Correlation between positive chronotropic effect and norepinephrine release induced by acetone in the rat right atrium.

The effects of acetone on contraction rate and norepinephrine (NE) release of rat right atrium were investigated. Acetone, in the concentration range 10-210 mM increased the atrial contraction rate (ACR) in a dose-dependent manner, but in concentrations exceeding 210 mM, caused a gradual reduction in the ACR from the peak. The positive chronotropic effect of acetone on ACR can be reduced by adding 0.002 mM of propranolol (a non-selective beta 1- and beta 2-adrenergic receptor blocker), or by pretreating the rat with reserpine (an NE depleter) (5 mg/kg body weight, i.p., 24 h prior to experiment). These findings lead to the hypothesis that the increase in ACR induced by acetone may be partly due to an increase in NE release from sympathetic nerve endings in the atrium by acetone. To test this speculative hypothesis, the effect of acetone on [14C]NE + cold NE release from the right atrium, preinoculated with 0.25 microM of [14C]NE + cold NE for 20 min at 35 degrees C, was carried out using a simple technique developed in our laboratory. The acetone (10-1000 mM)-stimulated peak of NE release (pmol/g atrium/min) and summed NE release (pmol/g atrium/5 min) in excess of the basal spontaneous NE release were analyzed. The dose-response curves of the effect of 10-210 mM of acetone on the ACR and the peak of NE release were parallel. However, acetone concentrations above 210 mM caused a gradual drop of the curve of the ACR from its maximum while still enhancing the curve of the NE release. This continued gradually up to an acetone concentration of 500 mM. The atrial NE release reached a maximum at acetone concentrations between 500 and 1000 mM. This indicates that the increase in ACR caused by acetone in the range 10-210 mM may be partly due to an increase in NE release from the sympathetic nerve terminals in the atrium. However, an acetone concentration above 210 mM may be too toxic to the muscle fibers and/or the pacemaker and/or the conducting system, and so even though the NE release is still increasing, it can not enhance the ACR any further. It is generally speculated that the release of NE from the sympathetic nerve endings in the heart induced by the great number of organic solvents and general anesthetics contributes to the cause of tachycardia, arrhythmia and fibrillation of the heart.(ABSTRACT TRUNCATED AT 400 WORDS)

Antagonism of the effect of isoprenaline on heart rate by pilocarpine.

1 The interaction of pilocarpine and isoprenaline on heart rate was investigated in the spontaneously beating, right isolated atrium of the rat.2 The log dose-effect curve of isoprenaline, measured in the presence of various concentrations of pilocarpine, was not modified when the concentration of the latter did not exceed 10(-6)M even though significant slowing of the heart had occurred. At concentrations higher than 10(-6)M a rapid but graded shift to the right of isoprenaline response curves occurred so that at pilocarpine 10(-5)M the pD(2) of isoprenaline was reduced from 11 to 3.3; cocaine slightly reduced this antagonism.3 It is concluded that pilocarpine antagonizes isoprenaline by some mechanism which is not of the simple competitive type.

Mechanism of catecholamine antagonism in rat heart produced by pilocarpine and related drugs.

1 High concentrations of pilocarpine and methacholine consistently lowered the potencies of a series of adrenoceptor agonists as shown by displacement of complete cumulative dose-effect curves for their positive chronotropic action on rat isolated atria. The order of potency of the agonists was characteristic of beta-adrenoceptor activation and this was converted to the type which characterizes alpha-adrenoceptor activation when pilocarpine was present.2 Propranolol effectively blocked the adrenoceptor agonists in the presence of pilocarpine and phentolamine abolished the antagonistic actions of pilocarpine. Atropine, which by itself did not affect the action of the adrenoceptor agonists, abolished both the bradycardia and antagonism produced by pilocarpine.3 It is concluded that pilocarpine antagonizes adrenoceptor agonists by muscarinic cholinoceptor activation without involving classical adrenoceptors.

Inotropic actions of lignocaine and phenytoin.

