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.

Effects of fluorocarbons, chlorinated solvents, and inosine on the cardiopulmonary system.

The effects of fluorocarbons and chlorinated solvents on the cardiopulmonary system are reviewed. The new information, not hitherto reported, relates to the antagonistic action of inosine, a naturally occurring nucleoside formed in the body by deamination of adenosine. The effect of inosine on methylene chloride toxicity was investigated in open chest dogs anesthetized with pentobarbital sodium. Methylene chloride (5% in air or 50,000 ppm) elicited a decrease of ventricular contractility represented by the diminished left ventricular (dp/dt)(max) and myocardial contractile force measured directly with a Walton-Brodie strain gauge arch. Coronary blood flow decreased slightly after exposure to methylene chloride. Arterial blood pressure and heart rate did not change. The negative inotropic effect of methylene chloride was reversed or prevented to a substantial extent by intravenous infusion of inosine (5 mg/kg-min). The effect of the latter compound was also characterized by significant coronary vasodilation. It was shown by the experiments that the cardiostimulatory action of inosine was associated with improved hypoxic adaptability of the coronary blood vessels. In contrast, the effect of catecholamines (epinephrine and isoproterenol) was not accompanied by such a beneficial coronary vascular effect. On the basis of these results, the conclusion has been arrived at that inosine might be recommended as a useful antidote in methylene chloride poisoning in particular, and of poisoning by chlorinated solvents and fluorocarbons in general.

Cardiopulmonary effects of progestational agents in emphysematous rats.

PIP: Experiments were designed to investigate whether induced emphysema would lead to pulmonary hypertension and cor pulmonale. Also additional proof was sought on the effect of progestational hormones in preventing the occurrence of emphysema in rats. Measurements of mechanical properties of the lung, of pulmonary circulation and cardiac function of the emphysematous rats were made. To some a solution of .5 ml/100 gm body weight of phytohemagglutinin was injected intratrocheally during the first week and 1 mg/100 gm body weight during the second week. Subcutaneous injections were given daily for 6 weeks. 1 group received .1 ml of .5% methocel. Another group received 5 mg/kg progesterone and a third group, .1 mg/kg medroxyprogesterone. Only about 50% of the rats survived all of these procedures. After 6 weeks the special measurements were made. The functional residual capacity of the group receiving phytohemagglutinin was increased to 4.3 ml compared with 3 ml for control rats with saline injections only and 2.8 ml for the rats with tracheal constriciton only. Also histologic examination of the lungs showed a greater percentage of air spaces in rats having had the combined procedure. This histological change was interpreted as pulmonary emphysema. The protective action of progesterone was based on normal values for functional capactiy (3 ml) and normal values for percentage of air spaces in histologic section of the lung. Both the progesterone and medroxyprogesterone prevented the development of the abnormal functional changes of emphysema. Blood changes determined by catheterization of the carotid artery support the occurrence of lesions which were interpreted as emphysema after the tracheal procedures. Tracheal obstruction was considered responsible for the abnormal values of gas tension in the arterial blood. The emphysematous rats showed higher blood pressures than those without emphysema but values for those with only tracheal obstruction were also higher than controls. The high levels of pulmonary arterial pressure were associated with hypoxia and relieved by inhalation of high oxygen. Cardiac output was diminished in those with as well as those without emphysema. This reduction may be an early functional manisfestation prior to cardiac enlargement and cor pulmonale. Rats with tracheal constriction had elevated pulmonary vascular resistance. The only electrocardiographic changes in emphysematous rats were increased height of P waves. Results indicate that the antiemphysematous effect of progesterone is not exerted on the cardiopulmonary system. The reactivity of the bronchial musculature is not affected. The administration of sympathomimetic bronchodilators does not prevent the appearance of emphysema.^ieng

The Bezold-Jarisch reflex. A historical perspective of cardiopulmonary reflexes.

The Bezold-Jarisch reflex is an eponym for a triad of responses (apnea, bradycardia, and hypotension) following intravenous injection of veratrum alkaloids in experimental animals. The observation was first reported in 1867 by von Bezold and Hirt, and confirmed in 1938-1940 by Jarisch. The triad depends on intact vagi and is mediated through cranial nervous medullary centers controlling respiration, heart rate, and vasomotor tone. The respiratory effects are mediated through pulmonary vagal afferents and the bradycardia and vasodepression through cardiac vagal afferents. The veratrum alkaloids activate all known receptors in the carotid-aortic and cardiopulmonary areas. The cardiopulmonary receptors (baroreceptors, cough receptors, and parenchymal stretch receptors) also respond to other chemical substances: nicotine, capsaicin, venom, antihistaminics, halogenated anesthetics, diguanides, and serotonin (5-hydroxytryptamine). Derivatives of last-mentioned amine activate Type 1, 2, or 3 receptors and have potential therapeutic use. Since several types of cardiopulmonary receptors participate in the Bezold-Jarisch reflex, it has been difficult to develop a blockade to one type of receptor for therapeutic use (cough, bronchospasm, pulmonary hypertension, or coronary vasospasm). Axon reflexes influence pulmonary blood vessels, bronchial blood vessels, and bronchial smooth muscles. These intrapulmonary reflexes need further study as to how they relate to the Bezold-Jarisch reflex in health and disease. The cardiopulmonary and carotid-aortic reflexes can serve as defense mechanisms against chemical hazards that are likely to be inhaled in the workplace and in the environment.

