© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
A historic overview of the paper
An excitatory nociceptive cardiac reflex elicited by bradykinin and potentiated by prostaglandins and myocardial ischaemia (1976)
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KEYWORDS Autonomic nervous system; Ischemia; Vasoactive agents; Vasoconstriction/dilation
The work described in this paper has a long and complex history. Its origin can be traced back to 1964 when, after receiving my M.D. degree, I was offered by Dr. John Vane (whom I had met in Poland in 1963) a postdoctoral fellowship in his laboratory in the Deptartment of Pharmacology, Royal College of Surgeons of England in London. My work there made use of the original blood-bathed organ (BBO) bioassay technique of Vane [1] to study the release of catecholamines by histamine and by peptides, including bradykinin. This was my first introduction into the pharmacology of bradykinin, which turned out to be of great value for its subsequent use in studies of cardiac reflexes.
My interest in cardiac reflexes had been stimulated by studies of the adrenergic response associated with acute myocardial infarction in dogs, which were carried out in collaboration with Dr. L. Ceremuzynski during 1967–1970 in the Medical Research Centre of the Polish Academy of Sciences in Warsaw. This research, which again made use of the BBO technique of Vane for a continuous assessment of catecholamine release induced by acute coronary ligation, had been made possible by a generous gift of essential parts of equipment that I received from John Vane for setting up this technique after returning to my laboratory in Poland early in 1965.
Studies into the mechanisms of sympatho–adrenal activation associated with acute myocardial infarction clearly indicated that the release of catecholamines from the adrenal medulla and from postganglionic sympathetic nerve terminals which follows an acute coronary ligation [2] results mainly from a reflex stimulation originating from cardiac receptors located within or at the borderline area of the ischaemic myocardium. Findings of this study also indicated that the afferent pathway for the reflex discharge of catecholamines from the adrenal medulla may be either through vagal or sympathetic cardiac nerves, or via both these pathways [3].
That myocardial ischaemia excited cardiac receptors subserved by either vagal or spinal sympathetic afferent fibres had been already well established. However, the reflexogenic function of cardiac sympathetic afferents, unlike that of vagal afferents, had not been at that time generally accepted. This was because excitation of these afferents either by myocardial ischaemia, or by electrical or chemical stimulation with intracoronary injection of veratridine could not be shown to produce reflex excitatory cardiovascular effects when the vagus nerves were intact (for Refs. see the original paper and Ref. [4]). It was, therefore, a great challenge to attempt to discover whether cardiac sympathetic afferents, like their vagal counterparts, could initiate reflex circulatory changes in animals with intact cardiac innervation.
While still in Warsaw, I designed a project with an aim to assess whether epicardial application of some ischaemic metabolites (e.g., lactate) can induce reflex blood pressure responses in cats; it was a desperate attempt and the project had to be abandoned, because with only a kymograph and a mercury manometer at my disposal it was an impossible task to achieve. It was not until 3 years later, in 1974, when I was again invited by Dr. John Vane to join his research group, this time in the Wellcome Research Laboratories in Beckenham, that I was able to undertake this project.
During the late 1960s and early 1970s, while I was preoccupied with studies of adrenergic mechanisms in myocardial infarction and made futile attempts to induce nociceptive cardiac reflexes, John Vane and his coworkers, including Sergio Ferreira, had been conducting pioneering research with prostaglandins (PGs), especially their role in inflammation and nociception. It was most fortunate, therefore, that I had a chance to collaborate with Sergio and John and benefit from their experience in investigating effects of bradykinin and PGs.
An original experimental approach, involving both epicardial and intracoronary routes of drug administration, combined with the use of naturally occurring chemical substances, like bradykinin and PGs, to activate a nociceptive cardiac reflex could be the main reason for successfully interesting other researchers in the results of this study. By applying bradykinin either to the surface of the left ventricle or by intracoronary injection, we were able to separate neurally-mediated from vasoactive effects of bradykinin. Furthermore, by comparing cardiovascular responses produced by epicardial application of either bradykinin or nicotine (Fig. 2 from the original paper), we were able to demonstrate for the first time in the long history of cardiac chemoreflex studies that an excitatory cardiovascular reflex can be evoked by chemical activation of cardiac sympathetic afferents in animals with intact vagal nerves. Finally, studies of the effects of PGs, myocardial ischaemia and indomethacin on bradykinin-induced reflex effects, provided the basis for a hypothesis that bradykinin and PG released by the ischaemic heart act in concert to stimulate the sensory sympathetic nerves that signal the pain of myocardial ischaemia, and the sympathetic reflex mechanisms responsible for the cardiovascular events accompanying anginal attacks.
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- Vane J.R. The use of isolated organs for detecting active substances in the circulating blood. Br J Pharmacol (1964) 23:361–373.
- Staszewska-Barczak J., Ceremuzynski L. The continuous estimation of catecholamine release in the early stages of myocardial infarction in the dog. Clin Sci (1986) 34:531–539.
- Staszewska-Barczak J. The reflex stimulation of catecholamine secretion during the acute stage of myocardial infarction in the dog. Clin Sci (1971) 41:419–439.[Web of Science][Medline]
- Coleridge J.C.G., Coleridge H.M. Handbook of physiology, Section 2: The cardiovascular system. Berne R.M., Sperelakis N., Geiger S.B., eds. (1979) Vol. 1. Bethesda: American Physiological Society. 653–676. The heart.
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