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Hyperventilation Thallium-201 imaging was evaluated for the examination of the existence of ischemia in the cases of diffuse vasoconstriction under the ergonovine maleate provocative test for coronary artery. Transient myocardial perfusion defect (PD) was demonstrated in 14 patients with ergonovine induced vasospasm (group S), and 13 of these patients also demonstrated redistribution (RD) (92.4%). In 14 patients with diffuse vasoconstriction (group D), nine demonstrated PD, and all of them revealed RD. On the other hand, only one of ten (10%) patients demonstrated PD and RD in a group of patients without spasm or diffuse vasoconstriction (group N). In addition, the left ventricular myocardium was divided into nine segments on a SPECT image, and the mean minimum washout rate (WOR) of each segment was evaluated. These values were compared with the percent change of the lung/heart ratio between early and delayed images (delta L/H%). Both the mean minimum WOR mean and delta L/H% of group D were significantly smaller than that of group N (p < 0.001), and only approximated to group S. Thus, the possibility of myocardial ischemia of diffuse vasoconstrictive coronary artery is implicated and such patients are supposed to be treated medically as vasospastic angina.

Long-term changes in vasocontractility were examined in 23 coronary segments from 20 patients with variant angina using computer-based quantitative coronary angiography and ergonovine provocation tests repeated at an interval of 42 +/- 14 months. Measurements of vasospasticity at the sites of fixed stenoses were compared with values predicted by an elementary geometric theory based on the assumption that the cross-sectional area of a vessel wall is constant regardless of its state of vasoconstriction. While all patients were symptomatic initially, only 11 remained symptomatic at follow-up. At the initial provocation test, the response was correctly predicted in four segments, was lower than expected in one, and was stronger in 18. At follow-up, only one of the four segments in which the response had been initially predicted correctly again showed the predicted response and the remaining three showed a response weaker than expected; the one segment which was initially hypocontractile remained hypocontractile at follow-up; and of the 18 segments which were initially hypercontractile, 12 exhibited hypercontractility again, four had the predicted value and the remaining two showed hypocontractility. In only one of 23 segments did the geometric theory predict the behaviour of vasospasticity at the site of fixed stenosis on both tests. Vasospastic responsiveness is a dynamic process demonstrating temporal variability and is not directly predicted by geometric theory.

Phenothiazine and thiabendazole were studied for their ability to antagonize venoconstriction induced by ergonovine, and the biogenic amine serotonin, in the isolated dorsal pedal vein of cattle. The two compounds are commercially available, approved for usage in cattle and have been reported to reverse some of the toxic effects associated with the intake of Acremonium coenophialum-infested fescue forage by cattle. Neither compound had any antagonistic activity against venoconstriction induced by ergonovine. However, thiabendazole did have some activity against venoconstriction induced by serotonin. Ergot alkaloids are known to cause venoconstriction through effects on biogenic amine receptors, including serotonergic receptors, and since thiabendazole has anti-serotonin activity, part of the reported beneficial effects of thiabendazole in alleviating fescue toxicity may be due to the anti-serotonin activity of the drug. Further work is needed to determine if phenothiazine and thiabendazole have any effect on other types of alkaloids that are present in A. coenophialum-infested fescue.

Ergonovine produces physiologic coronary artery narrowing in many patients without focal coronary spasm. The effect of ergonovine-induced coronary vasoconstriction on coronary vasodilatory reserve is unknown. Therefore we studied 10 patients with atypical chest pain and angiographically normal coronary arteries. The heart rate and blood pressure were recorded continuously and coronary Doppler flow velocity was measured continuously with a 20 MHz Doppler-tipped catheter. Ergonovine caused diffuse narrowing of the vessels in all patients, with a 12% +/- 5% change in diameter of the left anterior descending coronary artery (p less than 0.001). There was a significant change in systolic (17% +/- 12% change; p less than 0.05) and mean arterial pressure (13% +/- 13% change; p less than 0.05), with no significant change in mean coronary flow velocity with ergonovine. Ergonovine also did not attenuate the maximal hyperemic response with papaverine. Thus despite an increase in myocardial demand and a decrease in caliber of conductance coronary vessels, the coronary autoregulatory flow responses were intact after the administration of ergonovine.

