Relative inotropic and chronotropic activity of beta-adrenoceptor stimulants in anaesthetised, areflexic dogs

The use of different methods of measuring contractility and the effects of cardiovascular reflexes are among the factors which complicate the assessment of selective inotropic activity of beta-adrenoceptor agonists. The effects of dobutamine, prenalterol, noradrenaline and isoprenaline on heart rate, iliac blood flow, left ventricular pressure, max dP/dt and (dP/dt) divided by IIT (integrated isometric tension) were evaluated in anaesthetised dogs in which the hearts were denervated and blood pressure held constant. All the drugs caused dose-dependent increases in heart rate and contractility. The relative chronotropic and inotropic activity of each agonist was evaluated. At most doses studied the agonists exerted similar chronotropic and inotropic activity when compared to the non-selective agonist isoprenaline. It is likely that the inotropic selectivity observed with prenalterol and dobutamine in previous studies depends on factors other than direct drug action.     

Desensitization of beta2-adrenoceptor-mediated responses by short-acting beta2-adrenoceptor agonists in human lung mast cells

1 The principal aim of the present study was to determine whether long-term treatment of human lung mast cells (HLMC) with the clinically-relevant beta(2)-adrenoceptor agonists, salbutamol and terbutaline, leads to desensitization of beta(2)-adrenoceptor-mediated responses in these cells. 2 The non-selective beta-adrenoceptor agonist, isoprenaline, and the selective beta(2)-adrenoceptor agonists, salbutamol and terbutaline, inhibited the IgE-mediated release of histamine from HLMC. Salbutamol (pD(2); 7.7+/-0.3) and terbutaline (pD(2); 7.3+/-0.2) were roughly equipotent as inhibitors of histamine release although both agonists were less potent than isoprenaline (pD(2); 8.6+/-0.2). 3 Isoprenaline (10(-5) M), salbutamol (10(-5) M) and terbutaline (10(-5) M) enhanced total cell cAMP levels in HLMC over basal by 361+/-90, 150+/-38 and 165+/-35%, respectively. 4 Long-term exposure (24 h) of HLMC to either salbutamol (10(-7) M) or terbutaline (10(-7) M) led to a subsequent reduction in the effectiveness of salbutamol and terbutaline (both 10(-9)-10(-4) M) to inhibit histamine release. However, salbutamol was significantly (P<0.05) more effective than terbutaline at promoting the functional desensitization. 5 Radioligand binding studies, using iodinated cyanopindolol, were performed to determine beta(2)-adrenoceptor density in cell membranes after pretreatment (24 h) of cells with either salbutamol (10(-6) M) or terbutaline (10(-6) M). Both agonists reduced beta(2)-adrenoceptor density in membranes to about the same extent (approximately 25% reduction) but these changes in receptor density were not statistically significant (P>0.05). 6 These data indicate that long-term exposure of mast cells to salbutamol causes greater levels of desensitization to beta(2)-adrenoceptor-mediated responses in HLMC than terbutaline. These findings may have wider clinical significance in the context of asthma treatment as compromised mast cell inhibition could result following long-term exposure of mast cells to short-acting bronchodilators.     

4种β2肾上腺素受体激动药对大鼠体外心脏功能影响比较

目的评价β2肾上腺素受体激动药对大鼠体外心脏功能的影响。方法以Langendorff灌流,通过Medlab记录系统观察硫酸沙丁胺醇、左旋沙丁胺醇、硫酸特布他林和富马酸福莫特罗对大鼠体外心脏左心室收缩压、左心室内压上升/下降最大速率、心率和心律的影响。结果选择性β2肾上腺素受体激动药显著增加心脏左心室收缩压、左心室内压上升/下降最大速率和心率,均高于对照值,差异有统计学意义（P＜0.05）,并引起室性期前收缩及心动过速,随浓度增加效应增强;左旋沙丁胺醇和富马酸福莫特罗引起的效应均比硫酸沙丁胺醇小,差异有统计学意义（P＜0.05）;选择性β2肾上腺素受体阻断药可以完全阻断选择性β2肾上腺素受体激动药对心脏的作用,选择性β1肾上腺素受体阻断药部分阻断选择性β2肾上腺素受体激动药对心脏的作用。结论选择性β2肾上腺素受体激动药对心脏有不同程度的毒性作用,左旋沙丁胺醇对心脏的安全性高于硫酸沙丁胺醇,福莫特罗对心脏的影响小于硫酸沙丁胺醇和特布他林,福莫特罗和左旋沙丁胺醇的安全性相当。     