1. The inotropic effects of two antiarrhythmic drugs, lignocaine and phenytoin, were studied in electrically driven isolated rabbit atrial preparations. The time-effect relationship of each drug was investigated with different concentrations and frequencies of stimulation.2. The effects of time of exposure, drug concentration and heart rate on the development of beat alterations (cessation of beat, skipped beat, alternating variation of force of contraction and extrasystole) were also studied.3. When the chronotropic effects of both drugs were prevented, the inotropic effects were positive or negative depending on the concentration of drug, time of exposure and frequency of stimulation.4. At concentrations higher than those obtained in the blood of man on maintenance doses, alteration of the beat occurred but was consistent with the peak blood concentrations immediately after the injection of standard clinical doses. The time of onset of beat alteration shortened when either drug concentration or frequency of stimulation was increased.5. The beat alteration produced by antiarrhythmic drugs can account for various adverse effects associated with their clinical use. These effects include transient ventricular tachycardia and extrasystole during and shortly after injection of drug, ventricular tachycardia, ventricular fibrillation and cardiac arrest due either to excessive dose or to persistent tachyarrhythmia if the dose is not excessive.

Pharmacological significance of biogenic amines in the lungs: 5-hydroxytryptamine.

1. A technique for the spectrofluorometric analysis of 5-hydroxytryptamine, histamine, noradrenaline and dopamine in a single lung sample has been developed. The method is a combination of the extraction procedure of Shore & Olin (1958), plus the modification introduced by Hogans (1967) for the analysis of three of the four amines. The fourth amine, histamine, was analysed by the method of Shore, Burkhalter & Cohn (1959), which was combined with the analysis of the other three amines. The combined procedure consisted principally of disintegrating the lung tissue in butanol and subsequent separation of amines for measurement of fluorescence, either directly, as for 5-hydroxytryptamine, or after formation of fluorophores, as for histamine, noradrenaline and dopamine. It has been possible to analyse all four amines from a sample of the lung in which the bronchopulmonary responses have been investigated.2. The concentration of 5-hydroxytryptamine in the lung of seven species ranges from about 0.5 mug/g in the guinea-pig, dog and man to about 7 mug/g in the rabbit. The pulmonary resistance is increased after an injection of 5-hydroxytryptamine in the rat and guinea-pig.3. The guinea-pig is more sensitive to 5-hydroxytryptamine than the rat. In both animal species, the content of 5-hydroxytryptamine in the lung is elevated by administration of either 5-hydroxytryptamine or 5-hydroxytryptophan. In the rat, the administration of p-chlorophenylalanine reduces the content of 5-hydroxytryptamine in the brain but not in the lung.4. It is suggested that the 5-hydroxytryptamine contained in the lung tissue is stored mainly in the platelets and in the mast cells.

Pharmacological significance of biogenic amines in the lungs: noradrenaline and dopamine.

1. The noradrenaline concentration in the lung was less than 0.5 mug/g in eight animal species.2. In the cat, dog, rabbit and goat, tyramine produced a fall in pulmonary resistance, which was reduced by the administration of either reserpine or cocaine. Although an infusion of noradrenaline increased the content of this amine in the lung of the cat, previously depleted by reserpine, the bronchodilator property of tyramine was not restored. The infusion of isoprenaline did not restore the response to tyramine. The role of either catecholamine in mediating the bronchomotor response to tyramine could not be ascertained.3. The concentration of dopamine was as high as 6.4 mug/g in the goat lung and less than 0.5 mug/g in the lungs of the cat, rabbit, dog, rat, mouse, guinea-pig and man. Dopamine, injected intravenously into the cat, dog, rabbit and goat, produced a slight rise in pulmonary resistance. This increase was blocked by tolazoline, indicating that the response was mediated by alpha-adrenoceptors in the bronchial passages. No procedure has been observed to influence the dopamine content of the lung. The release of dopamine cannot, however, be excluded until the blood in the bronchial veins has been analysed.

Pharmacological significance of biogenic amines in the lungs: histamine.

1. Eight animal species were investigated for the histamine content of the lung and can be divided into two groups: the low-level group, ranging from 2 to 7 mug/g, consisting of the mouse, rat, guinea-pig and rabbit; and the high-level group, ranging from 12 to 35 mug/g, consisting of the cat, dog, goat and human. In two species of the high-level group (cat and dog) the amount of histamine that elicited an increase in pulmonary resistance was one-fifth to one-tenth of the dose that elicited an increase in species of the low-level group (rat and rabbit). There is an inverse relationship between the content of histamine and the dose of histamine that produces a 25% increase in pulmonary resistance.2. Anaphylaxis increases the histamine content of the lung of the rabbit but not of the lung of the guinea-pig. In both species, anaphylaxis is accompanied by an elevation of the concentration of 5-hydroxytryptamine in the lung, indicating the trapping of platelets in the lung.3. The development of severe parasitaemia in the mouse inoculated with Plasmodium berghei is accompanied by an elevation of the histamine content of the lung. This increase appears to be part of the response of the lung to parasitaemia.