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Mechanisms of pain in angina pectoris—A critical review of the adenosine hypothesis

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Summary

Clinical characteristics: Angina pectoris represents a visceral pain caused by reversible myocardial ischemia. The majority of ischemic attacks are symptomless. When pain is manifested, it appears late during the ischemic event. The pain is complex in its quality and bears little relation to the region of myocardial ischemia. Pain shows a sensitive dependence on initial conditions suggesting a mechanism with deterministic chaotic dynamics for the association between myocardial ischemia and pain.Neurophysiological substrate: Ganglia are present within the heart, particularly in epicardial fat. The blood supply of intrinsic cardiac ganglia arises primarily from branches of the proximal coronary arteries. Both afferent and efferent neurons within the intrinsic cardiac nervous system exist, while the majority of neurons in that location may be local circuit neurons. Integration takes place not only in the intrinsic cardiac nervous system, but also in mediastinal, middle cervical, and stellate ganglia. Cardiac afferent receptors are also connected to cell bodies in dorsal root and nodose ganglia, as well as intrathoracic ganglia. Myocardial regions have no spatial representation in these ganglia. Adenosine, among a number of substances, can modulate the activity generated by cardiac afferent nerve endings and intrinsic cardiac neurons. Such effects appear to be exerted at A1 receptors.Adenosine as a pain messenger: During myocardial ischemia adenosine is released in large quantities into the interstitial space. The endothelium takes up the major amount of adenosine. Thus only small increments of adenosine are detected in the blood-stream. Given as an intravenous bolus to healthy volunteers or to patients with ischemic heart disease and angina pectoris, adenosine provokes angina pectorislike pain, which is similar to habitual angina pectoris with regard to quality and location. Pain is provoked in the absence of ECG signs of ischemia. Patients with asymptomatic myocardial ischemia are less sensitive to adenosine, whereas patients with Syndrome X are more sensitive with respect to adenosine-provoked pain. When adenosine is given intraarterially, including into the coronary arteries, pain is provoked in the corresponding vascular bed. Adenosine-provoked pain and ischemic pain are counteracted by previous administration of the adenosine receptor antagonist theophylline. Adenosine-provoked pain is enhanced by nicotine or substance P.Conclusion: Angina pectoris displays complex characteristics at both the clinical and neural substrate levels. Adenosine is the only candidate substance identified that fulfills criteria for a messenger between myocardial ischemia and the genesis of pain. It is concluded that ischemically released adenosine causes specific spatiotemporal neural summation of afferent neuronal activity, which elicits an alarm reaction with manifestation of pain.

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  1. Department of Medicine, Huddinge University Hospital, S-141 86, Huddinge, Sweden

    Christer Sylvén MD, PhD (FACC, FESC)

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  1. Christer Sylvén MD, PhD
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Sylvén, C. Mechanisms of pain in angina pectoris—A critical review of the adenosine hypothesis. Cardiovasc Drug Ther 7, 745–759 (1993). https://doi.org/10.1007/BF00878926

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  • DOI: https://doi.org/10.1007/BF00878926

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