Comparison of the beta2-adrenoceptor selectivity of rimiterol, salbutamol and isoprenaline by the intravenous route in man.

1 The bronchodilating efficacy and the degree of beta2-adrenoceptor selectivity of rimiterol, salbutamol and isoprenaline were determined in seven subjects who exhibited histamine-induced bronchoconstriction. 2 Rimiterol, 0.5 (high dose) and 0.05 (low dose) mug kg-1 min-1, salbutamol, 0.3 and 0.03 mug kg-1 min-1, isoprenaline, 0.05 and 0.005 mug kg-1 min-1 and placebo were administered by a single intravenous injection over 6 min, and the protection against histamine-induced bronchoconstriction, changes in heart rate, pulse pressure and skeletal muscle tremor were measured. 3 Rimiterol (98%), salbutamol (96%) and isoprenaline (69%) protected against histamine-induced bronchoconstriction. For these ventilatory responses, there was a heart rate increase of 31.9, 24.7 and 44.3 beats/min for rimiterol, salbutamol and isoprenaline respectively. The three drugs produced similar increases in pulse pressure and tremor. 4 Significant dose-responses were obtained for all the parameters with each drug. 5 Isoprenaline was approximately 7 and 5 times as potent as rimiterol and salbutamol respectively in bronchodilator action when equimolar doses were compared. Similarly, isoprenaline was approximately 14 and 10 times as potent in increasing the heart rate as rimiterol and salbutamol respectively. 6 Rimiterol, a new beta-adrenoceptor stimulating drug, is an effective bronchodilator and has similar beta2-adrenoceptor selectivity to salbutamol when administered intravenously. The relative potencies and degrees of beta2-adrenoceptor selectivity of these drugs depend partly on their route of administration.     

Celiprolol: a positive inotropic beta-adrenoceptor blocking agent in conscious dogs.

1. beta-Adrenoceptor blocking agents are used to manage various cardiovascular disorders. A limiting factor in their use is the suppression of the cardiac contractile state. In our study, we examined the cardiac effects of celiprolol, a new beta-adrenoceptor blocking agent with reported positive inotropic effects. 2. Dogs were instrumented by use of sterile surgical techniques for the study of myocardial inotropic state, heart rate and internal left ventricular dimensions. Following complete recovery from surgery, experiments were conducted in the conscious state. 3. Intravenous injection of celiprolol (3 mg kg-1) in nine dogs, increased LV dP/dt by 13 +/- 2.6%, velocity of shortening (LV dD/dt) by 9.2 +/- 3.4%, and heart rate by 19 +/- 4.6% and decreased LV end-diastolic diameter by 1.8 +/- 0.8%, all significantly (P less than 0.05). Celiprolol blocked the inotropic actions of isoprenaline (0.5 micrograms kg-1) but only partially reduced its hypotensive effects. Propranolol, in contrast, reduced LV dP/dt by 17 +/- 3.3% and heart rate by 8.1 +/- 2.7% (P less than 0.05) while totally abolishing the hypotension, tachycardia and increase in LV dP/dt caused by isoprenaline. Following beta-adrenoceptor blockade with propranolol and with heart rate held constant by electrical pacing, celiprolol increased LV dP/dt by 16 +/- 4.0%, LV dD/dt by 12 +/- 3.0% and reduced LV end-diastolic diameter by 3.5 +/- 0.5% (P less than 0.05). 4. Thus, in conscious dogs, celiprolol increases inotropic state and reduces preload independently of beta 1-adrenoceptor mechanisms and the Bowditch phenomenon, while effectively blocking beta 1-receptors in the heart. These properties would make celiprolol useful in patients where a conventional beta-adrenoceptor blocking agent might lead to pump failure.     

