Analysis of the inotropic: chronotropic selectivity of dobutamine and dopamine in anaethetised dogs and guinea-pig isolated atria.

The previously reported in vivo inotropic selectivity of dobutamine and dopamine compared with isoprenaline has been demonstrated in anaesthetised bivagotamised open chest dogs. Responses of heart rate, right ventricular tension, left ventricular dP/dtmax, and blood pressure were measured. Compared with isoprenaline, dobutamine and dopamine were 1.8 and 2.4 times more active in increasing cardiac contractility than rate. The inotropic selectivity of dopamine but not that of dobutamine was abolished by pretreatment of dogs with syrosingopine. In guinea-pig isolated atria, isoprenaline, dobutamine, and dopamine were all slightly rate selective although this was less for dopamine. In atria incubated with phenoxybenzamine from guinea-pigs pretreated with reserpine only the dopamine dose-response curves were displaced to the right indicating a considerable indirect sympathomimetic component. The in vivo inotropic selectivity of dopamine could therefore be explained on the basis of this indirect activity being manifested at lower doses in the myocardium where the stores of catecholamines are more abundant than at the sinoatrial node. However, it is concluded that the inotropic selectivity of dobutamine seen in vivo is not due to indirect activity, reflex effects, or to a difference in the beta-adrenoceptors mediating the rate and tension responses of the heart. Possible alternative explanations are discussed.

Combined alpha- and beta-adrenoceptor blocking drug AH 5158: further studies on alpha-adrenoceptor blockade in anaesthetized animals.

1. AH 5158, 5-(1-hydroxy-2-((1-methyl-3-phenylpropyl)amino)ethyl)salicylamide, competitively antagonised phenylephrine-induced vasopressor responses in anaesthetized dogs, thus confirming that the drug possesses alpha-adrenoceptor blocking activity. 2. In contrast, AH 5158 was a relatively ineffective antagonist of vasopressor responses to noradrenaline in anesthetized dogs. Thus, at the lowest dose-level tested (1 mg/kg) AH 5158 abolished the increase in pulse width caused by noradrenaline, but otherwise had little or no blocking effect in doses as high as 10 mg/kg. Propranolol (0.1 mg/kg) also abolished the increase in pulse width caused by noradrenaline. With both drugs this effect is thought to be a consequence of blockade of the beta-adrenoceptor-mediated cardia stimulant action of noradrenaline. 3. The interaction between AH 5158 and noradrenaline in spinal dogs, anaesthetized cats and pithed rats was very similar to that seen in anaesthetized dogs. 4. Noradrenaline pressor responses were effectively antagonized by AH 5158 in anaesthetized dogs pretreated with cocaine. The degree of block was similar to that obtained when phenylephrine was the agonist in untreated dogs. 5. These results are consistent with the hypothesis that AH 5158 blocks a cocaine-sensitive inactivation process for noradrenaline in addition to blocking alpha- and beta-adrenoceptors. The resultant increase in the level of circulating noradrenaline would tend to counteract the adrenoceptor blocking action of the drug. 6. The implications of these findings are discussed.

A non-adrenergic inhibitory nervous pathway in guinea-pig trachea.

1 Electrical stimulation of the guinea-pig isolated tracheal tube causes a biphasic response, initially excitatory and then inhibitory. The excitatory response was abolished by atropine leaving the inhibitory response unaffected.2 The inhibitory response was greatly reduced but not abolished by propranolol or guanethidine. A residual inhibitory response was still present in tracheas in which sympathetic nerve function had been abolished by pretreatment with syrosingopine or 6-hydroxydopamine. These results show that the inhibitory response is predominantly adrenergic but that a small non-adrenergic component is also present.3 The non-adrenergic inhibitory response was abolished by lignocaine and tetrodotoxin suggesting that it is nervous in origin.4 Optimal stimulation parameters for the predominantly adrenergic inhibitory response were a pulse width of 0.7-2 ms, a stimulation period of 7 s and a frequency of 20 Hz. For the non-adrenergic inhibitory response, optimal stimulation parameters were a pulse width of 2 ms, a stimulation period of 12 s and a frequency of 20 Hz.5 Evidence obtained with pharmacological antagonists, enzyme inhibitors and activators suggested that the transmitter mediating the non-adrenergic inhibitory nervous response is unlikely to be: acetylcholine, histamine, 5-hydroxytryptamine, cyclic 3',5'-adenosine monophosphate or a prostaglandin.6 The adenosine uptake blocking drugs dipyridamole, hexobendine and Dilazep potentiated the non-adrenergic inhibitory nervous response and unmasked inhibitory responses to adenosine and adenosine 5'-triphosphate.7 It is concluded that electrical stimulation of the guinea-pig trachea, in addition to activating cholinergic and adrenergic nervous pathways, may activate a separate and distinct inhibitory nervous pathway. This pathway has some features in common with the non-adrenergic non-cholinergic inhibitory pathways in gastro-intestinal muscle.

