinephrine, isoprenaline, phentolamine, propranolol, aminophylline and theophylline on blood pressure was studied. The kinins potentiated the hypertensive action of norepinephrine and epinephrine, weakened the hypotensive action of isoprenaline, potentiated the hypotensive action of propranolol, and had no effect on the action of phentolamine, aminophylline and theophylline.     

The influence of kinins on the action of circulatory drugs. II. The influence of bradylinin on the action of selected drugs on the isolated rat heart

The influence of bradykinin and bradykinin in conjunction with norepinephrine, epinephrine, isoprenaline, phentolamine and propranolol on the work of the isolated rat heart was studied. Amplitude of cardiac contractions, their frequency, and coronary flow were recorded. The kinin had no influence on the work of the isolated rat heart, inhibited the stimulating action of norepinephrine, epinephrine and isoprenaline on the heart muscle, and had no effect on the action of phentolamine and propranolol.     

Effects of dopamine on L-type Ca2+ current in single atrial and ventricular myocytes of the rat

1. The effects of dopamine on the L-type Ca2+ current (ICa,L) of both atrial and ventricular single myocytes and on the force of contraction of atrial trabeculae in rat heart were investigated. 2. Dopamine increased atrial ICa,L at concentrations higher than 1 microM, but had little or no effect on ICa,L at lower concentrations. The increase in ICa,L at high concentrations was reversed by propranolol and acetylcholine, but not by phentolamine. Activation and inactivation kinetics of ICa,L were not altered by dopamine. 3. In rat ventricular myocytes in which the D4 receptor mRNA does not express, dopamine (20-100 microM) also increased the ICa,L amplitude and propranolol reversed this effect. 4. Clozapine, a potent D4 receptor antagonist, blocked the augmenting effect of dopamine on ICa,L. However, this effect could be explained by beta-antagonism, since clozapine also inhibited the isoprenaline effect. 5. In the atrial trabeculae, the increase in contraction by dopamine (1 to 30 microM) was reversed by 1 microM propranolol, but not by 2 microM phentolamine. Low doses of dopamine (0.01 to 0.3 microM) did not affect the contraction in the controls or during a modest stimulation of the beta-adrenoceptor with 0.01 microM isoprenaline. 6. These results indicate that the positive inotropic action of dopamine is mediated through direct stimulation of the beta-adrenoceptor in both atrial and ventricular myocytes. Involvement of D4 receptor appears unlikely in the regulation of the atrial contraction.     

Effect of fibrinogen degradation products on the rat blood vessels

Effect of fibrinogen degradation products on the rat blood vessels. Acta Physiol. Pol. 1977, 28 (2): 153--159. It was found that fibrinogen degradation products (FDP) exert a slight hypotensive effect and increase the flow of Tyrode's solution through isolated hindpaw of rat. The investigated peptides failed to change significantly the action of noradrenaline and had an additive effect with isoprenaline. Propranolol reduced the effects of FDP and isoprenaline. It is suggested that the described effects may be due to stimulation of the vascular beta-adrenergic receptors by FDP.     

Influences of beta-blocking agents on cardiovascular actions induced by endothelin-3 administered intracerebroventricularly in anesthetized rats

Possible involvement that the pressor and positive chronotropic effects of endothelin-3 (ET-3) administered intracerebroventricularly (i.c.v.) participate in the central beta-adrenoceptor has been studied in urethane anesthetized rats. ET-3 administered i.c.v. at dose of 50 pmol elicited the increase in blood pressure and heart rate over a long duration, but a dose of 30 pmol had a minimal effect. These cardiovascular responses to ET-3 were significantly reduced by intravenous pretreatment with pentolinium, ganglionic blocking agent, and phentolamine, alpha-blocker. Also pressor responses to ET-3 were abolished dose-dependently by i.c.v. pretreatment with propranolol at a dose of 1 mumol, nonselective beta-blocker and ICI 118551, beta 2-selective adrenoceptor blocker, but not by i.c.v. pretreatment with metoprolol, atenolol, beta 1-selective blocker, procaine and phentolamine. These results suggest that ET-3 may play a role in cardiovascular regulation through the activation of the sympathetic nervous system involved in the central beta 2-adrenoceptor system.     

