Background. Oxygen-derived free radicals are thought to injure the ischemic heart during coronary microvascular embolization.

Intracoronary thrombus is regarded as a potentially important factor in the etiology of unstable angina, but the incidence of intracoronary thrombus in unstable angina has not been clearly defined. To determine the occurrence of intracoronary thrombus during ongoing angina pectoris, coronary angiography was performed during spontaneous ischemic attacks in 37 patients with prolonged rest angina. All patients exhibited significant (>50%) stenoses of at least one major coronary artery. Of the 37 patients, 21 (57%) had intracoronary thrombus in major coronary arteries, whereas 14 (38%) had fixed narrowings without evidence of intracoronary thrombus and two exhibited coronary spasm. ST segment elevation was observed in 16 of 21 patients with thrombus and in all of the patients with coronary spasm, but all the patients with organic stable obstruction showed ST segment depression. Twenty of the 21 patients with thrombus improved after thrombolytic therapy with intracoronary injection of urokinase; obstructed arteries were reopened, or narrowings were attenuated, with relief of ischemic symptoms. In patients with fixed obstructions, the rate-pressure product during active symptoms was significantly higher than during an asymptomatic period, indicating that a transient increase in myocardial oxygen demand may contribute to the ischemic attack in these patients. A high incidence (71%) of recurrent symptoms was observed in patients with intracoronary thrombus even after successful thrombolysis, in contrast to a much lower incidence (36%) in those without intra-coronary thrombus. Myocardial infarction within 4 weeks after catheterization was observed more frequently in patients with intracoronary thrombus (24%) than in those without thrombus (7%). Thus our results indicate that the incidence of intracoronary thrombus is quite high during ongoing attacks of unstable angina, although a transient increase of myocardial oxygen demand also plays an important etiologic role. It is also suggested that patients with thrombus fare less well than those with organic stable obstruction. Circulation 77, No. 3, 526-534, 1988. RECENT ANGIOGRAPHIC STUDIES have suggested that intracoronary thrombus plays an important etiologic role not only in myocardial infarction-5 but also in unstable angina.6 t7 Nevertheless, there is considerable variation in the reported incidence of coronary thrombus in patients with unstable angina, with figures varying from 1%7 to 85%8 in several r t6-14 reports. 14This inconsistency in the reported incidence of thrombus may be partly attributable to variability in the timing of angiographic study with respect to the last anginal attack; a relatively low incidence of thrombus (1% to 12%) was reported in patients cathe-terized 30 to 90 days after the last attack,6 7 9 10 12 whereas the incidence was higher (52% to 85%) when angiography was performed soon after active symptoms.8 13 14 Angioscopy performed during coronary artery bypass surgery also revealed a high incidence of intracoronary thrombus in patients with a...

We have recently reported that coronary microembolization sustains myocardial ischemia with hyperemic response of coronary blood flow (CBF) induced by massive release of adenosine from the ischemic myocardium. In this study, we tested the hypothesis that this hyperemic flow caused by released adenosine improves myocardial ischemia. In eight dogs (control), microspheres (5.0 X 10(4)/ml of base-line CBF) were repetitively injected until CBF decreased toward zero, and the changes in CBF, fractional shortening, lactate extraction ratio (LER), and adenosine release were studied. In 15 other dogs, an identical procedure was done with an intracoronary infusion of prazosin (4 micrograms.kg-1.min-1, n = 8) or theophylline (0.1 mg.kg-1.min, n = 7) to elucidate the effect of adenosine, since prazosin inhibits release of adenosine from ischemic myocardium and theophylline blocks adenosine receptors. In 16 other dogs, hemodynamic and metabolic parameters were examined with and without these drugs after a single injection of microspheres (1.0 X 10(5)/ml of base-line CBF). In the control group, CBF increased to 170 +/- (SE) 14% of the base-line CBF at 16-30% of maximal embolization. In contrast, intracoronary infusion of prazosin markedly attenuated adenosine release and hyperemic response and significantly deteriorated both fractional shortening and LER. Theophylline also significantly attenuated the hyperemic response and tended to decrease both fractional shortening and LER. A salutary effect of adenosine release was further confirmed by the improvement of ischemic changes in the same dog after withdrawal of prazosin and theophylline associated with an increase in CBF. Thus we conclude that adenosine released from ischemic myocardium improves ischemia in microembolization through the hyperemic response.