Characterization of the coronary vascular -adrenoceptor in the pig.

The beta-adrenoceptor in pig coronary vascular smooth muscle has been characterized by the use of a selective agonist, salbutamol and a selective antagonist, practolol. In coronary artery strips contracted with KCI, salbutamol had only marginal relaxant activity and was a partial agonist compared with isoprenaline. Practolol had relatively high antagonist potency against isoprenaline (pA(2) 6.59). It is concluded that the pig coronary vascular,beta-adrenoceptor is of the beta(1)-type.

A comparison of some cardiovascular properties of propranolol, MJ 1999 and quinidine in relation to their effects in hypertensive animals.

1. A comparison of some cardiovascular effects of propranolol, MJ 1999 and quinidine has been made in rats and dogs.2. After intravenous, subcutaneous or oral administration to rats and dogs, propranolol was found to be 2-4 times more potent than MJ 1999 in blocking the chronotropic and vasodepressor responses to intravenously administered isoprenaline.3. Propranolol and quinidine affected the e.c.g. of rats and dogs in a similar manner.4. At dose-levels causing effective blockade of beta-receptors propranolol and MJ 1999 had no hypotensive effect after short- or long-term administration to conscious hypertensive rats and dogs.5. At very high dose-levels propranolol and quinidine, but not MJ 1999, lowered blood pressure in the hypertensive rat. This effect of propranolol is probably related to one or more of the properties that propranolol and quinidine have in common rather than to a blockade of beta-receptors.6. The possible relevance of these results to the use of propranolol as a hypotensive agent in man is discussed.

Receptors for 5-hydroxytryptamine and noradrenaline in rabbit isolated ear artery and aorta.

5-Hydroxytryptamine (5-HT) is thought to be implicated in the vascular disturbances of the external carotid artery bed associated with migraine. As part of a study of the pharmacology of some 5-HT antagonists used in the treatment of migraine we have examined the interactions of these drugs with 5-HT and noradrenaline in rabbit isolated ear artery and aortic strip. The results provide new information on the distribution of 5-HT-receptors in these preparations. In the aorta, 5-HT and noradrenaline were of similar potency in producing contractions. Methysergide produced very small contractions and was about 1000 times less potent than the other two agonists. In the ear artery noradrenaline produced monophasic vasoconstrictor responses, whereas 5-HT and methysergide produced prolonged biphasic responses. 5-HT was about 700 times less potent and methysergide about 4500 times less potent than noradrenaline. Methysergide was a better agonist in the ear artery than in the aorta. Biphasic responses to 5-HT and methysergide were also obtained in ear arteries from reserpine-treated rabbits indicating that neither agonist was acting by releasing endogenous noradrenaline. Pizotifen, cyproheptadine and phentolamine had no agonistic actions in either the aorta or ear artery. In the aorta methysergide, pizotifen and cyproheptadine were potent antagonists of 5-HT and much weaker antagonists of noradrenaline. Phentolamine possessed the opposite profile of selectivity. These results show that there are distinct receptors for 5-HT and noradrenaline in rabbit aorta. In the ear artery the pA2 values for each of the four antagonists were virtually identical against 5-HT and noradrenaline and similar to those obtained on alpha-adrenoceptors in the aorta. We conclude that 5-HT and noradrenaline act directly at alpha-receptors to produce vasoconstriction in the ear artery and that this preparation does not contain specific 5-HT receptors. This insight into the distribution of 5-HT receptors and alpha-receptors allows interpretation of the various actions of methysergide. In the aorta, methysergide was a potent antagonist at 5-HT-receptors and a weak partial agonist at alpha-receptors. In the ear artery, methysergide was a partial agonist at alpha-receptors; it was only a weak antagonist of 5-HT because this preparation does not contain specific 5-HT-receptors. The cross-reactivity demonstrated throughout these experiments indicates that 5-HT-receptors and alpha-receptors, although distinct entities, have features in common. These results are discussed in relation to the mode of action of methysergide, pizotifen and cyproheptadine in the treatment of migraine.

Effect of labetalol on the uptake of [3H]-(-)-noradrenaline into the isolated vas deferens of the rat.