Profile of the DNA recognition site of the archaeal homing endonuclease I-DmoI

1. Long-term treatment with beta 2-adrenoceptor agonists can lead to a decreased therapeutic efficacy of bronchodilatation in patients with obstructive pulmonary disease. In order to examine whether or not this is due to beta-adrenoceptor desensitization, human bronchial muscle relaxation was studied in isolated bronchial rings after pretreatment with beta 2-adrenoceptor agonists. Additionally, the influence of pretreatment with dexamethasone on desensitization was studied. 2. The effect of beta 2-agonist incubation alone and after coincubation with dexamethasone on density and affinity of beta-adrenoceptors was investigated by radioligand binding experiments. 3. In human isolated bronchi, isoprenaline induces a time- and concentration-dependent beta-adrenoceptor desensitization as judged from maximal reduction in potency by a factor of 7 and reduction of 73 +/- 4% in efficacy of isoprenaline to relax human bronchial smooth muscle. 4. After an incubation period of 60 min with 100 mumol l-1 terbutaline, a significant decline in its relaxing efficacy (81 +/- 8%) and potency (by a factor 5.5) occurred. 5. Incubation with 30 mumol l-1 isoprenaline for 60 min did not impair the maximal effect of a subsequent aminophylline response but led to an increase in potency (factor 4.4). 6. Coincubation of dexamethasone with isoprenaline (120 min; 30 mumol l-1) preserved the effect of isoprenaline on relaxation (129 +/- 15%). 7. In radioligand binding experiments, pretreatment of lung tissue for 60 min with isoprenaline (30 mumol l-1) resulted in a decrease in beta-adrenoceptor binding sites (Bmax) to 64 +/- 1.6% (P < 0.05), while the antagonist affinity (KD) for [3H]-CGP-12177 remained unchanged. 8. In contrast, radioligand binding studies on lung tissue pretreated with either dexamethasone (30 mumol l-1) or isoprenaline (30 mumol l-1) plus dexamethasone (30 mumol l-1) for 120 min did not lead to a significant change of Bmax (160 +/- 22.1% vs 142.3 +/- 28.7%) or KD (5.0 nmol l-1 vs 3.5 nmol l-1) compared to the controls. 9. In conclusion, pretreatment of human bronchi with beta-adrenoceptor agonists leads to functional desensitization and, in lung tissue, to down-regulation of beta-adrenoceptors. This effect can be counteracted by additional administration of dexamethasone. Our model of desensitization has proved useful for the identification of mechanisms of beta-adrenoceptor desensitization and could be relevant for the evaluation of therapeutic strategies to counteract undesirable effects of long-term beta-adrenoceptor stimulation.     

Opposite modulation of noradrenaline and ATP release in guinea-pig vas deferens through prejunctional beta-adrenoceptors: evidence for the beta 2 subtype

Activation of prejunctional beta-adrenoceptors has been suggested to increase the release of noradrenaline but to decrease the neural release of ATP in the guinea-pig vas deferens. Experiments were carried out to determine the subtype of beta-adrenoceptor involved. In [3H]-noradrenaline-preincubated tissues superfused with medium containing prazosin and suramin, isoprenaline (1-100 nM), salbutamol (0.01-1 microM) and terbutaline (0.1-10 microM) increased the overflow of tritium but reduced the overflow of ATP elicited by electrical stimulation (210 pulses/7 Hz). The effects of isoprenaline were blocked by the beta 2-selective antagonist 1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3- [(1-methylethyl)amino]-2-butanol (ICI 118,551; 100 nM). In prazosin- and suramin-free medium, isoprenaline (100 nM) did not change the overflow of ATP elicited by exogenous noradrenaline (10 microM). Isoprenaline (1-100 nM), salbutamol (0.01-1 microM) and terbutaline (0.1-10 microM) reduced the initial twitch contraction elicited by electrical stimulation (210 pulses/7 Hz) in prazosin- and suramin-free medium as well as the isolated purinergic neurogenic contraction obtained by exposure to prazosin. They increased or tended to increase the secondary sustained concentration elicited by electrical stimulation in prazosin- and suramin-free medium as well as the isolated adrenergic neurogenic contraction obtained in the presence of suramin. The inhibition by isoprenaline of the isolated purinergic contraction was attenuated by ICI 118,551 (100 nM) but not by the beta 1-selective antagonist 1-[2-((3-carbamoyl- 4-hydroxy)phenoxy)ethylamino]-3-[4-(1-methyl-4- trifluoromethyl-2-imidazolyl)phenoxy]-2-propanol (CGP 20712A; 100 nM). The results confirm the opposite beta-adrenoceptor-mediated modulation of noradrenaline and neural ATP release in the guinea-pig vas deferens. They show that the prejunctional beta-adrenoceptor is of the beta 2-subtype.     

