Effect of beta adrenergic receptor agonists and blockaders on the action of bradykinin

A study was made of the effect of beta-adrenomimetics (isoprenaline, orciprenaline, inoline) and beta-adrenoblockers (propranolol, pindolol, oxprenolol, atenolol and practolol) on changes in the tone of smooth muscles of an isolate ileum of guinea-pigs, increase in microvascular permeability and depressor reaction in rats induced by bradykinin. beta-Adrenomimetics decreased spasmogenic and microcirculatory effects of bradykinin. Depending on the selectivity and presence of partial agonistic activity, beta-adrenoblockers exerted different influence on changes in the tone of extravasal muscles and permeability induced by bradykinin. In doses of 0.1, 0.5 and 1 mg/kg (intravenously) beta-adrenoblockers potentiated and prolonged the depressor effect of bradykinin.     

Role of transmembrane ion currents in the mechanism of action of beta-adrenoblockers

The effects of propranolol, oxprenolol, pindolol, labetalol, and atenolol on the isoproterenol-stimulated slow calcium current as well as on spontaneous slow calcium and fast sodium currents were studied in frog trabeculae by the double sucrose bridge technique. Administration of beta-adrenoblockers in low doses (10(-7)-10(-6)M) antagonized the stimulatory effect of isoproterenol on the slow calcium current (pindolol greater than oxprenolol greater than or equal to propranolol = labetalol greater than atenolol). When administered in high doses (2 X 10(-6)-10(-4)M) the beta-adrenoblockers reduced the slow calcium current. Meanwhile, some of them (propranolol, oxprenolol, labetalol) suppressed the fast sodium current.     

Atenolol,sustained-release oxprenolol,and long-acting propranolol in hypertension.

The effect of once-daily atenolol, sustained-release oxprenolol (a new formulation of oxprenolol presented as a compressed tablet in a waxed matrix), and long-acting propranolol (a new formulation presented as spheriods in a capsule) was studied in a double-blind crossover trial in 23 carefully selected hypertensive outpatients. After a run-in period with matching placebo each patient received atenolol (100 mg/day), sustained-release oxprenolol (160 mg/day), long-acting propranolol (160 mg/day), and placebo according to a randomised sequence. After four weeks'' treatment with sustained-release oxprenolol blood pressure in the two to four hours before the next dose was not significantly lower than after placebo. The effectiveness of atenolol and of the new formulation of propranolol in reducing blood pressure was confirmed. These results suggest that the present formulation of sustained-release oxprenolol should be reconsidered.     

Effect of different beta-blocking drugs and adrenaline on the conversion of thyroxine to triiodothyronine in isolated rat hepatocytes

The in vitro effect of various selective and non-selective beta-blocking drugs and adrenaline on the conversion of thyroxine (T4) to triiodothyronine (T3) was studied in suspensions of isolated rat hepatocytes after 90 min of incubation. Compared with the untreated controls propranolol caused a dose-related inhibition of the T4 to T3 conversion in conc of 100, 200 and 400 microM. The other beta-blocking drugs studied, timolol, oxprenolol, atenolol and metoprolol, were without any effect on this in vitro conversion. Propranolol did not interfere with the cellular association of T4 or the degradation of T4 and T3. Adrenaline 200 microM caused a small decrease of T3 in the medium and a corresponding increase in the intracellular content of T3. The inhibitory effect of propranolol 200 microM was not antagonized by equimolar concentrations of adrenaline. Our study suggests that the inhibitory effect of propranolol on the conversion of T4 to T3 in hepatocytes is caused by a direct chemical effect of the drug unrelated to its beta-blocking and membrane stabilizing properties.     

Prevention of isoproterenol-induced cardiac hypertrophy by beta-blocking agents in the rat.

The effect of the beta-blocking agents propranolol and oxprenolol on isoproterenol-induced cardiac hypertrophy has been investigated in the rat. To evaluate the degree of inhibition biochemical parameters related to cardiomegaly were measured. When given alone in the dose range used for protection, the beta-blocking agents did not cause any significant change in total myocardial RNA, DNA and protein. Depending on the dose applied, propranolol and oxprenolol prevented partially or totally the cardiomegaly induced by isoproterenol.     

Effect of beta-adrenoblockers on prostaglandin-induced ocular hypertension in rabbits

It has been demonstrated in experiments on unanesthetized rabbits that propranolol instilled into the eye conjunctival sac caused a decrease in normal intraocular pressure and reduced prostaglandin-induced ocular hypertension. Thymolol and atenolol decreased the normal ophthalmic tone but did no affect eye hypertension. Oxprenolol and talinolol did not affect the normal ophthalmic tone and did not remove the elevation of intraocular pressure induced by PGE2.     