The β-adrenoceptor selectivity profile of BRL 37344 in the pithed rat

1 Rats were pithed in order to srupt baroreflex pathways. Heart rate was used as a measure of β₁-adrenoceptor activity, blood pressure as a measure of β₂-adrenoceptor activity and oxygen consumption and brown adipose tissue temperature as measures of β₃-adrenoceptor activity. 2 The effects of the selective β₃-adrenoceptor agonist BRL 37344 were compared with those of isoprenaline, a non-selective β -adrenoceptor agonist, and denopamine and salbutamol, which are respectively β₁ and β₂-adrenoceptor agonists. 3 Denopamine was 10-fold more potent on heart rate than blood pressure, whilst salbutamol was 18-fold more potent on blood pressure than heart rate. These findings confirm that in this preparation increases in heart rate are predominantly β₁-adrenoceptor-mediated, whilst blood pressure is β₂-adrenoceptor-mediated. Further confirmation is provided by the blockade with atenolol, of the chronotropic effect, but not the blood pressure effect, of isoprenaline. 4 BRL 37344 was the most potent β -adrenoceptor agonist on both oxygen consumption and brown adipose tissue temperature, revealing the β₃-nature of these responses. Dose-response curves for oxygen consumption and brown adipose tissue temperature were identical, whichever of the β -adrenoceptor agonists was used. Both systems may be considered equally effective as indicators of β₃-adrenoceptor agonist activity.     

COMPARISON OF THE CARDIAC EFFECTS OF β-ADRENORECEPTOR AGONISTS IN ANAESTHETISED AND CONSCIOUS DOGS

• 1 The cardiovascular effects of some β-adrenoreceptor agonists on heart rate, blood pressure and myocardial contractility (maximum rate of change of left ventricular pressure/integrated isometric tension) were measured in pentobarbitone-anaesthetised and conscious, instrumented greyhounds.
• 2 In anaesthetised dogs isoprenaline increased heart rate and myocardial contractility and reduced blood pressure. Prenalterol and RO 363, in equiactive inotropic doses, induced greater increases in heart rate than isoprenaline if blood pressure fell by less than 25 mmHg. Salbutamol had hypotensive activity at all doses and appeared to be a relatively selective inotrope.
• 3 None of the agonists caused blood pressure to fall in the conscious dogs. Prenalterol and RO 363 were more effective inotropic stimulants, producing smaller increases in heart rate and more pronounced increases in myocardial contractility. Salbutamol, however, elicited greater increases in heart rate in the conscious animals and the inotropic selectivity demonstrated in the anaesthetised animals was lost.
• 4 The direct effects of the β-adrenoreceptor agonists, without modification by reflexes could be observed in the anaesthetised animals. The differences in the actions of the agonists in the conscious animals appear to be attributable to the state of the baroreceptor reflex control system and the relatively enhanced responsiveness of the heart.

     

Tracheal relaxing effects and beta2 adrenoceptor selectivity of S1319, a novel sponge-derived bronchodilator agent, in isolated guinea-pig tissues.