Increased interleukin-8 release by beta-adrenoceptor activation in human transformed bronchial epithelial cells

1. The effect of beta-adrenoceptor activation on release of the neutrophil chemoattractant, interleukin-8 (IL-8), was examined in human transformed bronchial epithelial cells (16HBE cells). 2. The combined beta 1- and beta 2-adrenoceptor agonist, isoprenaline, time- (100 nM, 2-18 h) and concentration- (1-30 nM) dependently increased IL-8 protein content in the cell culture supernatant as measured by an enzyme immunosorbent assay standardized for DNA by fluoro-colorimetry. 3. Isoprenaline (1-100 nM, 15 min) increased cyclic AMP concentration-dependently. 4. The effect of isoprenaline (100 nM) was inhibited by the beta-adrenoceptor blocker propranolol (10 microM). The maximum magnitude of IL-8 increase caused by beta-adrenoceptor activation was 40% of that caused by the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha 100 ng ml-1). 5. The selective beta 2-adrenoceptor agonist salbutamol (1 microM), increased IL-8 protein similarly to isoprenaline and the cyclic AMP analogue, dibutyryl cyclic AMP (1 mM) produced a corresponding effect. 6. Pretreatment with isoprenaline (100 nM) followed by TNF-alpha (20 ng ml-1) increased IL-8 additively. 7. In conclusion, beta-adrenoceptor stimulation increased the release of the neutrophil chemoattractant, IL-8 in 16HBE cells, via an increase in intracellular cyclic AMP. beta-adrenoceptor stimulation adds to the IL-8 increase caused by the pro-inflammatory cytokine TNF-alpha. If this mechanism exists in vivo, beta-adrenoceptor activation may increase neutrophil chemotaxis into the airways.     

Evidence that phentolamine is not an inhibitor of extraneuronal uptake

1. Tracheal segments from guinea-pigs pretreated with 6-hydroxydopamine were incubated in isoprenaline at 37 degrees C for 5 min in the absence or presence of phentolamine. Catechol-O-methyl transferase was inhibited by 100 mumol l-1 U-0521. Tissues were prepared for fluorescence histochemistry and accumulated isoprenaline in trachealis smooth muscle cells (fluorescence) was measured by microphotometry. 2. Phentolamine, in concentrations up to 100 mumol l-1, had no effect on isoprenaline fluorescence. 3. It is concluded that phentolamine does not inhibit extraneuronal uptake in concentrations used to block alpha-adrenoceptors in isolated tissue experiments. Thus, is can be present in experiments designed to examine the effects of extraneuronal uptake inhibitor drugs on beta-adrenoceptor-mediated responses.     

Prejunctionally mediated inhibition of neurotransmission by isoprenaline in rat vas deferens

