Comparative chronotropic activity of β‐adrenoceptive antagonists
TL;DR: Consideration of chemical structure and physico‐chemical properties did not explain the differences between the agonist activities of the adrenoceptive antagonists.
Abstract: 1. Chronotropic dose-response curves (non-cumulative) for β-adrenoceptive antagonists were constructed from results in rats anaesthetized with pentobarbitone and depleted of catecholamines by pre-treatment with syrosingopine.
2. Depletion of catecholamines lowered resting heart rate and reduced the threshold to the chronotropic action of isoprenaline by about 50%. Eight β-adrenoceptive antagonists produced a dose-dependent chronotropic response but the maximum response was in all cases smaller than that obtained with isoprenaline. The order of activity was dichloroisoprenaline>LB 46>practolol>INPEA>oxprenolol>pronethalol>alprenolol>I.C.I. 45,763 (Ko 592). Propranolol and sotalol were without significant activity. The duration of the chronotropic response to the antagonists was more prolonged than that to isoprenaline. Propranolol caused a parallel shift to the right of the dose-response curves for the agonist effects of the antagonists.
3. Estimation of β-adrenoceptor blocking activity in anaesthetized cats gave an order of activity dissimilar to that found for maximum agonist responses: LB 46 > oxprenolol > alprenolol > propranolol > I.C.I. 45,763 > practolol > dichloroisoprenaline > sotalol > INPEA > pronethalol.
4. Consideration of chemical structure and physico-chemical properties did not explain the differences between the agonist activities of the adrenoceptive antagonists.
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TL;DR: Of 656 asthmatic patients referred specifically for allergy assessments, 544 gave positive immediate skin prick tests to at least one of 22 common allergens used routinely, and there was a highly significant association of positive history with positive prick test for all allergens studied.
Abstract: Of 656 asthmatic patients referred specifically for allergy assessments, 544 (84 percent) gave positive immediate skin prick tests to at least one of 22 common allergens used routinely. Comparison of these skin test positive patients with the 102 (16 percent) who were skin test negative showed a number of significant differences. The majority of the skin test positive patients (52 percent) were less than 10 years old at the time of onset of the asthma, whereas, of the skin test negative patients, 56 percent were aged over 30 years at the time of onset. Seventy per cent report rhinitis compared with 48 per cent of the skin test negative patients, and 29 per cent reported infantile eczema compared with 9 per cent. Symptoms attributed to house dust, pollens, and animals were noted two to three times more frequently by the skin test positive patients, while corticosteroid drugs had been used more commonly by the skin test negative patients (45 percent compared with 35 percent). No significant differences were observed with the other factors studied, namely, history of urticaria or angio-oedema, family history of "allergic" disease, and awareness of sensitivity to foods, aspirin or penicillin. Prick test reactions in the skin test positive patients were most commonly seen to house dust or the acarine mite, Dermatophagoides farinae (82 percent), followed by pollens (66 percent), animal danders (38 percent), foods (16 percent), Aspergillus fumigatus (16 percent), and other moulds (21 percent). There was a highly significant association of positive history with positive prick test for all allergens studied.
172 citations
TL;DR: Tissue-engineered scale models of the human left ventricle made of nanofibrous scaffolds that promote native-like anisotropic myocardial tissue genesis and chamber-level contractile function and the modelling of structural arrhythmia are reported.
Abstract: Laboratory studies of the heart use cell and tissue cultures to dissect heart function yet rely on animal models to measure pressure and volume dynamics. Here, we report tissue-engineered scale models of the human left ventricle, made of nanofibrous scaffolds that promote native-like anisotropic myocardial tissue genesis and chamber-level contractile function. Incorporating neonatal rat ventricular myocytes or cardiomyocytes derived from human induced pluripotent stem cells, the tissue-engineered ventricles have a diastolic chamber volume of ~500 µl (comparable to that of the native rat ventricle and approximately 1/250 the size of the human ventricle), and ejection fractions and contractile work 50–250 times smaller and 104–108 times smaller than the corresponding values for rodent and human ventricles, respectively. We also measured tissue coverage and alignment, calcium-transient propagation and pressure–volume loops in the presence or absence of test compounds. Moreover, we describe an instrumented bioreactor with ventricular-assist capabilities, and provide a proof-of-concept disease model of structural arrhythmia. The model ventricles can be evaluated with the same assays used in animal models and in clinical settings. Scale models of the human left ventricle made of tissue-engineered nanofibrous scaffolds and primary rat cardiomyocytes or human-stem-cell-derived cardiomyocytes enable the study of contractile function and the modelling of structural arrhythmia.
153 citations
TL;DR: Observations suggest that the antihypertensive action of propranolol and other β-blockers does not result from their effects on plasma renin activity.
Abstract: Long-term treatment with propranolol was shown to produce a sustained suppression of the renin-aldosterone system in hypertensive patients, despite concurrent diuretic treatment. However, the antihypertensive effect of this treatment correlated poorly with its effects on plasma renin activity and urinary aldosterone excretion. When prindolol, another beta-adrenergic blocking drug, was substituted for propranolol, blood pressure control was retained, but there was a prompt rise in plasma renin activity, which was not attributable to changes in electrolyte balance. These observations suggest that the antihypertensive action of propranolol and other beta-blockers does not result from their effects on plasma renin activity.