1. S1319 (4-hydroxy-7-[1-(1-hydroxy-2-methylamino)ethyl]-1, 3-benzothiazol-2(3H)-one acetate), a novel non-catecholamine beta-adrenoceptor agonist, has been compared with isoprenaline, salbutamol and formoterol for activity in vitro on a range of beta-adrenoceptor containing preparations from guinea-pig. 2. S1319, like isoprenaline, salbutamol and formoterol, relaxed preparations of guinea-pig trachea (contracted by histamine) in a concentration-dependent manner. The relaxing activity of S1319 appeared to be more potent than that of isoprenaline and salbutamol, and similar to that of formoterol (pD2 values of 10.58+/-0.03 vs 7. 60+/-0.01, 7.50+/-0.01 and 10.52+/-0.04, respectively), and was blocked by the beta2-adrenoceptor selective antagonist (ICI 118,551). The intrinsic activity of S1319 was close to 1.0. 3. In the beta1-adrenoceptor containing preparations, guinea-pig right and left atria, a monophasic inotropic response of S1319 was observed. The pD2 value of S1319 for left atrial and right atrial inotropism was 6.70+/-0.15 and 7.81+/-0.01, respectively. 4. The selectivity ratio (trachea/left atrial inotropism) of S1319, formoterol, salbutamol and isoprenaline was 8523, 284, 4.8 and 0.45, respectively. The relative selectivity ratio of S1319 was 18743, 1858 and 30 times greater than that of isoprenaline, salbutamol and formoterol, respectively. 5. Relaxant responses of guinea-pig trachea to S1319 declined rapidly when the agonist was washed from the tissues, with complete recovery within 30 min. The duration of action of S1319 was similar to that of isoprenaline and less than that of salbutamol and formoterol. 6. In summary, S1319, a sponge-derived beta-adrenoceptor agonist, is a potent and selective beta2-adrenoceptor agonist with a short-duration of action in isolated guinea-pig tracheas.     

Effects of a range of beta2 adrenoceptor agonists on changes in intracellular cyclic AMP and on cyclic AMP driven gene expression in cultured human airway smooth muscle cells.

1. The effects of the selective beta2 adrenoceptor agonists salbutamol, terbutaline and salmeterol and the non-selective beta adrenoceptor agonist isoprenaline on [3H]-cyclic AMP formation and cyclic AMP response element (CRE) driven luciferase expression, assessed using the construct p6CRE/luc, were studied in primary cultures of human airway smooth muscle (HASM) cells. 2. Optimal transfection conditions for transient expression of pGL3 Control were 4 microg DNA/well71 in a 6 well plate and 1.8 microl Transfectam/microg DNA. Expression was maximal at 48 - 72 h. 3. Salbutamol (maximum response 19%, EC50 0.6 microM), terbutaline (maximum response 38%, EC50 2.3 microM) and salmeterol (maximum response 18%, EC50 0.0012 microM) were all partial agonists for cyclic AMP formation compared with isoprenaline (EC50 0.08 microM). However, all of the beta2 adrenoceptor agonists produced increases in CRE-driven luciferase activity, in cultured HASM transfected with the vector p6CRE/luc, which were equivalent or greater (salmeterol) than those seen with isoprenaline. 4. Both salbutamol and salmeterol were more potent at increasing luciferase expression than in elevating cyclic AMP levels in these cells. The potency ratios (EC50 (cyclic AMP)/EC50 (LUC)) for the agents studied were isoprenaline: 0. 2 fold, terbutaline: 3 fold, salbutamol: 24 fold, salmeterol: 38 fold. 5. These data suggest that important quantitative differences exist in the ability of beta2 adrenoceptor agonists to increase whole cell cyclic AMP levels in airway smooth muscle and to drive gene expression via a CRE-driven mechanism.     

An assessment of the partial agonist activity of Ro 31-1118, flusoxolol and pindolol in man.

1. The effects of single oral doses of three beta-adrenoceptor partial agonists (Ro 31-1118, flusoxolol and pindolol), two beta-adrenoceptor antagonists (propranolol and atenolol), two beta-adrenoceptor agonists (salbutamol and prenalterol) and placebo on sleeping heart rate, quality of sleep, supine heart rate, exercise heart rate, blood pressure, forearm blood flow and finger tremor were studied in eight healthy male volunteers. 2. Sleeping heart rate was increased by Ro 31-1118, flusoxolol, pindolol, salbutamol and prenalterol and decreased by propranolol and atenolol. 3. None of the drugs studied affected quality of sleep. 4. Supine heart rate was increased by flusoxolol, prenalterol and salbutamol, unaffected by Ro 31-1118 and pindolol and reduced by propranolol and atenolol. 5. Exercise heart rate was reduced by both beta-adrenoceptor antagonists and the three partial agonists and unaffected by salbutamol and prenalterol. 6. Systolic blood pressure was increased by Ro 31-1118, flusoxolol, salbutamol and prenalterol, unaffected by pindolol and reduced by propranolol and atenolol. Diastolic blood pressure was reduced by salbutamol and prenalterol. 7. Forearm blood flow was increased by Ro 31-1118, salbutamol and prenalterol, unchanged by pindolol and flusoxolol and decreased by atenolol and propranolol. 8. Finger tremor was increased by Ro 31-1118, flusoxolol, pindolol, salbutamol, and prenalterol. 9. beta-adrenoceptor partial agonists have different effects on the cardiovascular system and finger tremor to beta-adrenoceptor antagonists. 10. While Ro 31-1118 and flusoxolol are antagonists mainly at the beta 1-adrenoceptor they have agonist activity at both beta 1- and beta 2 adrenoceptors. 11. While pindolol is a non-selective antagonist its agonist activity is mainly at the beta 2-adrenoceptor.     