Effects of isoprenaline on monophasic contractions evoked by electric field stimulation were studied in rat isolated prostatic vas deferens. Isoprenaline reduced electrically evoked contractions (EC50: 0.27 +/- 0.05 microM), and propranolol concentration-dependently antagonized the effect of isoprenaline. In contrast, isoprenaline (0.3-3 microM) did not affect the contractile response induced by exogenous noradrenaline or ATP, while forskolin (100 nM) attenuated agonist-induced contraction. In some tissues, adrenergic and purinergic components of the electrically evoked contraction were isolated by exposure to alpha,beta-methylene ATP (3 microM) and prazosin (3 microM), respectively. Isoprenaline induced a greater inhibition of purinergic than adrenergic component of the electrically evoked contraction. Iberiotoxin (50 nM), glibenclamide (3 microM), 4-aminopyridine (0.3 mM) and tetraethylammonium ions (1 mM) attenuated the effect of isoprenaline. These results indicate that isoprenaline-induced inhibition of the electrically evoked (both purinergic and adrenergic) contraction was mediated primarily through activation of prejunctional beta-adrenoceptors, which probably inhibited release of contractile transmitters from sympathetic nerves supplying vas deferens. Lack of effect of isoprenaline on agonist-induced contraction does not favour a functional role of beta-adrenoceptors in vas smooth muscle.     

Drug effects on intraocular pressure and vascular flow in the bovine perfused eye using radiolabelled microspheres

A novel technique is described in which the effect of the beta-adrenoceptor antagonists timolol and carteolol, and the vasodilators sodium nitroprusside (SNP) and verapamil on intraocular pressure (IOP) and the distribution of ocular flow in the bovine arterially perfused eye is investigated using radiolabelled microspheres. At maximum IOP-reducing dose timolol was found to significantly reduce perfusion in the choroid and, at higher dose, it was found to significantly reduce perfusion in the iris. By contrast, a maximal IOP-reducing dose of carteolol markedly reduced perfusion in the iris, ciliary body and choroid. Vasoconstriction induced by carteolol was not inhibited by the alpha-antagonist phentolamine. Against a background of vascular tone induced by noradrenaline, SNP and verapamil were found to significantly increase perfusion in the iris, ciliary body and choroid. The effects of these drugs upon the vasculature of the bovine perfused eye are varied and complex and may not bear a direct relationship to their ocular hypotensive effect.     

Alpha 2-adrenergic receptors regulate generation of cyclic AMP in the pineal gland, but not in cerebral cortex of chick

A beta-adrenoceptor agonist isoprenaline potently stimulated cyclic AMP formation in chick cerebral cortical slices. L-Noradrenaline (10-1000 microM) also increased cortical nucleotide synthesis, the effect being antagonized by beta-adrenoceptor blocker propranolol, and not affected by alpha 1- and alpha 2-adrenoceptor blockers, prazosin and yohimbine, respectively. Clonidine, a selective alpha 2-agonist, had no effect on cerebral cyclic AMP production stimulated by both isoprenaline and forskolin. However, clonidine (0.001-10 microM) concentration-dependently suppressed forskolin-driven cyclic AMP synthesis in intact chick pineal glands. In living chicks clonidine suppressed the nocturnal activity of cyclic AMP-dependent serotonin N-acetyltransferase, a rate-limiting enzyme in melatonin biosynthesis, the effect being prevented by yohimbine. The data suggest that the cyclic AMP generating system of the pineal gland, but not that of cerebral cortex in chick, is negatively regulated by alpha 2-adrenergic receptor-mediated signal.     

Use of D-myo inositol 1,2,6 trisphosphate to inhibit contractile activity in rat ventricular cardiomyocytes induced by neuropeptide Y and other cardioactive peptides through phospholipase C