Five fluorocarbons for administration of aerosol bronchodilators.

The exposure of the upper respiratory tract to aerosol propellants produces apnea, bradycardia, and biphasic fall and rise in aortic blood pressure in anesthetized dogs. This response represents the irritation of sensory receptors in the nasal and nasopharyngeal mucosa and is not elicited with aerosol propellants administered via a tracheal cannula bypassing the upper respiratory tract. When this is done, a different reflex is elicited, consisting of tachycardia that is mediated by the thoracic sympathetic nerves. There is either bronchodilation or bronchoconstriction depending on the type of propellant. The three propellants (11, 12, and 114) widely used in aerosols, when inspired in large doses, elicit both bradycardia and tachycardia and induce bronchoconstriction or bronchodilation. Two additional propellants (115 and C318), which are not ordinarily used to dispense bronchodilator drugs, do not elicit any change in heart rate and produce only bronchodilation. It is suggested that these two propellants merit further investigation and may replace the three widely used ones if these prove the use and abuse of aerosols.

Pentoxifylline: a new drug for the treatment of intermittent claudication. Mechanism of action, pharmacokinetics, clinical efficacy and adverse effects.

During the past decade, the effectiveness of peripheral vasodilator drugs in the treatment of chronic occlusive arterial disease has been questioned. Pentoxifylline is a hemorheologic agent with primary actions that include increasing erythrocyte flexibility, reducing blood viscosity and increasing microcirculatory flow and tissue perfusion. The result is improved supply of oxygen to ischemic muscles of the limbs. In several double-blind studies, pentoxifylline increased walking distance of patients with intermittent claudication in comparison to placebo or vasodilators. Like other methylxanthines, pentoxifylline is well absorbed in the gastrointestinal tract, almost completely metabolized in the body and excreted in the urine. The most significant difference in its pharmacokinetics is that, unlike other methylxanthines, it is bound to the erythrocytic membrane where it is initially metabolized. Although pentoxifylline has been shown to be effective in the treatment of intermittent claudication, additional research is needed to determine its use as adjunctive therapy in patients with concurrent coronary or cerebrovascular disease.

Toxicity of aerosol propellants in the respiratory and circulatory systems. IX. Summary of the most toxic: trichlorofluormethane (FC 11).

The acute inhalational toxicity of trichlorofluoromethane (FC 11) is summarized in this paper. There is a striking similarity in threshold concentrations between the mouse and the rat on one hand and the dog and the monkey on the other. The mouse and rat require lower levels of concentration, i.e. (1 to 2.5%) to influence the respiratory system but higher levels (2.5 to 5.0%) to affect the circulatory system. The respiratory systems of the monkey and the dog have about the same sensitivity as those of the other two species in that the threshold level of FC 11 is 2.5 to 5%. The circulatory systems of the monkey and the dog can be influenced by a concentration of 0.5%.

Toxicity of aerosol propellants in the respiratory and circularoty systems. X. Proposed classification.

The 15 propellants are grouped into four classes on the basis of results of investigation reported in this series of publications. Class 1 low-pressure propellants of high toxicity; Class 2 low-pressure propellants of intermediate toxicity; Class 3 high-pressure propellants of intermediate toxicity; and Class 4 high-pressure propellants of low toxicity.

Toxicity of aerosol propellants in the respiratory and circulatory systems. VI. Influence of cardiac and pulmonary vascular lesions in the rat.

Three propellants were selected for investigation in rats because of their non-uniform effect in mice and monkeys. Trichlorofluoromethane (FC 11) provoked arrhythmia in all three animal species, dichlorodifluoromethane (FC 12) in monkeys and rats but not in mice, and difluoroethane (FC 152a) only in rats. In rats the alterations in heart rate and electrocardiographic pattern during inhalation of these propellants are largely brought about by release of catecholamines from the adrenal gland, because adrenalectomy or prior injection of beta-adrenergic blocking drugs decreased the incidence of cardiac effects. Rats that have pulmonary vascular thrombosis or cardiac necrosis become more sensitive to proarrhythmic activity of these propellants.

Toxicity of aerosol propellants in the respiratory and circulatory systems. VII. Influence of pulmonary emphysema and anesthesia in the rat.

Experimental induction of pulmonary emphysema caused an increase in sensitivity of the rat to toxicity from inhalation of propellants. The emphysematous rat showed an exaggerated reduction in pulmonary compliance in response to inhalation of trichlorofluoromethane (FC 11). In emphysematous and non emphysematous rats without anesthesia the inhalation of FC 11 caused tachycardia, arrhythmias and other abnormalities in the electrocardiogram. The tachycardiac response was eliminated by induction of barbiturate anesthesia, which increased the sensitivity of the heart to occurrence of abnormalities in the electrocardiogram in response to inhalation of FC 11 as well as of dichlorodifluoromethane (FC 12) and difluoroethane (FC 152a). The acceleration in heart rate in response to inhalation of FC 11, hypoxia or hypercapnea was prevented by prior treatment with a beta-blocking drug.