This study was undertaken to elucidate whether alpha-1 adrenoceptor activity is beneficial to contractile dysfunction during reperfusion after a brief period of ischemia (stunned myocardium) in 54 open-chest dogs. Contractile dysfunction assessed by fractional shortening (FS) was observed 3 hours after the onset of reperfusion following 15 minutes of complete occlusion of the left anterior descending coronary artery. Pretreatment with prazosin (4 micrograms/kg/min i.c.) further deteriorated contractile dysfunction compared with the untreated condition (12.7 +/- 0.6% versus 6.9 +/- 0.4% with prazosin treatment, p less than 0.001). Conversely, alpha 1-adrenoceptor agonists, methoxamine (1.0 microgram/kg/min i.c.) and norepinephrine (0.24 microgram/kg/min i.c.) with rauwolscine and propranolol, significantly attenuated contractile dysfunction (FS in the methoxamine-treated group, 17.3 +/- 0.3%, p less than 0.001 versus the untreated group; FS in the norepinephrine-treated group, 18.0 +/- 0.9%, p less than 0.05 versus 13.6 +/- 1.1% in the propranolol group). Both adenosine release and hyperemic coronary flow response during the early reperfusion period were significantly attenuated in the prazosin-treated group, and both were enhanced in the alpha 1-adrenoceptor stimulation groups. These results suggest that beneficial effects of alpha 1-adrenoceptor activity may be due to the enhanced release of adenosine. To test the cause-effect relation between the extent of adenosine release and contractile dysfunction during reperfusion, 8-phenyltheophylline was infused to block adenosine receptors in the methoxamine-treated group. The treatment with 8-phenyltheophylline completely abolished (FS, 7.4 +/- 0.3%) the beneficial effect of the enhanced adenosine release by alpha 1-adrenoceptor stimulation. Furthermore, in the prazosin-treated group, adenosine (9 micrograms/kg/min) was additionally infused into the left anterior descending coronary artery 5 minutes before and 2 hours after the onset of reperfusion. Both hyperemic coronary flow and contractile dysfunction (FS, 17.3 +/- 0.3%) recovered to the levels of the alpha 1-adrenoceptor stimulation groups. However, treatment with papaverine could not prevent deleterious effects of prazosin despite the fact that comparable hyperemic flow was obtained. Instead, lactate production up to 10 minutes after the onset of reperfusion was significantly larger (p less than 0.01) despite augmented contractile function in the prazosin-treated and the 8-phenyltheophylline with methoxamine-treated groups compared with the untreated group. The electron microscopic examination revealed no irreversible myocardial injury with and without pharmacological interventions. Thus, we conclude that alpha 1-adrenoceptor activity can reduce the magnitude of myocardial stunning and that its cellular mechanism is due to enhanced adenosine release by alpha 1-adrenoceptor activity.(ABSTRACT TRUNCATED AT 400 WORDS)

We have previously reported that alpha 2-adrenoceptor stimulation enhances adenosine-induced coronary vasodilation. In the present study, we tested the hypothesis that alpha 2-adrenoceptor activity exerts beneficial effects on myocardial ischemia through augmentation of vasodilatory effects of released adenosine. In open-chest dogs, the left anterior descending coronary artery was perfused through an extracorporeal bypass tube from the carotid artery. Propranolol was infused into the bypass tube to exclude the metabolic effects of norepinephrine. When clonidine (0.24 micrograms/kg/min i.c.) was infused for 10 minutes after reduction of coronary blood flow by partial occlusion of the bypass tube, coronary blood flow was increased by 43% from 27 +/- 1 ml/100 g/min despite no changes in coronary perfusion pressure (38 +/- 5 mm Hg) and a slight decrease in adenosine release. Both fractional shortening and lactate extraction ratio of the perfused area were significantly improved (fractional shortening, 1.8 +/- 1.0 to 10.9 +/- 1.5%, p less than 0.001; lactate extraction ratio, -57.8 +/- 6.5 to -31.9 +/- 2.4%, p less than 0.005). Identical results were observed in the denervated hearts, indicating that the beneficial effect of clonidine is not attributed to the prevention of norepinephrine release from the sympathetic nerve terminals. The beneficial effects of clonidine were prevented by yohimbine, an alpha 2-adrenoceptor blocking agent. An adenosine receptor antagonist, 8-phenyltheophylline, also prevented the beneficial effects of clonidine, indicating that these beneficial effects are mediated by effects of adenosine. Furthermore, the extent of augmentation of coronary flow in the ischemic heart was coincided with that of augmentation of exogenous adenosine-induced hyperemic flow (40%) by clonidine. Production of cyclic AMP in the coronary artery during myocardial ischemia was augmented by clonidine. In 12 other dogs, myocardial ischemia was produced by intracoronary embolization of microspheres (15 microns in diameter). Clonidine enhanced (39%) the hyperemic coronary flow and improved both fractional shortening and lactate extraction ratio. Thus, we conclude that alpha 2-adrenoceptor stimulation can ameliorate myocardial ischemia mainly due to enhancement of vasodilatory effects of adenosine released from the ischemic myocardium.