1. D-Myo inositol 1,2,6 trisphosphate (alpha-trinositol, pp56), an isomer of the second messenger substance, inositol 1,4,5 trisphosphate, has an interesting pharmacological profile that includes antagonism of a number of neuropeptide Y (NPY)-mediated cellular processes. The ability of pp56 to inhibit selectively the myocardial contraction mediated by NPY in relation to the responses to other cardioactive peptides, including endothelin-1, calcitonin gene-related peptide (CGRP), secretin and vasoactive intestinal peptide (VIP), was assessed. In order to investigate the possible interaction of pp56 with mechanisms of inositol phosphate signalling generated in heart muscle cells by activation of the beta-isoenzyme of phospholipase C (PLC beta), noradrenaline was used as a positive control, and isoprenaline and forskolin were included as negative controls. 2. Ventricular cardiomyocytes, isolated from the hearts of adult rats, were stimulated to contract at 0.5 Hz in the presence of calcium ion (2 mM). The concentrations of agonists used were in the region of their maximally effective concentrations for myocyte contraction and the concentration of pp56 was in the range of 1-100 microM. Contractile activity was monitored by video microscopy and maximum shortening determined by image analysis. 3. In the absence of agonist, contractile amplitudes following 20 min preincubation with pp56 were not different from that observed in the absence of pp56. Pp56 (1-100 microM) inhibited significantly the positive contractile response to noradrenaline (5 microM) in the presence of propranolol (500 nM), such that the response was almost completely attenuated at the highest concentration of the inhibitor. Pp56 did not inhibit the positive contractile responses to forskolin (40 microM) or isoprenaline (100 nM). 4. NPY alone does not influence the basal level of contraction of cardiomyocytes, but can attenuate isoprenaline-stimulated contraction and can increase contractile amplitude from basal when the transient outward current is blocked with 4-aminopyridine. In the presence of isoprenaline (100 nM), the negative response to NPY (100 nM) was attenuated significantly by pp56 (1-100 microM). With 4-aminopyridine, the positive contractile response to NPY (200 nM) was decreased by pp56, although this was not statistically significant. 5. Pp56 inhibited the positive contractile responses to CGRP (1 nM) and endothelin-1 (20 nM) completely, but did not affect the responses to secretin (20 nM) or VIP (20 nM). 6. In conclusion, these data challenge the previously obtained selectivity of pp56 as an antagonist of NPY-mediated cellular processes, since responses to CGRP and endothelin-1 were at least equally sensitive. Furthermore, as pp56 discriminated clearly in its inhibition of responses to alpha-adrenoceptor by comparison with beta-adrenoceptor/adenylate cyclase stimulation, it appears that pp56 may be a useful pharmacological agent with which to distinguish between PLC beta-dependent and PLC beta-independent coupling mechanisms. On this basis, further evidence has been obtained that, in rat cardiomyocytes, the contractile responses to NPY, CGRP and endothelin-1 are attributable to the activation of PLC beta-dependent pathways, whereas the responses to secretin and VIP are mediated by PLC beta-independent pathways.     

Tramadol induces antidepressant-type effects in mice

Tramadol is a clinically-effective, centrally-acting analgesic. This drug is a racemic mixture of two enantiomers, each one displaying different mechanisms: (+)tramadol displays opioid agonist properties and inhibits serotonin reuptake while (-)tramadol inhibit preferentially noradrenaline reuptake. The action of tramadol on the monoaminergic reuptake is similar to that of antidepressant drugs. Therefore, we have examined the effects of (+/-)tramadol, (+)tramadol and (-)tramadol in a test predictive of antidepressant activity, the forced swimming test in mice. Both (+/-)tramadol and its (-) enantiomer displayed a dose-dependent reduction on immobility; while the effect induced by the (+) enantiomer was not significant. Inhibition of noradrenaline synthesis, but not of serotonin synthesis, was capable of blocking the effect of (+/-)tramadol. The alpha-adrenoceptor antagonist phentolamine, as well as the alpha2-adrenergic antagonist yohimbine, and the beta-adrenoceptor blocker propranolol countered the immobility-reducing action of (+/-)tramadol. Moreover, neither the serotoninergic blocker methysergide nor the opioid antagonist naloxone antagonized the effect of (+/-)tramadol. Our results show that (+/-)tramadol and (-)tramadol have antidepressant-like effect in mice, probably mediated by the noradrenergic system rather than the serotoninergic or opioidergic ones.     