Hemodynamic effects of aerosol propellants. II. Pulmonary circulation in the dog.

The inhalation of trichlorofluoromethane (FC11), dichlorotetrafluoroethane (FC114) and dichlorodifluoromethane (FC12) caused a reduction in mean aortic blood pressure but only FC11 and FC114 caused a reduction in mean pulmonary arterial pressure. The primary cause of the fall is a decrease in pulmonary blood flow. When blood flow to a lobe is kept constant and the adrenergic alpha receptors are blocked by injection of phentolamine, the inhalation of FC11 caused vasodilation. In the intact circulation, the vasodilation is masked by release of catecholamines which constrict the pulmonary blood vessels.

Hemodynamic effects of aerosol propellants. I. Cardiac depression in the dog.

The inhalation of fluorocarbons caused a depression of myocardial contractility, aortic hypotension, a decrease in cardiac output and an increase in pulmonary vascular resistance. The minimal concentrations that elicited these changes are as follows: 1% trichlorofluoromethane (FC11); 2.5% dichlorotetrafluoroethane (FC114); and 10% dichlorodifluoromethane (FC12). Inhalation of 20% octafluorocyclobutane (FC318) and difluoroethane (FC152a) did not influence these hemodynamic parameters. As in previous comparisons, the most widely used aerosol propellants are potentially cardiotoxic in the anesthetized dog.

Toxicity of aerosol propellants in the respiratory and circulatory systems. VIII. Respiration and circulation in primates.

The low-pressure propellants influence predominantly the circulation, whereas the high pressure propellants affect the respiration in anesthetized monkeys. There are four groups according to the level of toxicity: Class 1, low-pressure propellants of high toxicity that cause tachycardia and hypotension; Class 2, low-pressure propellants of intermediate toxicity that influence either circulation or respiration or both; Class 3, high-pressure propellants of intermediate toxicity that cause bronchoconstriction; and Class 4, high-pressure propellants of low toxicity that do not influence respiration or circulation even when inhaled at levels of up to 20 percent concentration.

Hemodynamic effects of aerosol propellants. III. Vascular resistance in the canine hind limb.

The question as to whether or not the hypotension observed as part of the effect of tricholorofluoromethane (FC11), dichlorofluoromethane (FC 12), dichlorotetrafluoroethane (FC 114) and methyl chloroform was due to a vasodepressor component of action, in addition to the previously documented depression in myocardial contractile force, was answered by testing these agents in an anesthetized dog preparation in which one hind limb was perfused at constant flow through the femoral artery. 5% FC 11, 20% FC 12 and 20% FC 114 decreased vascular resistance of the perfused limb, as reflected by decrease in mean femoral arterial perfusion pressure, in vagotomized but not in intact preparations. Methyl chloroform decreased vascular resistance even in intact preparations. Spontaneous blood flow in the intact femoral artery decreased following FC 11 and methyl chloroform administration in vagotomized preparations and was associated with marked decrease in mean aortic pressure. Blockade of alpha and beta adrenergic receptors with phentolamine and propranolol in the vagotomized preparation had no modifying influence of the effect of FC 11 and methyl chloroform. It may be concluded from this study that FC 11, FC 12 and FC 114 exhibit a vasodepressor activity on skeletal muscle vascular bed which is readily overcome by the hypotension-induced activation of the sympathetic system but which becomes evident when reflex activity is prevented by vagotomy. Methly choloroform exhibits a vasodepressor effect even in intact preparations probably because of concomitant depression of reflex activity through its general anesthetic action. A decrease in spontaneous femoral blood flow following FC 11 and methyl chloroform administration is referable to the accompanying severe hypotension notwithstanding concomitant vascular relaxation. Neither FC 11 nor methly chloroform directly liberate catecholamines from their sites of storage.

Pharmacology of pentoxifylline, a hemorheologic agent for the treatment of intermittent claudication.

Physiological and pathophysiological aspects of systemic and cardiac haemodynamics are reviewed with appraisal of Carl J. Wiggers merits and contributions to the research and developments in this field and his early recognition of the significance of the flow properties of blood in impaired circulation. Pharmacological agents involved in treatment of peripheral vascular diseases are discussed with special regard to the haemorheologically active xanthine derivative pentoxifylline. The profile of pentoxifylline as it emerges from experimental pharmacological and clinical studies is presented paying special attention to the haemorheological properties of the drug. Pharmacokinetic features of pentoxifylline are surveyed touching absorption, blood levels, metabolism and excretion aspects. Basing on the available data pentoxifylline is regarded as a promising drug in the treatment of circulatory ischemic disorders, especially in intermittent claudication.