1 The effects of the combined alpha- and beta-adrenoceptor blocking drug, labetalol, on the uptake of [3H]-(-)-noradrenaline into the isolated vas deferens of the rat have been determined and compared with those of some other alpha-adrenoceptor blocking drugs and cocaine. 2 Labetalol, like cocaine, produced a simple competitive inhibition of [3H]-(-)-noradrenaline uptake and was about 4 times less potent than cocaine. It is concluded that labetalol is a potent inhibitor of uptake1. Phentolamine and thymoxamine also inhibited [3H]-(-)-noradrenaline uptake, and were respectively 8 and 14 times less potent than cocaine. Tolazoline, piperoxan and yohimbine were inactive in concentrations up to 30 microgram/ml. 3 The uptake1 blocking action of labetalol could explain, at least in part, the previously reported difference in its ability to block noradrenaline and phenylephrine vasopressor responses in the anaesthetized dog. 4 The possibility that uptake1 inhibitory concentrations of labetalol could be present in the blood of subjects receiving normal antihypertensive doses of the drug is discussed.

The selectivity of beta-adrenoceptor antagonists on cardiovascular and bronchodilator responses to isoprenaline in the anaesthetized dog.

1 The actions of five beta-adrenoceptor antagonists, chosen because of reported differences in their selectivities, were compared using the positive chronotropic, vasodepressor and bronchodilator responses to isoprenaline in anesthetized dogs. 2 Propranolol was a potent antagonist of the isoprenaline responses in all three systems. 3 Practolol and acebutolol (M & B 17,803) blocked the positive chronotropic responses to isoprenaline to a greater extent than the vasodepressor or bronchodilator responses. 4 Butoxamine and alpha-methyl dichloroisoprenaline showed the opposite selectivity, blocking the vasodepressor and bronchodilator responses to isoprenaline to a greater extent than positive chronotropic responses. However, both drugs were considerably less potent than the other antagonists studied and their selectivities were less clear-cut than those of practolol or acebutolol. 5 All the antagonists lowered the resting heart rate and to a lesser extent the diastolic blood pressure. The effects of propranolol, practolol and acebutolol on heart rate probably result from cardiac beta-adrenoceptor blockade. With butoxamine and alpha-methyl dichloro isoprenaline, however, the effects on heart rate probably result from a direct cardiodepressant action. 6 The relevance of the results to the problem of the sub-classification of beta-adrenoceptors is discussed.

Selectivity of beta-adrenoceptor agonists and antagonists on bronchial, skeletal, vascular and cardiac muscle in the anaesthetized cat.

1 The potencies of fifteen beta-adrenoceptor agonists of widely differing chemical structures were compared with that of (-)-isoprenaline on bronchial muscle, soleus muscle, blood pressure and heart rate in the anaesthetized cat. The beta-adrenoceptor antagonist potencies of propranolol and practolol were determined against (-)-isoprenaline in the same model. 2 (-)-Isoprenaline was the most potent agonist and its action was essentially unselective. Thus, on all four parameters the minimal effective dose was 0.003-0.01 mug/kg and maximal or near maximal responses were produced by 0.3-1 mug/kg. Trimetoquinol was also an essentially unselective agonist. 3 For thirteen of the remaining fourteen agonists, potency was similar on bronchial muscle, soleus muscle and blood pressure but significantly lower on heart rate. 4 The remaining agonist - AH 7616 (4-hydroxy-alpha1-[[(1-methyl-3,3-diphenyl-propyl)amino]-methyl]-m-xylene-alpha1, alpha3-diol, acetate) - was also significantly less potent on heart rate than on the other parameters; in addition, it was clearly less potent on soleus muscle and blood pressure than on bronchial muscle when 5-hydroxytryptamine (5-HT) was used to induce bronchospasm. However, when acetylcholine was used instead of 5-HT the potency of AH 7616 on induce bronchospasm. However, when acetylcholine was used instead of 5-HT the potency of AH 7616 on bronchial muscle, soleus muscle and blood pressure was very similar. AH 7616 may therefore possess a specific 5-HT antagonist action in addition to its beta-adrenoceptor agonist action. 5 The fifteen test agonists were longer acting than (-)-isoprenaline and this was particularly true of trimetoquinol and soterenol. 6 The beta-adrenoceptor antagonist potency of propranolol was almost identical on bronchial muscle, soleus muscle and blood pressure and very slightly lower on the heart. Practolol was 10-12 times more potent on the heart than on bronchial muscle, soleus muscle and blood pressure. 7 These findings suggest that it may not be possible to separate the bronchodilating and tremorenhancing properties of beta-adrenoceptor agonists. The results with agonists and antagonists are in accord with Lands' dual beta-adrenoceptor sub-classification.