Adrenoceptor mechanisms in the cardiovascular effects of cocaine in conscious squirrel monkeys.

The purpose of the current experiment was to study the role of various adrenoceptor subtypes in the cardiovascular response to cocaine in conscious squirrel monkeys. A variety of adrenoceptor antagonists were administered i.v. prior to the administration of 0.3 mg/kg cocaine (i.v.). Cocaine alone produced an increase in both blood pressure and heart rate. The non-selective alpha adrenoceptor antagonist phentolamine produced a dose-dependent antagonism of the pressor effect of cocaine, as did the alpha-1 selective antagonist prazosin. The alpha-2 selective antagonist yohimbine had no effect on the pressor effect of cocaine. The non-selective beta antagonist propranolol enhanced the pressor effect of cocaine as did the beta-1 selective antagonist atenolol. However, the effect of atenolol was not dose-dependent. The beta-2 selective antagonist ICI 118,551 and labetalol, which blocks both alpha and beta adrenoceptors, did not alter the pressor effect of cocaine. Propranolol, atenolol, and labetalol all antagonized the tachycardiac effect of cocaine in a dose-dependent manner, while the beta-2 antagonist ICI 118,551 did not. Phentolamine, prazosin and yohimbine also reduced the tachycardiac effect of cocaine, although these effects were dose-dependent only for yohimbine, which also significantly elevated baseline heart rate. These results indicate that alpha-1 adrenoceptor mechanisms mediate the pressor effect of cocaine, while beta-1 adrenoceptor mechanisms are involved in the tachycardiac effect of cocaine in squirrel monkeys. Propranolol potentiated cocaine's pressor effect through beta-2 independent mechanisms. Thus, neither alpha-2 nor beta-2 adrenoceptor mechanisms appear to be involved in cocaine's cardiovascular effects.     

The nature of differences in beta-adrenergic receptors]

Results of investigation of the affinity between teranol (practalol), alpheprol (alprenolol), propranolol to beta-adrenoreceptors of various organs confirmed the division of these receptors into two subtypes. The action of isadrin on beta1-adrenoreceptors of the myocardium and smooth muscles of the gastrointestinal tract was accompanied by changes in Ca2+ entrance into the cells. With the action of isadrin on beta2-adrenoreceptors of the trachea and the vessels there was seen an intensification of the Ca2+ ions from the cells and a reduction of the smooth muscle tone.     

Seasonal variations in the content of catecholamines in carp heart (Cyprinus carpio)

1. Seasonal changes in epinephrine and norepinephrine contents were demonstrated in ventricular muscle tissues of carp heart. 2. Patterns of changes in epinephrine and norepinephrine contents were similar; high during late spring-to-summer and low in winter; however, the fluctuation in epinephrine content was greater than that of norepinephrine. 3. Tyramine caused a positive inotropic effect in isolated electrically-stimulated ventricular muscles of carp heart. The inotropic effect was totally blocked by reserpine, reduced by propranolol, but not altered by atenolol. 4. These results suggest that the catecholamines released from sympathetic nerve terminals may contribute to the regulation of the seasonal change in the function of cardiac muscles in the carp.     

Iloprost (ZK 36374) modulates the responses to beta-adrenoceptor agonists in guinea-pig airways and pulmonary vasculature

The effect of iloprost on airway smooth muscles and its influence on the actions of beta-agonists and histamine were studied in the isolated perfused lung and isolated tracheal strips from guinea-pigs. Bolus injection of iloprost into the pulmonary artery elicited a concentration-dependent decrease in pulmonary perfusion pressure and an increase in airway resistance. These effects are not mediated through cholinergic, serotoninergic and histaminergic receptors. A rapid tachyphylaxis affected the effect of iloprost in airway resistance but not in pulmonary perfusion pressure. Iloprost did not induce a response in the isolated tracheal strips and did not alter the effect of histamine in both tracheal strips and airway resistance. This compound, however, caused an inhibition in the airway resistance-reducing effect of adrenaline and isoprenaline in the isolated perfused lung and a potentiation in the perfusion pressure-increasing effect of adrenaline. Iloprost also inhibited the relaxing effect of adrenaline and isoprenaline in the isolated tracheal strips precontracted with histamine and potentiated the inhibitory effect of propranolol against adrenaline and isoprenaline. From these results it was concluded that: Iloprost, a stable analogue of prostacyclin, modulates the beta-adrenoceptor blocking effect of propranolol in both airway smooth muscles and pulmonary vasculature.     