126 citations
Cites background from "Comparative chronotropic activity o..."
...This difference may exist because prindolol has a greater intrinsic sympathomimetic activity than the other two agents, being about half that of the reference ,-adrenergic agonist isoprenaline (Barrett and Carter, 1970), a potent stimulator of renin release (Ayers et al., 1969)....
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TL;DR: 4‐Hydroxypropranolol is a potent β‐adrenoceptor blocking drug with both intrinsic sympathomimetic activity and membrane stabilizing activity.
Abstract: 1. 4-Hydroxypropranolol, a metabolite produced after oral administration of propranolol, has been shown to be a β-adrenoceptor blocking drug. It is of similar potency to propranolol in antagonizing the effects of isoprenaline on heart rate and blood pressure in cats and against isoprenaline protection of guinea-pigs from bronchospasm. It is not cardioselective.
2. In rats depleted of catecholamine 4-hydroxypropranolol produced an increase in heart rate, suggesting that it has intrinsic sympathomimetic activity.
3. In anaesthetized dogs 4-hydroxypropranolol produced a decrease in heart rate and dP/dt and an increase in A-V conduction time at doses within the range 0·09-1·25 mg/kg. These effects are a result of β-adrenoceptor blockade. In dogs depleted of catecholamines these same doses produced an increase in heart rate and dP/dt and a decrease in A-V conduction time. These responses were antagonized by propranolol, and were due to the intrinsic sympathomimetic activity of the compound. At higher doses (5·25 and 13·25 mg/kg) a further dose dependent decrease in heart rate and dP/dt and an increase in A-V conduction time occurred. This trend was also seen in animals depleted of catecholamines. These changes represent membrane stabilizing activity of 4-hydroxypropranolol.
4. 4-Hydroxypropranolol is a potent β-adrenoceptor blocking drug with both intrinsic sympathomimetic activity and membrane stabilizing activity.
121 citations
TL;DR: It was concluded that the degree of intrinsic sympathomimetic activity possessed by an adrenergic betareceptor blocking agent is responsible for acute changes in heart rate and cardiac output, and cardioselectivity is of no importance in this respect.
Abstract: Changes in cardiac output, heart rate and arterial blood pressure were determined in 31 healthy volunteers after i. v. administration of equipotent doses of five different adrenergic betareceptor blocking drugs. Propranolol was given to seven subjects, atenolol to five, practolol to seven, pindolol to five, and (a new drug) ICI 89,406 to seven. Each drug was given in six logarithmically spaced doses. Propranolol is non-cardioselective and lacks intrinsic sympathomimetic activity. Atenolol, practolol, and ICI 89,406 are cardioselective. Practolol, pindolol, and ICI 89,406 have intrinsic sympathomimetic activity. Cardiac output was determined by impedance cardiography at supine rest. The dose-response curves for cardiac output and heart rate were of three different types: one obtained after administration of drugs without intrinsic activity, represented by propranolol and atenolol, both of which caused a maximal decrease in cardiac output of about 27%, and in heart rate of about 21%. A second type, obtained after drugs with moderate intrinsic sympathomimetic activity, represented by practolol, showed small but significant decreases in cardiac output of 12%, and in heart rate of 11 per cent. A third type, after drugs with marked intrinsic sympathomimetic activity, was represented by pindolol and ICI 89,406, which did not significantly reduce cardiac output or heart rate. The blood pressure was essentially unchanged in all subjects, even after the largest dose of any of the drugs. It was concluded that the degree of intrinsic sympathomimetic activity possessed by an adrenergic betareceptor blocking agent is responsible for acute changes in heart rate and cardiac output, and cardioselectivity is of no importance in this respect.
109 citations
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TL;DR: 1-(3949 Dichlorophenyl)-2-isopropylaminoethanol hydrochloride (20522), the dichloro analog of isoproterenol, selectively blocked some inhibitory effects of epinephrine and isoprotserenol.
Abstract: 1-(3949 Dichlorophenyl)-2-isopropylaminoethanol hydrochloride (20522), the dichloro analog of isoproterenol, selectively blocked some inhibitory effects of epinephrine and isoproterenol. The depressor action of isoproterenol and the secondary depressor action of epinephrine were inhibited by the dichloro analog which of itself had at most caused a transient fall in blood pressure. The inhibitory effect of epinephrine on isolated rabbit intestine was blocked by 20522. On rat uterus, however, 20522 failed to block epinephrine relaxation except with doses in which the analog itself caused considerable decrease in tone. The dichloro analog caused only slight decrease of intrapulmonary resistance to air flow in the ergotoxine-treated decerebrate-pithed dog, but had no action on pilocarpine bronchoconstriction. The administration of 20522 blocked the usual epinephrine or isoproterenol release of this bronchoconstriction. On isolated guinea pig tracheal chain, 20522 inhibited epinephrine and isoproterenol relaxation of pilocarpine-induced spasm. This action appeared to be competitive since large doses of epinephrine could partially overcome the blocking action of 20522. Further, 20522 was washed off only with difficulty, suggesting a rather tight drug-receptor complex. It seemed probable that 20522 was combining with certain "adrenergic inhibitory receptor sites" without itself causing much physiological effect., and yet was competing for these sites with physiologically active amines.