The effect of “selective” β-adrenoceptor blocking drugs on the myocardial circulation

1. A comparison has been made of the effects of a relatively specific beta(1)-adrenoceptor blocking drug (practolol) and a relatively specific beta(2)-adrenoceptor blocking drug (butoxamine) on myocardial and general haemodynamics in anaesthetized cats.2. Practolol, in a dose (10 mg/kg, intravenously) which had little effect on arterial pressure, heart rate, myocardial blood flow or myocardial vascular resistance, markedly reduced the effects of isoprenaline infusions on heart rate, aortic dp/dt, myocardial blood flow, vascular resistance and metabolic heat production, and the cardiac effort index. Isoprenaline induced vasodepression was unaffected.3. Butoxamine (5 mg/kg, intravenously) decreased heart rate, aortic dp/dt, the cardiac effort index and myocardial blood flow and increased myocardial vascular resistance. This is taken as further evidence for the existence of beta(2)-adrenoceptors in the myocardial microcirculation.4. After butoxamine, the effects of isoprenaline on myocardial blood flow, myocardial vascular resistance and heart rate were unaffected but the peripheral vasodilator effect was abolished. The effects on aortic dp/dt and the cardiac effort index were potentiated.5. It is concluded that the effect of isoprenaline in increasing myocardial blood flow is due predominantly to increased cardiac work and oxygen consumption and that practolol, since it has little direct effect on myocardial blood flow yet abolishes the cardiac stimulant and oxygen wasting effects of released catecholamines, has properties which indicate that it should be an effective and safe anti-anginal drug.     

Cardiostimulatory effects of prenalterol,a beta-1 adrenoceptor partial agonist,in vivo and in vitro

Summary The cardiostimulatory effects of prenalterol, a beta-1-adrenoceptor partial agonist, were studied in vivo and in vitro and compared to those evoked by isoprenaline, a full agonist, and to those of other partial agonists.In the anaesthetized rat, prenalterol and terbutaline were found not to elevate the myocardial cyclic AMP content; this was in sharp contrast to isoprenaline. Both partial agonists did, however, produce significant effects on heart rate.In the anaesthetized cat, prenalterol exhibited chronotropic and inotropic intrinsic activities of 88 and 76% respectively in relation to isoprenaline. No statistically significant increase in myocardial cyclic AMP content could however be detected.Prenalterol did not stimulate adenylate cyclase significantly in the cat myocardial homogenate. This was also true of the beta-2-adrenoceptor selective partial agonist procaterol. In this preparation, isoprenaline, noradrenaline and adrenaline acted as full agonists. Furthermore, prenalterol produced a concentration-dependent inhibition of isoprenaline-activated adenylate cyclase.Our data indicate that maximal cardiac stimulation occurs at a low level of adenylate cyclase activation and low myocardial cyclic AMP concentration when provoked by a full beta-adrenoceptor agonist. The maximal physiological effects of a partial agonist such as prenalterol may consequently be achieved at a marginal activation of the adenylate cyclase.The present data may thus support the hypothesis of a large beta-adrenoceptor reserve for full agonists in the heart.     