Vanidilol: a vanilloid-type vasorelaxant and ocular hypotensive beta-adrenoceptor blocker with partial beta-2-agonist activity

Vanidilol, [4'-(2-hydroxy-3-(tert-butylamino)propoxy)-3'-methoxyphenyl] -benzaldehyde, newly synthesized from vanillin, is a vanilloid-type beta-adrenoceptor blocker. The beta-adrenoceptor-blocking properties of vanidilol were studied both in vivo and in vitro. Intravenous injection of vanidilol (1.0, 3.0, 5.0 mg/kg) in anesthetized Wistar rats produced a decrease in blood pressure and a dose-dependent bradycardia response. Vanidilol inhibited the tachycardia effects induced by (-)isoproterenol, but had no blocking effect on the arterial pressor responses induced by phenylephrine. In isolated guinea-pig tissues, vanidilol attenuated the (-)isoproterenol-induced positive chronotropic and inotropic effects of the atria and trachea relaxation responses in a concentration-dependent manner. The parallel shift to the right of the concentration-response curve of (-)isoproterenol suggested that the agent was a beta-adrenoceptor competitive antagonist. The apparent pA2 values for vanidilol on the right atria, left atria and trachea were 7.67 +/- 0.03, 7.89 +/- 1.02 and 7.66 +/- 0.15, respectively, denoting that vanidilol was a nonselective beta-blocker. The intrinsic sympathomimetic activity of vanidilol and propranolol was determined on isolated atria and trachea from reserpinized guinea pigs. Propranolol caused significantly negative inotropic and chronotropic effects at 10(-6) mol/l or above, whereas vanidilol possessed less cardiodepressant activities than propranolol. In reserpinized tracheal strips, vanidilol produced dose-dependent relaxant responses, but propranolol was ineffective. Preincubating the preparations with ICI 118,551 (0.1-10 nmol/l), a beta 2-adrenoceptor antagonist, significantly shifted the concentration-relaxation curves of vanidilol to a region of higher concentrations. In isolated guinea-pig thoracic aorta, vanidilol (0.1-10 mumol/l) inhibited the phenylephrine (10(-5) mol/l)-induced tonic contraction in vascular smooth muscle which was related to the block of calcium influx. In 20% saline-perfused rabbits, vanidilol showed a marked delay in intraocular pressure recovery, demonstrating an ocular hypotensive action. Binding characteristics of vanidilol and propranolol were evaluated in [3H]dihydroalprenolol binding to porcine ventricular membranes. Vanidilol was less potent than propranolol in competing for the beta-adrenoceptor-binding sites. On the other hand, vanidilol had a high hydrophilicity in comparison with propranolol. In conclusion, vanidilol exhibited nonselective beta-adrenoceptor blocking, vasorelaxant and ocular hypotensive activities, but was devoid of alpha-adrenoceptor blocking and beta 1-agonist activity. Partial beta 2-adrenoceptor agonist activity and inhibitory activity on calcium influx may share in the vasorelaxant activity.     

Mechanism of the interaction of propranolol and a potent vasodilator antihypertensive agent - minoxidil

A study, using non-invasive techniques, was carried out in ten patients with essential hypertension to examine the mechanism of the hypotensive effect of propranolol when used in combination with a potent vasodilator antihypertensive - minoxidil. The hypotensive effect of minoxidil, a mean (+/- SEM) decrease of 42.4 +/- 4.3 mm Hg, was accompanied by a marked increase in heart rate, cardiac index and plasma renin activity and a significant decrease in total peripheral resistance, limb vascular resistance and pre-ejection period. Addition of propranolol further reduced mean arterial pressure by an average of 12.9 +/- 2.0 mm Hg. Propranolol returned cardiac index to control values and total peripheral resistance index rose but not to control levels. Plasma renin activity was significantly reduced by propranolol. By multiple regression analysis no correlation was found between propranolol-induced decrease in mean arterial pressure and changes in cardiac index, total peripheral resistance index or plasma renin activity. Quantitatively, the reduction in cardiac index observed probably accounted for the hypotensive effect of propranolol. The role of plasma renin activity reduction in the hypotensive effect of propranolol in this situation remains to be clarified. The findings in the present study were consonant with the known actions of vasodilator antihypertensive agents and propranolol and indicate the applicability of non-invasive methodology to the investigation of cardiovascular drugs in man.     

Effect of adrenergic blocing agents on peripheral noradrenaline induced thermoregulatory responses in the pigeon at heat

1. The hyperthermic effect of intramuscular NA at 32 degrees C was abolished by propranolol but not by phentolamine preinjection. 2. The lack of hyperthermic response was at least partly due to the blocking effect of propranolol on beta-receptor mediated in heart rate. 3. After NA the respiratory rate was gradually increased in birds preinjected either with propranolol or with phentolamine.     