379 citations
TL;DR: Measurement of the initial rates of noradrenaline uptake during perfusion with various concentrations of nonradioactive (+)- and (-)-noradrenalin showed that the uptake process exhibited stereochemical specificity, which suggested that diffusion did not play any significant role in the entry of nor adrenaline into the tissue.
Abstract: The uptake of noradrenaline by the isolated perfused rat heart was studied after perfusion with a medium containing various concentrations of (+/-)-[(3)H]-noradrenaline. Simultaneous measurement of the uptake of [(3)H]-noradrenaline and of the net increase in the noradrenaline content of the heart showed that [(3)H]-noradrenaline entering the heart both increased the tissue content and exchanged with endogenous noradrenaline. A large part (about 75%) of the endogenous noradrenaline pool, however, exchanged very slowly if at all with exogenous noradrenaline. The initial rates of noradrenaline uptake satisfied Michaelis-Menten kinetics with a Km for (+/-)-noradrenaline of 6.64x10(-7) M. Further analysis of the uptake process indicated that noradrenaline entered into at least two intracellular pools at different rates. Measurement of the initial rates of noradrenaline uptake during perfusion with various concentrations of nonradioactive (+)- and (-)-noradrenaline showed that the uptake process exhibited stereochemical specificity. The Km values for (+)- and (-)-noradrenaline were 13.9x10(-7) and 2.66x10(-7) M respectively. Cocaine acted as a potent competitive inhibitor of noradrenaline uptake. This finding suggested that diffusion did not play any significant role in the entry of noradrenaline into the tissue.
267 citations
Journal Article•
TL;DR: The adrenergic receptors of mammalian hearts are functionally homologous to the adrenergic inhibitory receptors of other tissues, agreeing with the hypothesis of Ahlquist that the cardiac inotropic and chronotropic sympathetic receptors are of the beta type, receptors which subserve inhibitory functions in other organs.
Abstract: DCI, a dichloro analogue of isoproterenol (β - hydroxy - N - isopropyl - 3,4 - dichloro - phenethylamine hydrochloride; Lilly 20522), selectively blocks the cardiac positive inotropic and chronotropic effects of adrenergic stimuli in dogs with intact circulatory systems and in isolated hearts of rabbits. In dogs complete blockade of the cardiac positive inotropic effects of small doses of epinephrine, norepinephrine and isoproterenol and of supramaximal stimulation of the cardiac sympathetic nerves is obtained with cumulative doses of DCI of 3 mg/kg and greater. Depression of contractile force was frequently observed in response to sympathomimetic amines and to sympathetic nerve stimulation after administration of large doses of DCI. No inhibition of the positive inotropic effects of digoxin, theophylline or calcium chloride was observed. In dogs blockade of the positive chronotropic effects of isoproterenol but not of theophylline was obtained with DCI. In isolated rabbit hearts DCI has qualitatively the same blocking action on the effects of the amines but not on those of calcium, theophylline or ouabain. The dichloro analogues of epinephrine (DCE) and norepinephrine (DCNE) have similar blocking actions to those of DCI but are less potent. DCI, in both dog and rabbit heart, initially stimulates and with subsequent doses depresse the heart. DCNE has similar effects in the dose but in the rabbit heart it, like DCE, produces only depression. The cardiac depressant effects are not antagonized by atropine. Ephedrine, which also produces initial cardiac stimulation and subsequent depression with high doses in the dog, does not inhibit the cardiac stimulant actions of other sympathomimetic amines. The vasopressor effect of epinephrine in dogs is potentiated by DCI, that of norepinephrine is relatively unchanged, while that of cardiac sympathetic nerve stimulation is blocked, presumably due to the cardiac blockade. The vasodepressor effect of isoproterenol is completely blocked, but not reversed, by DCI in the dog. DCI, on intravenous administration, transiently lowers blood pressure, while DCNE produces a prolonged rise. DCNE does not appear to inhibit the vasopressor actions of epinephrine and norepinephrine or the vasodepressor action of isoproterenol. On the basis of the selective blockade by DCI of the excitatory effects of adrenergic stimuli on the heart and of their inhibitory effects on other organs ( e.g. , the vasodepressor effect of isoproterenol) and the lack of blockade of adrenergic vasopressor action, it is concluded that the adrenergic receptors of mammalian hearts are functionally homologous to the adrenergic inhibitory receptors of other tissues. This conclusion agrees with the hypothesis of Ahlquist that the cardiac inotropic and chronotropic sympathetic receptors are of the beta type, receptors which subserve inhibitory functions in other organs, in contrast to the alpha receptors which subserve sympathetic excitatory responses in all organs except the heart.
221 citations