The selectivity of beta-adrenoceptor antagonists at the human beta1, beta2 and beta3 adrenoceptors

Beta-adrenoceptor antagonists ("beta-blockers") are one of the most widely used classes of drugs in cardiovascular medicine (hypertension, ischaemic heart disease and increasingly in heart failure) as well as in the management of anxiety, migraine and glaucoma. Where known, the mode of action in cardiovascular disease is from antagonism of endogenous catecholamine responses in the heart (mainly at beta1-adrenoceptors), while the worrisome side effects of bronchospasm result from airway beta2-adrenoceptor blockade. The aim of this study was to determine the selectivity of beta-antagonists for the human beta-adrenoceptor subtypes. (3)H-CGP 12177 whole cell-binding studies were undertaken in CHO cell lines stably expressing either the human beta1-, beta2- or the beta3-adrenoceptor in order to determine the affinity of ligands for each receptor subtype in the same cell background.In this study, the selectivity of well-known subtype-selective ligands was clearly demonstrated: thus, the selective beta1 antagonist CGP 20712A was 501-fold selective over beta2 and 4169-fold selective over beta3; the beta2-selective antagonist ICI 118551 was 550- and 661-fold selective over beta1 and beta3, respectively, and the selective beta3 compound CL 316243 was 10-fold selective over beta2 and more than 129-fold selective over beta1. Those beta2-adrenoceptor agonists used clinically for the treatment of asthma and COPD were beta2 selective: 29-, 61- and 2818-fold for salbutamol, terbutaline and salmeterol over beta1, respectively. There was little difference in the affinity of these ligands between beta1 and beta3 adrenoceptors. The clinically used beta-antagonists studied ranged from bisoprolol (14-fold beta1-selective) to timolol (26-fold beta2-selective). However, the majority showed little selectivity for the beta1- over the beta2-adrenoceptor, with many actually being more beta2-selective. This study shows that the beta1/beta2 selectivity of most clinically used beta-blockers is poor in intact cells, and that some compounds that are traditionally classed as "beta1-selective" actually have higher affinity for the beta2-adrenoceptor. There is therefore considerable potential for developing more selective beta-antagonists for clinical use and thereby reducing the side-effect profile of beta-blockers.     

Effects of beta-adrenoceptor agonists in human bronchial smooth muscle.

1. We have investigated the potency and duration of action of isoprenaline and a range of beta-adrenoceptor agonists as relaxants of inherent tone in human superfused, isolated bronchial smooth muscle, a tissue reported to contain a homogeneous population of beta 2-adrenoceptors. 2. All of the beta-adrenoceptor agonists caused concentration-related inhibition of inherent tone, with isoprenaline having an EC50 of 27 nM. The rank order of agonist potency was: formoterol > or = -salmeterol > or = clenbuterol > fenoterol = isoprenaline > terbutaline > or = salbutamol > quinprenaline. 3. Relaxant responses to salmeterol were fully reversed by the selective beta 2-adrenoceptor blocking drug, ICI 118551, demonstrating the involvement of beta 2-adrenoceptors. 4. Rt50, i.e. the time taken for 50% recovery from the effects of an EC50 concentration of agonist, differed considerably between the different beta 2-adrenoceptor agonists. Most agonists were short-acting, having Rt50 values less than 13 min. Quinprenaline was of moderate duration, with an Rt50 value of > or = 20 min. In contrast, salmeterol was extremely long-acting, with no sign of recovery within 4 h. 5. Estimates of relative potency and duration of action were similar to those previously determined for these agonists in the guinea-pig isolated trachea. These results suggest, therefore, that guinea-pig trachea is a suitable alternative to human bronchus for the evaluation of the actions of beta-adrenoceptor agonists on airways smooth muscle.     

In situ assessment of the role of the beta 1-, beta 2- and beta 3-adrenoceptors in the control of lipolysis and nutritive blood flow in human subcutaneous adipose tissue.