The action of adrenoceptor agonists and antagonists on the guinea pig and dog trachea

The action of beta- and alpha-adrenoceptor agonists (isoprenaline, orciprenaline, noradrenaline, phenylephrine and ephedrine) and antagonists (propranolol, metipranolol, exaprolol, BL 445 and phentolamine) on the resting tension and cAMP level of the guinea pig and the mechanical and electrical activities of the dog trachea were studied. By activating beta 2-adrenoceptors, isoprenaline and orciprenaline relaxed the smooth muscle, elevated the membrane potential and attenuated the excitatory effect of histamine on membrane potential and muscle tension. Noradrenaline and phenylephrine, acting on alpha 1-receptors, did not affect the membrane potential and increased the basal tension of the dog trachea only insignificantly. Ephedrine, in high concentrations, however, hyperpolarized the smooth muscle membrane and relaxed the dog trachea, while it did not alter the cAMP level in the guinea pig preparations. It is, therefore unlikely that alpha 1-adrenoceptors play a major role in the excitation of the dog trachea under resting conditions whereas the participation of alpha 2-receptors in the mechanisms of adrenergic relaxation could not be ruled out. All the beta-adrenoceptor antagonists studied enhanced the action of low isoprenaline concentrations and competitively antagonized it in high concentrations. The order of their antagonistic potency in the guinea pig trachea was as follows: metipranolol greater than propranolol = exaprolol greater than or equal to BL 445. It was suggested that metipranolol and exaprolol are nonselective beta-adrenoceptor antagonists, similarly as propranolol, whereas BL 445 shown some beta 1-selectivity. In contrast to their antagonistic effects on the membrane activities and muscle tension, both histamine and isoprenaline increased the level of cAMP in smooth muscle cells and, when present simultaneously, their effect was additive. The mechanism of histamine-induced cAMP level elevation and the possible involvement of different subcellular compartments in the action of isoprenaline and histamine in relation to the contraction-relaxation cycle is discussed.     

Functional anatomy of the vagal innervation of the cervical trachea of the dog.

The canine cervical trachea has been used for numerous studies regarding the neural control of tracheal smooth muscle. The purpose of the present study was to determine whether there is lateral dominance by either the left or right vagal innervation of the canine cervical trachea. In anesthetized dogs, pressure in the cuff of the endotracheal tube was used as an index of smooth muscle tone in the trachea. After establishment of tracheal tone, as indicated by increased cuff pressure, either the right or left vagus nerve was sectioned followed by section of the contralateral vagus. Sectioning the right vagus first resulted in total loss of tone in the cervical trachea, whereas sectioning the left vagus first produced either a partial or no decrease in tracheal tone. After bilateral section of the vagi, cuff pressure was recorded during electrical stimulation of the rostral end of the right or left vagus. At the maximum current strength used, stimulation of the left vagus produced tracheal constriction that averaged 28.5% of the response to stimulation of the right vagus (9.0 +/- 1.8 and 31.6 +/- 2.5 mmHg, respectively). In conclusion, the musculature of cervical trachea in the dog appears to be predominantly controlled by vagal efferents in the right vagus nerve.     

Raynaud's phenomenon as side effect of beta-blockers in hypertension.

A series of 102 hypertensive patients were assessed for the frequency of symptoms of Raynaud''s phenomenon and absent peripheral pulses. Out of 21 patients receiving methyldopa alone only one had cold hands and feet whereas among patients on beta-blockers the incidence was 50%. The frequency of both symptoms and absent pulses was highest in patients taking propranolol compared with those taking atenolol or oxprenolol. Patients without a foot pulse were much more likely to have cold hands. A change from propranolol to oxprenolol in some symptomatic patients resulted in improvement. In two patients the skin temperature fell after an 80-mg dose of propranolol. The mechanism by which beta-blockers induce Raynaud''s phenomenon is still not clear.     