Severe coronary artery spasm can occur in orthotopic cardiac transplant recipients. To investigate the possible mechanisms and relevance of coronary spasm to the subsequent development of coronary disease, the response of the coronary arteries to intracoronary ergonovine maleate was studied in 10 patients who had undergone orthotopic cardiac transplantation and were shown to have normal coronary arteries at angiography. Ergonovine in doses of 1, 5 and 10 micrograms was injected into the left coronary artery followed by 2 mg of isosorbide dinitrate. Proximal coronary artery luminal diameters were measured using automated computerized quantitative angiography of the left anterior descending (LAD) and circumflex (LCX) vessels. Five patients (responders) demonstrated a dose response curve to intracoronary ergonovine which was similar to that previously seen in non-transplant patients (mean percentage diameter change +/- SEM, -24.68 +/- 1.93 for LAD, -24.06 +/- 3.91 for LCX). The remaining five patients (non-responders) demonstrated a virtually flat dose response curve significantly different from that of the responders (P = 0.001 for LAD, P = 0.013 for LCX). Angiography after 2 years demonstrated significant coronary disease in four of the five responders to ergonovine. In contrast, the five non-responders to ergonovine continue to have no detectable disease by angiography.

Recent in vitro studies on isolated coronary and mesenteric arteries have shown that hyperlipidemia appears to hypersensitize the vascular arterial smooth muscle to drugs such as ergonovine and that this increased contractility seems to be mediated by a serotinergic mechanism. This results in vasospasm with exposure to certain vasoactive drugs such as serotonin or norepinephrine. However, in vivo quantification of this observed phenomenon has not been done. In the present study we used Watanabe hereditary hyperlipidemic (WHHL) rabbits (cholesterol level 459 +/- 216 mg/dL) and the normal lipidemic New Zealand white (NZW) rabbit (cholesterol level 35 +/- 19) as a control in the study of hyperlipidemia and blood flow changes in response to various vasoactive drugs. Blood flow measurements were made by the video dilution technique (VDT) following catheterization of the superior mesenteric artery. The serotinergic vasoactive drug ergonovine maleate was injected into the superior mesenteric artery at low dose (0.002) mg/kg) and high dose (0.004 mg/kg). A significant decrease (p less than .05) in blood flow was observed in response to high-dose ergonovine maleate in WHHL rabbits compared to the NZW rabbits. This in vivo experiment confirms the in vitro studies showing that hyperlipidemia sensitizes mesenteric arteries in the presence of serotinergic stimuli. The vasodilators verapamil hydrochloride and calcitonin gene-related peptide (CGRP) injected into the superior mesenteric artery caused a marked increase in flow in both the WHHL and the normal lipidemic NZW rabbits. This model can be used in the assessment of superior mesenteric artery ischemia and its reversal.

The duration of the coronary artery vasoconstrictor effect of ergonovine maleate is an important clinical parameter that has not been clearly defined. Since ergonovine is generally administered in incremental, cumulative doses and since this agent may have potentially serious toxic effects related to its vasoconstrictor properties, knowledge of duration of this effect is crucial to its safe and efficacious use. We present clinical evidence of ergonovine-induced coronary artery spasm recurring after pharmacologic relief of a first episode of ergonovine-induced spasm. Recurrent spasm occurred 18 minutes after a cumulative dose of 0.15 mg ergonovine and 14 minutes after intravenous nitroglycerin was given to ameliorate the initial spasm. Therefore, clinical monitoring of patients after ergonovine administration should be designed to identify a possibly prolonged duration of vasoconstrictor effect of the drug. Sequential doses of ergonovine at intervals of ten minutes or less should be recognized as having cumulative effect. The duration of action of pharmacologic agents utilized to alleviate ergonovine-induced coronary artery spasm should exceed the potential duration of action of ergonovine in order to minimize the possibility of late spasm.