1. The involvement of beta 1-, beta 2- and beta 3-adrenoceptors in the control of lipolysis and nutritive blood flow was investigated in abdominal subcutaneous adipose tissue of healthy young adults by use of an in situ microdialysis technique. 2. Dialysis probes were infused either with isoprenaline (non-selective beta-adrenoceptor agonist), CGP 12,177 (selective beta 3-adrenoceptor agonist having beta 1-/beta 2-antagonist properties), dobutamine (selective beta 1-adrenoceptor agonist) or terbutaline (selective beta 2-adrenoceptor agonist). The recovery of each probe used for perfusion was calculated by an in vivo calibration method. The local blood flow was estimated through the measurement of the escape of ethanol infused simultaneously with the drugs included in the probe. 3. Isoprenaline infusion at 0.01 microM had a weak effect while higher concentrations of isoprenaline (0.1 and 1 microM) caused a rapid, sustained and concentration-dependent increase of glycerol outflow; the maximum increase was 306 +/- 34% with 1 microM. Isoprenaline also increased the nutritive blood flow in adipose tissue; a significant effect appeared at 0.1 microM isoprenaline and was greater at 1 microM. 4. CGP 12,177 (10 and 100 microM) increased the glycerol concentration in the dialysate (128 +/- 8 and 149 +/- 12%, respectively) and nutritive blood flow. Terbutaline and dobutamine (100 microM) both provoked rapid and similar increases in glycerol outflow (252 +/- 18 and 249 +/- 18%, respectively). Both, terbutaline and dobutamine increased nutritive blood flow. 5. It is concluded that beta 1- and beta 2-adrenoceptor subtypes are both mainly involved in the mobilization of lipids and in the control of nutritive blood flow. beta 3-Adrenoceptors play a weaker role in the control of lipolysis and nutritive blood flow in human subcutaneous abdominal adipose tissue.     

Actions of procaterol (OPC-2009), a new β2-adrenoceptor stimulant,on pulmonary resistance,contractions of the soleus muscle,and cardiovascular system of the anaesthetized cat

The β-adrenoceptor stimulant actions of procaterol hydrochloride [5-(1-hydroxy-2-iso-propylaminobutyl)-8-hydroxycarbostyril hydrochloride hemihydrate] were compared with those of isoprenaline, orciprenaline and salbutamol on pulmonary resistance, contractions of the soleus muscle, heart rate and diastolic blood pressure in the anaesthetized cat. All four drugs reduced the 5-HT-induced increase in pulmonary resistance, decreased the tension of incomplete tetanic contractions of the soleus muscle and the diastolic blood pressure, and increased the heart rate in a dose-related manner. The duration of the bronchodilator action of procaterol was far longer than that of orciprenaline or salbutamol while isoprenaline had the shortest duration. Procaterol was about 1·5 times more potent, and orciprenaline and salbutamol about 80 and 10 times less potent than isoprenaline in reducing the 5-HT-induced increase in pulmonary resistance and in decreasing the tension of incomplete tetanic contractions of the soleus muscle. Procaterol, orciprenaline and salbutamol were 3·5, 91·9 and 43·9 times less potent than isoprenaline in increasing the heart rate. Procaterol, orciprenaline and salbutamol were 3·4, 130·2 and 12·9 times less potent than isoprenaline in decreasing the diastolic blood pressure. Calculation of selectivity for bronchial vs cardiac β-adrenoceptors indicates that procaterol and salbutamol have a similar degree of selectivity for β₂-adrenoceptors mediating the bronchodilation, and that orciprenaline was an essentially unselective stimulant. Furthermore, the results support the suggestion that at present it is not possible to separate the bronchodilating and tremor-enhancing properties of β-adrenoceptor stimulants.     