Evidence for two types of excitatory receptor for 5-hydroxytryptamine in dog isolated vasculature.

1 As part of an investigation into the mode of action of anti-migraine drugs, a study of the excitatory receptors for 5-hydroxytryptamine (5-HT) has been carried out in a range of isolated vascular preparations from the dog.2 5-HT contracted the dog isolated femoral artery and saphenous vein over the concentration-range 1.0 x 10(-8) to 5.0 x 10(-6) mol/l.3 In the femoral artery methysergide and cyproheptadine were potent, competitive and specific antagonists of the contractile responses to 5-HT, with pA(2) values of 8.52 and 8.55 respectively.4 In the saphenous vein, methysergide was only a weak antagonist of 5-HT. In addition, it was an agonist over the concentration-range 5.0 x 10(-8) to 1.0 x 10(-5) mol/l. Cyproheptadine was a weak and unsurmountable antagonist of contractile responses to 5-HT and methysergide.5 Contractile responses to 5-HT and methysergide in the saphenous vein were not antagonized by morphine (3.0 x 10(-5) mol/l), indomethacin (5.0 x 10(-5) mol/l), phentolamine (5.0 x 10(-7) mol/l), propranolol (1.0 x 10(-6) mol/l), atropine (1.0 x 10(-6) mol/l), mepyramine (1.0 x 10(-6) mol/l) or cimetidine (1.0 x 10(-5) mol/l).6 In the external carotid and lingual arteries the pattern of activity obtained with methysergide and cyproheptadine was the same as that in the femoral artery, while in the auricular artery the pattern of activity was the same as that in the saphenous vein.7 The results are consistent with the hypothesis that there are two types of receptor mediating 5-HT-induced vasoconstriction in dog vasculature. One type, characterized by the pattern of activity obtained in the femoral artery, is like the previously described ;D-receptor'. The other type, characterized by the pattern of activity obtained in the saphenous vein, has not been described before. The verification of this hypothesis requires the identification of a specific antagonist of 5-HT and methysergide in the saphenous vein.

The alpha- and beta-adrenoceptor blocking potencies of labetalol and its individual stereoisomers in anaesthetized dogs and in isolated tissues.

1 The antagonist potencies of labetalol and each of its four stereoisomers have been compared at alpha 1-, beta 1- and beta 2-adrenoceptors in anaesthetized dogs and in isolated tissues. 2 The RR stereoisomer is a potent, non-selective antagonist at beta-adrenoceptors but has only weak alpha 1-adrenoceptor blocking activity. 3 The SR stereoisomer was the most potent antagonist at alpha 1-adrenoceptors, and it also had similar potency as an antagonist at beta-adrenoceptors. 4 The alpha- and beta-adrenoceptor blocking profile of the RS stereoisomer is intermediate between that of the RR and SR, but the SS stereoisomer is a relatively weak antagonist at both alpha- and beta-adrenoceptors. 5 It is concluded that, although most of the alpha 1-adrenoceptor blocking activity of labetalol is attributable to the SR stereoisomer and nearly all of its beta-adrenoceptor blocking activity resides in the RR stereoisomer, each of the stereoisomers contributes to the overall pharmacological profile of labetalol.

Comparison of the bronchodilator and cardiovascular actions of salbutamol, isoprenaline and orciprenaline in guinea-pigs and dogs.

1. Bronchodilator and cardiovascular actions of salbutamol and isoprenaline have been compared in guinea-pigs and dogs. Orciprenaline was also included in some experiments.2. All three drugs antagonized acetylcholine-induced increases in pulmonary resistance. In addition they increased heart rate and decreased arterial blood pressure.3. Compared with isoprenaline, salbutamol has relatively stronger actions on bronchial and vascular beta-adrenoceptors than on cardiac beta-adrenoceptors, on which its action is very weak. In contrast, orciprenaline has similar potencies on beta-adrenoceptors in these three tissues.4. The positive chronotropic potency of intravenously or orally administered salbutamol was increased in conscious dogs. These heart rate responses to salbutamol were probably mainly reflex in origin.5. Salbutamol and orciprenaline were both longer acting than isoprenaline.6. The results support the idea of two distinct groups of beta-adrenoceptors. Salbutamol differentiates between bronchial and vascular beta(2)-adrenoceptors on the one hand and cardiac beta(1)-adrenoceptors on the other. Isoprenaline and orciprenaline do not differentiate between beta(1)- and beta(2)-adrenoceptors.

Pharmacology of AH 5158; a drug which blocks both - and -adrenoceptors.

