Ergonovine-induced myocardial ischemia: no role for serotonergic receptors?

Abstract

Because ergonovine appears to produce coronary contractions by a serotonergic (5-HT) mechanism, we attempted to prevent ergonovine-induced ischemia in patients with vasospastic angina by pretreatment with ketanserin, a new selective 5-HT blocker. We studied seven patients with consistently positive results of ergonovine testing (ST segment elevation in three and ST segment depression in four). Ergonovine testing was performed before and after a bolus of 10 mg of ketanserin (all patients) and infusion of 2 to 4 mg/hr for 8 hr (six patients). To assess 5-HT blockade during ketanserin infusion, the constrictor response of hand veins to 5-HT was tested before and after ketanserin. Despite evidence of 5-HT blockade in hand veins, ergonovine-induced ischemia was not prevented by ketanserin in any patient, and there was no significant change in the dose of ergonovine required to provoke ischemia. In one patient, four spontaneous episodes of ST segment elevation occurred during infusion of ketanserin. The plasma concentrations of ketanserin at the time of ergonovine testing ranged from 61 to 127 ng/ml (mean 102) and were well above those that completely inhibit canine coronary 5-HT contractions in vitro. Although human coronary arteries may differ in their responsiveness to 5-HT or ketanserin, these data suggest that ischemia from ergonovine-induced coronary vasospasm is not mediated by 5-HT receptors. Circulation 70, No. 2, 178-183, 1984. CORONARY arterial spasm is now recognized as an important cause of ischemia in patients with all degrees of severity of coronary artery disease,' but the mechanisms responsible for its occurrence are still unknown. Ergonovine is the vasoconstrictor that most consistently provokes spasm in patients with angina at rest, 2 3 whose arteries appear hypersensitive to the drug at the site of spasm.4 Therefore the mechanism of ergonovine's action may be related to the cause (or causes) of spontaneously occurring spasm. Recent work in experimental animals has shown that coronary arterial contractions induced by ergonovine are mediated by serotonergic (5-HT) receptors5-7 and that the increased sensitivity of atherosclerotic rabbit aortas to ergonovine is at least partially mediated by a 5-HT mechanism. 178 tagonist with no partial agonist activity,'" provides an opportunity to test whether ergonovine-induced vasospasm in patients with angina is mediated by 5-HT receptors. In this study we attempted to block the effects of ergonovine by pretreatment with ketanserin in seven patients with ergonovine-induced ischemia. In six of the patients we also assessed the level of 5-HT blockade in peripheral veins during infusion of ketanserin by a test of venoconstriction in the hand. MethodsPatient selection. Seven patients with angina pectoris and an ischemic electrocardiographic response to ergonovine maleate formed the study group. Their clinical, electrocardiographic, and angiographic findings are summarized in table 1. In five patients angina occurred both at rest and during exertion, whil...

Effect of the thromboxane A2‐mimetic U46619 on 5‐HT1‐like and 5‐HT2 receptor‐mediated contraction of the rabbit isolated femoral artery

“…The concentrations of both 5-HT and TxA2 released presumably from aggregating platelets, are elevated in the coronary sinus blood of patients with angina involving coronary artery disease and vasospasm (Robertson et al, 1981; Van den Berg et al, 1989). In this scenario it would be anticipated from our results that 5-HTI-like receptor-mediated contraction would be augmented and thus provide an explanation for the failure of 5-HT2 receptor antagonists such as ketanserin to relieve vasospastic angina (De Caterina et al, 1984;Freedman et al, 1984).…”

“…Coronary vasospasm, occurring spontaneously or induced by ergonovine, is not prevented by the 5-HT2 receptor antagonist ketanserin; hence the role of 5-HT in vasospastic angina has been questioned (De Caterina et al, 1984;Freedman et al, 1984). However, it is now apparent that in some human blood vessels, including the umbilical, coronary, basilar and pial arteries, 5-HT can elicit contraction via ketanserin-resistant 5-HTI-like receptors in addition to ketanserin-sensitive 5-HT2 receptors (MacLennan et al, 1989;Connor et al, 1989;Parsons et al, 1989;Hamel & Bouchard, 1991).…”

Role of Coronary Vasoconstriction in Ischemic Heart Disease and Search for Novel Therapeutic Targets

“…Available vasodilators administered systemically are not always sufficient for the complete control of severe variant angina 57,58 and appear to have a smaller dilator effect on pre-arteriolar vessels than on proximal coronary arteries. Complete cardiac denervation, 59 serotonin 60,61 and thromboxane A2 62 blockade did not abolish episodes of coronary spasm. Therefore, the time has come to try and identify novel specific therapeutic targets against the strong coronary constrictor stimuli and against key molecular components of the enhanced constrictor responsiveness that typically characterizes these large and small vasomotor disorders.…”

Comparison of contractile responses to 5‐hydroxytryptamine and sumatriptan in human isolated coronary artery: synergy with the thromboxane A2‐receptor agonist, U46619

“…In a similar study, however, McFadden et al (1991) included patients with Prinzmetal's angina (diagnosed previously by intracoronary challenge with ergometrine (ergonovine)) and found that intracoronary infusions of 5-HT caused spasm (zero flow) which was resistant to ketanserin (McFadden et al, 1992). Ketanserin does not prevent either ergometrineinduced ischaemia (Freedman et al, 1984) or spontaneous attacks of variant angina (De Caterina et al, 1984) in man and although ergometrine activates many different types of receptors including a-adrenoceptors , both it (Muller-Schweinitzer, 1980;Sakanashi & Yonemura, 1980;Brazenor & Angus, 1981;Holtz et al, 1982), and the antimigraine drug methysergide (Saxena, 1974;Brazenor & Angus, 1981), cause contractions via receptors other than a-adrenoceptors. Thus, in the dog isolated coronary artery, ergometrine was found to be a potent agonist at unspecified 5-HT receptors (Brazenor & Angus, 1981) whilst in the rabbit saphenous vein, ergometrine was demonstrated to be a potent 5-HT1-like receptor agonist (MacLennan & Martin, 1990).…”