Influence of the thr164ile polymorphism in the beta2-adrenoceptor on the effects of beta-adrenoceptor agonists on human lung mast cells

We have examined the influence of the thr164ile polymorphism in the beta(2)-adrenoceptor on the ability of the beta-adrenoceptor agonists, isoprenaline and salbutamol, to stabilise human lung mast cells. A total of 124 mast cell preparations were genotyped and, of these, 120 were found to be homozygous (thr164thr) at position 164 of the beta(2)-adrenoceptor and 4 were heterozygous (thr164ile). None of the preparations was homozygous for ile at position 164. In these preparations, the effects of isoprenaline and salbutamol on the IgE-mediated release of histamine from mast cells were studied. Both isoprenaline and salbutamol inhibited histamine release in a concentration-dependent manner. Average inhibitory potencies for both agonists, as assessed by pD(2) values, were higher in homozygous than in heterozygous preparations. For isoprenaline, this difference was statistically significant (P < 0.005), whereas for salbutamol, it was not (P = 0.21). These data suggest that the thr164ile polymorphism in the beta(2)-adrenoceptor may influence the extent to which certain beta-adrenoceptor agonists inhibit the responses of mast cells.     

Positive inotropic effects of histamine in anaesthetized dogs.

1 The cardiovascular effects of histamine were examined in dogs anaesthetized with pentobarbitone 2 The effect of histamine on heart rate, blood pressure, left ventricular pressure, dP/dtmax and dP/dt: IIT (integrated isometric tension) was compared in the presence and absence of autonomic reflexes and blood pressure control. 3 In innervated animals with no attempt to control blood pressure, histamine produced dose-dependent decreases in blood pressure and heart rate and either positive or negative inotropic actions. 4 When autonomic reflexes were abolished, this variability in inotropic response was reduced and histamine produced a slight positive inotropic response. There was a decrease in blood pressure and a positive chronotropic response to histamine. 5 When blood pressure was controlled and the cardiac nerves were intact, histamine produced a decrease in heart rate. However, in the denervated animals, there was a slight increase in heart rate. 6 Inotropic responses to histamine in the blood pressure controlled groups were less variable than when blood pressure was uncontrolled. In all of these animals there was an increase in contractility, the increase being more marked in the denervated group. 7 The H2-receptor agonist impromidine produced a positive inotropic action in intact animals with uncontrolled blood pressure.     

The cardiovascular effects of ICI 118,587: A beta 1-adrenoceptor partial agonist.

1 In a preparation in which cardiovascular reflexes were prevented from occurring, ICI 118,587 (1-(p-hydroxyphenoxy)-3-beta-(morpholinocarbonamido) ethylamino-2-propranol fumarate) caused dose-dependent positive chronotropic and inotropic effects upon the dog heart. 2 The increase in heart rate brought about by ICI 118,587 was about 43% of the maximum increase produced by isoprenaline. 3 For a given chronotropic effect produced by either ICI 118,587 or isoprenaline, each compound produced a similar inotropic effect as indicated by an increase in LV dp/dtmax. 4 In contrast to the direct stimulant action of ICI 118,587 on the heart no direct effects on vascular smooth muscle were observed. 5 ICI 118,587 was shown to be a competitive antagonist of the chronotropic and vasodilator effects of isoprenaline on the heart and blood vessels and of the chronotropic effects of noradrenaline on the heart. 6 It is concluded that ICI 118,587 is a selective beta 1-adrenoceptor partial agonist.     

In vivo beta 2-adrenoceptor hyporesponsiveness in the cardiovascular system of the pig after Bordetella pertussis

The effects of Bordetella pertussis (B. pertussis) on autonomic receptor function were investigated in vivo in the cardiovascular and in particular in the coronary vascular system of the pig. For this purpose the pigs were injected i.p. with B. pertussis vaccine 4 days prior to the experiment. Blood pressure, heart rate, cardiac output, coronary flow, left ventricular pressure and its dP/dt were measured. B. pertussis induced an increase in the baseline values for heart rate, cardiac output, coronary flow and maximal rate of rise of left ventricular pressure (maxLVdP/dt). Left ventricular end diastolic pressure and coronary vascular resistance were decreased. Dose-response curves were made for the beta 2-sympathicomimetic salbutamol. Pretreatment with B. pertussis reduced the effect of salbutamol on LVEDP and maxLVdP/dt. Furthermore, the effects of salbutamol on coronary flow and coronary vascular resistance were nearly completely inhibited. In conclusion, the present in vivo study in pigs evidenced hyporesponsiveness of the coronary and cardiac beta 2-adrenoceptors.