A modified bromosulfalein assay for the quantitative estimation of protein

In the driven isolated left atrium of the rabbit theophylline shortened relaxation time in a similar manner to isoprenaline and histamine. 2 Phenylephrine lengthened relaxation time in a similar manner to calcium. 3 Theophylline caused phenylephrine to shorten relaxation time, which was inhibited by a beta-adrenoceptor blocking drug, but theophylline did not potentiate the effect of phenylephrine on peak tension. 4 Theophylline separated drug effects on cardiac relaxation and contraction: in the presence of theophylline at a low calcium concentration, phenylephrine shortened relaxation time by beta-adrenoceptor stimulation and increased peak tension by alpha-adrenoceptor stimulation. At a high calcium concentration, theophylline potentiated the effect of isoprenaline, histamine and phenylephrine on relaxation time but inhibited the effect on peak tension.     

Chronic administration of oxprenolol and metoprolol attenuate sympathetic cardiovascular responses only in non-adrenalectomized pithed rats

1. Oxprenolol and metoprolol (30 mg kg-1) were injected intraperitoneally (i.p.) for 1 day (acute treatment) and 6 weeks (chronic treatment) to Sprague-Dawley rats. 2. Increases of mean blood pressure and heart rate to noradrenaline (0.1-10 micrograms kg-1) and to electrical stimulation (0.5 msec, supramax V, 0.25-5 Hz) of the entire sympathetic outflow were measured in non-adrenalectomized (acute and chronic) and adrenalectomized (chronic) pithed rats. 3. Acute beta-adrenoceptor antagonist administration was without effect on mean blood pressure and heart rate increases to noradrenaline and electrical stimulation. 4. Chronic administration with oxprenolol significantly diminished the stimulation-induced increases of mean blood pressure and heart rate in non-adrenalectomized pithed rats. 5. Increases in heart rate, elicited by stimulation of the entire sympathetic outflow in non-adrenalectomized but not in adrenalectomized pithed rats, were decreased by metoprolol treatment. Both treatments were without effect on noradrenaline responses. 6. These results indicate that chronic beta-adrenoceptor antagonist treatment is associated with a reduction in the cardiovascular responses to sympathetic nerve-stimulation. However, this mechanism only operates when adrenomedullary adrenaline is present to facilitate the noradrenaline release through activation of presynaptic beta 2-adrenoceptors.     

Beta-adrenoceptor mediated facilitation of noradrenaline and adenosine 5'-triphosphate release from sympathetic nerves supplying the rat tail artery

1. The effects of prejunctional beta-adrenoceptor activation on electrically evoked noradrenaline (NA) and adenosine 5'-triphosphate (ATP) were studied by use of continuous amperometry and conventional intracellular recording techniques. Excitatory junction potentials (e.j.ps) were used as a measure of ATP release, and NA-induced slow depolarizations and oxidation currents as measures of NA release, from postganglionic sympathetic nerves innervating the rat tail artery in vitro. 2. Isoprenaline (0.1 microM) increased the amplitude of e.j.ps, slow depolarizations and oxidation currents evoked by short trains of stimuli at 1 to 4 Hz. The facilitatory effect of isoprenaline on e.j.ps and oxidation currents was most pronounced on responses evoked by the first stimulus in a train. 3. Isoprenaline (0.1 microM) did not detectably alter the amplitude-frequency distribution of spontaneous e.j.ps. 4. The facilitatory effect of isoprenaline on e.j.ps, slow depolarizations and oxidation currents was abolished by the beta-adrenoceptor antagonist, propranolol (0.1 microM). Propranolol alone had no effect on e.j.ps, slow depolarizations or oxidation currents. 5. Thus, activation of prejunctional beta-adrenoceptors increases the release of both NA and ATP from postganglionic sympathetic nerves. The findings are consistent with the hypothesis that NA and ATP are released from the same population of nerve terminals and presumably from the same vesicles.