Demonstration of beta 1-adrenoceptor mediating relaxation of porcine coronary artery by radioligand binding and pharmacological methods

beta-adrenoceptors in the porcine coronary artery were characterized by a radioligand binding assay using (-)-[3H]dihydroalprenolol (DHA) and also by measuring the relaxant response of isolated coronary artery to norepinephrine. Specific (-)-[3H]DHA binding in the porcine coronary artery was saturable, reversible and of high affinity (Kd = 1.6 nM) with a maximal number of binding sites of 63 fmol/mg protein, and it showed a pharmacological specificity as well as stereoselectivity which characterized beta-adrenoceptors. The Hofstee analysis of inhibition of (-)-[3H]DHA binding by atenolol, practolol and ICI 118551 has shown that the averaged concentration of beta 1 and beta 2-adrenoceptors in this tissue was 68% and 32% respectively. The relaxant response of isolated coronary artery to norepinephrine was competitively antagonized by (-)propranolol, (+)propranolol, atenolol, practolol and ICI 118551. The pA2 values of these adrenoceptor antagonists were significantly correlated with the Ki values for beta 1 but not beta 2-adrenoceptors determined by the (-)-[3H]DHA binding assay. Thus, the present study demonstrates that the relaxant response of porcine coronary artery to norepinephrine is predominantly mediated through the stimulation of beta 1-adrenoceptors on vascular smooth muscles.     

Exercise capacity, energy metabolism, and beta-adrenoceptor blockade. Comparison between a beta 1-selective and a non-selective beta blocker

The effects of beta 1 and beta 1/2 blockade on exercise capacity were studied in 9 healthy normotensive subjects. Progressive maximal bicycle ergometer tests, followed by an endurance test at 80% of maximal work load, were performed during randomized, double-blind 3 day treatment periods with placebo, atenolol (beta 1) and oxprenolol (beta 1/2). The reduction of maximal work capacity (ca. 10%) was similar with atenolol and oxprenolol, despite a more pronounced maximal heart rate reduction with atenolol (from 175 +/- 2 to 132 +/- 3 beats.min-1) than with oxprenolol (to 138 +/- 2 beats.min-1). Exercise time during the endurance test was reduced from 36 +/- 4 min with placebo to 27 +/- 3 min with atenolol (p less than 0.05) and 24 +/- 3 min with oxprenolol (p less than 0.01) (atenolol vs. oxprenolol: p less than 0.05). During the endurance test, plasma glycerol and non-esterified fatty acid concentrations were reduced with both atenolol and oxprenolol. The glycerol reduction was more pronounced with oxprenolol than with atenolol, plasma NEFA concentrations being similar. Plasma glucose and lactate concentrations were reduced by oxprenolol but not with atenolol. These data show that submaximal exercise capacity at work loads representing similar relative exercise intensities is reduced during non-selective and beta 1-selective beta blockade. This reduction may be related to the effects of beta 1 blockade on energy metabolism, with possibly an additional effect of beta 2 blockade.     

Propranolol has direct antithyroid activity: Inhibition of iodide transport in cultured thyroid follicles

The effect of propranolol on the process of thyroid hormone formation was studied in a physiological culture system. Porcine thyroid follicles were preincubated with propranolol for 24 h. Iodide transport, iodine organification, and de novo thyroid hormone formation were measured by incubating these follicles with the mixture of carrier-free 0·1 μCi Na ¹²⁵I and 50 nM NaI for 2 to 6 h at 37°C. A concentration of propranolol greater than 100 μM inhibited iodide transport in a dose-dependent manner; this inhibition was non-competitive with iodide and independent of thyrotropin (TSH). Reduced iodine organification and thyroid hormone formation was seen with 150 μM propranolol or greater. The inhibitory action of propranolol was not caused by beta-blocking activity, since D -propranolol (devoid of beta-blocking activity) inhibited iodide transport, and other beta-blockers (metoprolol, atenolol, and labetalol) did not inhibit iodide transport. The inhibition of iodide transport was most likely caused by membrane stabilizing activity since quinidine, which possess the same membrane stabilizing activity as propranolol, also inhibited iodide transport. TSH-mediated cAMP generation and Na ⁺K⁺ ATPase activity, membrane functions for iodide transport, were unaffected by propranolol. Our study has shown, for the first time, that propranolol has a direct antithyroid action, namely inhibition of iodide transport in the intact thyroid follicle.     

