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.

Cardiovascular disease and occupational exposure to environmental tobacco smoke.

Results of chemical analysis, animal experiments, and human studies are reviewed, criticized, and found not to support claims of an association between workers exposed to environmental tobacco smoke (ETS) and occupational coronary heart disease. This review also recommends refinement of the use of dose surrogates, as presently practiced by the Occupational Safety and Health Administration (OSHA), for regulating indoor emissions from combustion engines, coal furnaces, tobacco leaf processing, rayon viscose manufacturing, and rubber curing. The work standards OSHA uses for regulation of these complex mixtures could also be used in evaluating ETS and relate to the following constituents of ETS: nicotine, carbon monoxide, benzo[a]pyrene, and carbon disulfide. The data indicate that the levels of these substances potentially arising from ETS are many orders of magnitude below their respective PELs. Thus, based on the standards for exposure surrogates for other complex mixtures, the potential worker exposure from ETS does not require further regulation by OSHA, based on cardiovascular disease.

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.

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.

Inosine : a naturally occurring cardiotonic agent.

For many years, Inosine was considered to be a simple metabolite of adenosine which was devoid of any cardiovascular effects. This theoretical ineffectiveness can be explained in the light of recent studies by the use of inadequate doses. In fact, higher doses of inosine, a non-toxic nucleoside, have demonstrated, experimentally, a cardiovascular activity and the pharmacological profile of this naturally occurring substance has been defined. Like adenosine, inosine is a potent coronary vasodilator. The vasodilatation induced by inosine is only partly due to increased metabolic demands. Inosine has a direct action on coronary artery relaxation independent of the inotropic effect. It alters the balance between oxygen supply and demand which is reflected by an intramyocardial redistribution of oxygen in favour of the sub-endocardial zones. Inosine acts on the coronary circulation like a "regulator of myocardial nutrition", unlike adenosine, which can be thought of as a "coronary vasoregulator". This dissociation between the two nucleosides is apparently due to different vascular sites of action. The positive inotropic action of inosine, which has been demonstrated in both healthy and pathological myocardium in all of the experimental animal species studied, is not due to stimulation of the cardiac beta-adrenergic receptors, as beta-blockers do not antagonize the positive inotropic effect of inosine. This increase in myocardial contractile dynamics is evident in infarcted as well as healthy areas of myocardium. The inotropic and coronary vasodilator effects of inosine are not associated with any modification of the chronotropic function. Inosine is not arrhythmogenic, even at high doses. Furthermore, it does not affect atrioventricular conduction. It has been demonstrated that inosine is capable of antagonizing ouabain induced arrhythmias. Various clinical studies confirm the positive inotropic action of inosine, without any alteration in the post-load, the pre-load or the heart rate. The positive inotropic action of inosine can therefore be considered to be selective. Together with these haemodynamic effects, it has been shown that the addition of inosine to cardioplegic solutions improves the functional recovery of the myocardium, by increasing the quantity of energy-rich phosphates. Similar beneficial results have been obtained in renal transplantation, both experimentally and in clinical studies. The mechanism of action of inosine remains unknown. Are the haemodynamic effects of this compound due to its metabolic effects? Are there specific myocardial purinergic receptors? (ABSTRACT TRUNCATED AT 400 WORDS)

Peripheral vasodilators versus pentoxifylline for the treatment of intermittent claudication.

It should be recalled that the seven-center study conducted in the United States was initiated at a time when American physicians had recognized that past attempts to prove efficacy of peripheral vasodilators in treadmill testing had failed. The positive results derived from pentoxifylline treatment are significant because, for the first time, treadmill testing can prove the effectiveness of a hemorheologic drug, such as pentoxifylline, in the treatment of patients with intermittent claudication. Since treadmill testing is regarded as the most objective measurement of therapeutic success in claudicant patients, the positive results can assure us that hemorheologic drugs increasing erythrocyte flexibility are highly desired in treating peripheral vascular insufficiency, such as intermittent claudication.

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.

[Pharmacoloby of the bronchomotor tonus during anesthesia]. / Pharmacologie du tonus bronchomoteur au cours de l'anesthésie.

In a patient under general anesthesia, the occurrence of bronchospasm can be readily treated provided the cause is diagnosed early. The corrective drugs to dilate are readily available: atropine, epinephrine and theophylline. In the choice of preanesthetics, anesthetics and adjuvants, it is important to remember that there are differences in the bronchomotor effects; most curareform drugs constrict except pancuronium; most inhalational anesthetics dilate in contrast to intravenous anesthetics. In the event that bronchospasm cannot be re relieved by drugs, intubation and assisted breating can be applied to maintain adequate gas exchange in the alveoli.