Number 24, 2004
Angina Pectoris

Molecular mechanisms of cardiac ischemic pain

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Filippo Crea
Istituto di Cardiologia, Università Cattolica del Sacro Cuore, Rome, Italy
Correspondence: Filippo Crea, Istituto di Cardiologia, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy.
Tel: +39 63051166, fax: +39 63055535, e-mail: fcrea@rm.unicatt.it

Causes of angina
At the turn of the last century, Colbeck [1] proposed that ischemic cardiac pain might be related to distention of the ventricular wall (the ‘mechanical hypothesis’). Three decades later, Lewis [2] hypothesized that ischemic pain might be elicited by the intramyocardial release of algogenic substances induced by ischemia (‘chemical hypothesis’). However, only in the past 10 years have several clinical investigations contributed to clarification of the causes of angina.

Mechanical hypothesis
The negligible importance of mechanical distortion and distention of ventricular fibers in the genesis of angina is supported by the observation that ventricular dilatation, such as occurs during acute ventricular failure, myocardial biopsy, or valvuloplasty, does not tend to cause any painful sensation [3].
Mechanical factors, however, may play a part in the activation of sensory receptors localized at the periarterial level. This mechanism of cardiac pain may explain the localized chest pain frequently experienced by patients after successful stent implantation in the absence of myocardial ischemia [4–6].

Chemical hypothesis: the central role of adenosine
In the mid 1980s, Sylven et al observed that, during the infusion of adenosine, patients without evidence of coronary artery disease often complained of a short-lasting chest pain with features similar to those of anginal pain. As adenosine is rapidly formed during myocardial ischemia and released into the vascular bed [7], they hypothesized that adenosine could be a mediator of cardiac ischemic pain, and they tested this hypothesis by assessing the effects of intravenous boluses of increasing doses of adenosine in healthy volunteers [8]. Crea et al [9] showed subsequently that, in patients with chronic stable angina, intracoronary infusion of adenosine consistently caused pain with features identical to those experienced during daily-life episodes of transient myocardial ischemia, but in the absence of detectable signs of myocardial ischemia. Infusion of a similar dose of adenosine into the right atrium failed to elicit pain, thus proving that the pain elicited by the intracoronary infusion of adenosine originated from the heart.
Adenosine-induced cardiac pain is not secondary to myocardial ischemia, as it typically occurs in the absence of ischemic-like electrocardiographic changes and can be elicited by infusing adenosine into angiographically normal coronary branches and into vascular beds, such as those supplied by the brachial or the femoral arteries, where steal-induced ischemia cannot occur [9–12]. Of note, the pain caused by adenosine does not appear to be related to the mechanical distention of periarteriolar nerve endings, as the infusion of nifedipine or papaverine, which produce a comparable degree of vasodilatation, do not cause pain [13]. Furthermore, adenosine causes pain at doses larger than those provoking maximal vasodilatation [9]. In patients with exercise-induced angina, the severity of the anginal pain is significantly reduced by pretreatment with theophylline, a potent nonselective antagonist of adenosine P₁ receptors, in the presence of a similar degree of myocardial ischemia, thus suggesting that endogenous adenosine is, at least partially, responsible for the anginal pain [9]. Furthermore, theophylline reduces forearm ischemic pain [14], an effect that can not be mediated by improvement of an adenosine-induced steal phenomenon [15].
Taken together, these observations support the hypothesis that adenosine is an adequate stimulus for cardiac sensory receptors and that endogenous adenosine is a mediator, the first hitherto identified in man, of cardiac and muscular ischemic pain. Adenosine-induced pain does not appear to be influenced by β-blockade, atropine, naloxone, nitroglycerin, nifedipine, clonidine, cyclo-oxygenase inhibitors, and steroids, whereas it is increased by systemic pretreatment with nicotine, probably because of a central modulation of pain perception [16–19]. Recently, Gaspardone et al [20] have shown that, in man, the intra-arterial and intracoronary infusion of substance P, a polypeptide present in perivascular nerves and involved in the generation of neurogenic inflammation and in the mechanism of hyperalgesia, does not cause muscular or cardiac pain, yet it enhances adenosine-induced pain.

Receptors mediating the algogenic effects of adenosine
The cardiac effects of adenosine are caused by the stimulation of at least two subtypes (A₁ and A₂) of surface membrane P₁ receptors [21–23]. The stimulation of A₁ receptors, present in cardiomyocytes and perivascular sympathetic nerves [23,24], causes electrophysiological effects [25] and inhibits the neuronal release of catecholamines [23]. The stimulation of A₂ receptors, present in endothelial and vascular smooth muscle cells, causes coronary vasodilatation [26–29].
The identification of the receptor subtype involved in the genesis of adenosine-induced pain has been investigated with the use of bamiphylline [30]. In crude synaptic membranes prepared from rat brain, bamiphylline displaced radioligands from A₁ adenosine receptors, with a potency similar to that of 8-phenyl-theophylline; in contrast, it showed a negligible potency on A₂ adenosine receptors. This results in a high degree of A₁ receptor selectivity [31]. In humans, Pappagallo et al [32] found that bamiphylline reduced the pain induced by intradermal injection of adenosine, but not the A₂-receptor-mediated adenosine-induced cutaneous hyperemia, thus suggesting that A₁ receptors are involved in cutaneous nociception. In agreement with this, Gaspardone et al [33] subsequently found that the intravenous infusion of bamiphylline reduced adenosine-induced muscular and cardiac pain, but did not affect adenosine-induced coronary vasodilatation. Similarly, it has been confirmed that N-0861 (N6-endonorboran-2-yl-9-methyladenine), a selective A₁ adenosine antagonist, at a dose that blocks A₁-mediated electrophysiologic but not A₂-mediated vasodilatory effects of adenosine, reduces the pain caused by intravenous administration of adenosine [34]. Finally, in patients with exercise-induced angina, bamiphylline reduced the severity of anginal pain normalized for the maximal ST-segment depression, thus suggesting that, in man, the algogenic effects of endogenous adenosine also are mainly mediated by A₁-receptors [35].▪

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REFERENCES

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