BCTC和辣椒辣素对卵清蛋白致敏大鼠气管平滑肌张力的影响

目的：评价BCTC和辣椒辣素对气道高反应性大鼠气管平滑肌张力的影响。方法：健康成年SD大鼠32只,每只大鼠第1天和第8天腹腔加皮下注射卵清蛋白致敏,第15天连续雾化吸入卵清蛋白（OVA）三天,激发建立哮喘模型。分离气管平滑肌,随机分为四组,0组（Ovalbumin）卵清蛋白组,OC组（Ovalbumin＋capsaicin）卵清蛋白＋辣椒辣素组,0B组（Ovalbumin＋BCTC）,DSMO组（DSMO＋Ovalbumin）溶剂组。分别在4组溶液的刺激下测定离体气管平滑肌张力的变化。结果：离体气管平滑肌的张力OC组较0组为高;O组气管平滑肌张力比0B组高。结论：辣椒辣素增加致敏离体气管平滑肌张力,BCTC能够降低致敏大鼠气管平滑肌张力,对致敏离体平滑肌有松弛作用。     

Effect of prednisolon on trachea smooth muscle of normal rats and rats with fibrosing alveolitis

Effect of prednisolone on isolated preparations of trachea of normal rats and rats with fibrosing alveolitis was studied. Prednisolone at a concentration of 0.4 microg/l decreased responses of smooth muscle on stimulation of preganglionar nerve fibers at trachea areas with intramural ganglia in rats with acute alveolitis by 48%, while in normal rats--by 19% of control. In trachea preparations without ganglia, prednisolone at a dose of 10 microg/l decreased responses of muscle to the nerve fiber stimulation by 21.3%. The higher prednisolone doses were less efficient: 0.1-10 microg/l glucocorticoid practically did not affect the smooth muscle responses produced by stimulation of muscle cells. In rats with fibrosing alveolitis, 10 microg/l prednisolone restored the smooth muscle responses to control values in preparations of trachea with intramural ganglia. After the prednisolone treatment, amplitude of the rat trachea muscle contraction in response to the nerve fiber electric stimulation did not differ statistically significantly from control and 0.1-10 microg/l prednisolone did not change the response value. The conclusion is made that prednisolone affected the diseased rats more efficiently than the healthy animals. The character of the glucocorticoid effect depends on the presence of intramural ganglia in the trachea wall.     

Adrenergic mechanisms in control of plasma lipid concentrations.

The mechanisms of the changes in plasma lipids concentrations observed after beta-blockade were examined in 53 patients with hypertension receiving treatment with atenolol, metoprolol, propranolol, and oxprenolol in a randomised cross-over trial. Significant increases in mean plasma total and very-low-density lipoprotein (VLDL) triglyceride and reductions in high-density lipoprotein (HDL) cholesterol and free fatty acids concentrations wer observed with all four drugs, the increase in plasma triglyceride concentration being greatest after propranolol and oxprenolol. No significant changes were observed in total of LDL cholesterol concentrations, but HDL:LDL ratios and HDL cholesterol as a proportion of total cholesterol fell significantly. Thus plasma lipid concentrations should be monitored after three to six months of long-term treatment. Changes in triglyceride, HDL cholesterol and free fatty acid concentrations were associated with a highly significant reduction in clearance of soya oil (Intralipid) in 25 patients studied but were unrelated to changes in blood pressure. The fall in HDL cholesterol and rise in free fatty acid concentrations were significantly less in those with initially reduced HDL cholesterol or raised free fatty acid concentrations respectively. It is proposed that unopposed alpha stimulation inhibits lipoprotein lipase with a subsequent rise in plasma triglyceride and fall in HDL cholesterol concentration. Analysis of the relation between pretreatment concentrations and subsequent changes suggests that excessive alpha stimulation may impair production of HDL cholesterol in those with low HDL cholesterol concentrations before treatment. Subtle catecholamine-mediated changes in plasma lipid concentrations might provide a mechanism for the relation between stress and the development of cardiovascular events.     

Release of prostaglandin-like material from isolated cat tracheal muscle by electrical and mechanical stimulation.

Release of PGE-like material has been studied on the isolated continuously-superfused cat tracheal muscle using dynamic bioassay methods. The effluent of transmural electrically-stimulated cat tracheal muscle induced a contraction when superfused over the rat stomach fundus strip. This response did not alter with atropine, methysergide, phentolamine and propranolol but was inhibited by aspirin and Sc 19220. The same myotropic activity in the effluent was found when trachea was mechanically stimulated by an additional increase in tension. The effluent from mechanically- and electrically-stimulated tracheal muscle caused a definite relaxation when superfused over a second cat tracheal muscle contracted by serotonin and pretreated with propranolol. Electrically-stimulated cat trachea itself gave a relaxant response which was blocked by propranolol but potentiated by aspirin. From these results it was concluded that both electrical and mechanical stimulation can elicit a release of PGE-like material from isolated cat tracheal muscle.