1. AH 5158 differs from conventional adrenoceptor blocking drugs in producing competitive blockade of both alpha- and beta-adrenoceptors.2. AH 5158 is 5-18 times less potent than propranolol in blocking beta-adrenoceptors. It resembles propranolol in its non-selective blockade of beta(1)-cardiac and beta(2)-vascular and tracheal adrenoceptors and in its lack of intrinsic sympathomimetic activity.3. AH 5158 is 2-7 times less potent than phentolamine in blocking alpha-adrenoceptors. AH 5158 itself is more active on beta- than alpha-adrenoceptors.4. Blockade of noradrenaline vasopressor responses by AH 5158 in anaesthetized dogs was dose-dependent up to 1 mg/kg but no further blockade was obtained with larger doses of AH 5158. ;Self-limiting' blockade was not observed in dogs pretreated with cocaine, or in untreated dogs if the vasopressor agent was oxymetazoline instead of noradrenaline. A possible cause of ;self-limiting' blockade is discussed.5. In doses higher than those required for either alpha- or beta-adrenoceptor blockade, AH 5158 produced effects on cardiac muscle that are attributable to membrane-stabilizing activity. This was manifested as a negative inotropic action in spinal dogs and in guinea-pig left atrial strips, as a negative chronotropic action in syrosingopine pre-treated dogs, and as an increase in the effective refractory period of guinea-pig left atrial strips. AH 5158 was 3-11 times less potent than propranolol in these tests.6. In open chest dogs AH 5158 resembled propranolol in reducing cardiac output, rate and contractility, effects which are attributable to beta-adrenoceptor blockade. The drug differed from propranolol in decreasing rather than increasing total peripheral resistance and in causing larger decreases in arterial blood pressure at equipotent beta-adrenoceptor blocking doses. These differences are attributable to the alpha-adrenoceptor blocking actions of AH 5158.7. In anaesthetized dogs, intravenously administered AH 5158 antagonized both catecholamine and ouabain-induced arrhythmias. Orally administered AH 5158 lowered systolic arterial pressure in conscious renal hypertensive dogs.8. These results show AH 5158 to possess a novel profile of activity. Possible uses of the drug in cardiovascular disorders such as hypertension, angina pectoris and cardiac arrhythmias are discussed.

Salbutamol: a new, selective beta-adrenoceptive receptor stimulant.

1. Salbutamol is a beta-adrenoceptive receptor stimulant. Its pharmacological actions are reduced or abolished by beta-receptor antagonists.2. In anaesthetized animals, salbutamol, given intravenously, was slightly less active than isoprenaline in preventing spasm of bronchial smooth muscle but was considerably less active as a cardiac stimulant and vasodepressor substance. Its duration of action was about 2 to 3 times that of isoprenaline.3. Salbutamol given by mouth or aerosol to conscious guinea-pigs, greatly diminished bronchospasm caused by inhalation of acetylcholine. By mouth, salbutamol was more active and had a longer duration than isoprenaline or orciprenaline without affecting heart rate. By aerosol, salbutamol was approximately 10 times as active as isoprenaline and 100 times as active as orciprenaline. Its duration of action was much longer than that of isoprenaline or orciprenaline. Only isoprenaline produced an increase in heart rate by the aerosol route.4. On isolated guinea-pig trachea salbutamol had about 1/10 the activity of isoprenaline, on isolated atria about 1/2000.

Comparison of the actions of U-46619, a prostaglandin H2-analogue, with those of prostaglandin H2 and thromboxane A2 on some isolated smooth muscle preparations.

1 The actions of the prostaglandin H2 (PGH2) analogue, U-46619, have been compared with those of PGH2 on thromboxane A2 (TxA2) on a range of isolated smooth muscle preparations in a superfusion cascade system. 2 U-46619 was a potent agonist on guinea-pig lung strip, dog saphenous vein and rat and rabbit aortae. In contrast, U-46619 was weak or inactive on guinea-pig ileum and fundic strip, cat trachea and dog and cat iris sphincter muscles, preparations on which either PGE2 or PGF2 alpha was the most potent agonist studied. 3 PGH2 was active on all of the preparations and displayed little selectivity. On some of the preparations, the actions of PGH2 may have been mediated indirectly by conversion to other prostanoids. 4 In contrast, TxA2 displayed the same pattern of selectivity as U-46619, being a potent agonist on the lung strip and vascular preparations but weak or inactive on the others. 5 It is suggested that U-46619 is a selective TxA2-mimetic and that it should therefore be a valuable tool in the study of the actions of TxA2.