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CI-959, a cell-activation inhibitor that prevents the formation of oxygen-derived free radicals by inflammatory cells, was studied to determine its effects on myocardial infarct size and subsequent scar formation in dogs. The left circumflex coronary artery was occluded for 90 min, followed by 6 h of reperfusion. Drug infusion was started 15 min before reperfusion at a loading dose of 8 mg/kg i.v., followed immediately by 2 mg/kg i.v. infused over 80 min. The infarct size, assessed by TTC staining techniques, was significantly reduced in 12 dogs treated with CI-959 (23.3 ± 3.6 of the area at risk) when compared to 11 vehicle-treated animals (35.5 ± 4 of the area at risk, p < 0.05). This reduction in infarct size was not attributed to changes in regional myocardial blood flow, as measured by radioactive microspheres, or to a reduction in myocardial oxygen demand, as estimated by changes in the rate-pressure product. The scar thickness, measured after a 6-week recovery period in 9 animals treated with CI-959, was not significantly reduced in comparison with 11 controls. In vitro, CI-959 effectively inhibited oxygen free radical formation by canine neutrophils. The results of this study show that CI-959 significantly reduces the myocardial infarct size without causing scar thinning, which might lead to ventricular aneurysm, and suggests the most likely mechanism for its beneficial action is the prevention of formation of toxic oxygen radicals.

Balloon angioplasty has become an important intervention in clinical cardiology; however, the technique is associated with a high incidence of restenosis, requiring repeated procedures. Endothelin-1 (ET-1), specifically through its action on ETAreceptors, has been implicated in the cell proliferation and subsequent neointimal formation that leads to restenosis. Therefore we examined a potent antagonist of the ETAreceptor, A127722.5, in a pig model of balloon angioplasty in iliac and carotid arteries. Ten pigs received A-127722.5 (7.5 mg/kg b.i.d.) orally, starting 3 days before angioplasty and continuing for 4 weeks; 10 additional pigs were treated with the same dosing regimen of the angiotensin-converting enzyme (ACE) inhibitor captopril (3.0 mg/kg b.i.d.), while a third group of 10 animals received placebo. At 2 and 4 weeks after the start of treatment, these doses of the ETAreceptor antagonist and ACE inhibitor blocked the presser responses induced by big ET-1 and angiotensin I, respectively. In the iliac arteries, neointimal formation, neointimal/medial ratio, and maximal neointimal thickness were all significantly reduced, and the residual lumen area was significantly increased in pigs treated with the ETAreceptor antagonist compared with placebo and captopril-treated groups. Medial collagen content, collagen deposition, and medial growth also were significantly reduced relative to the placebo group. Beneficial effects also were observed in the carotid arteries, although the results were less striking. Captopril was ineffective in protecting against the effects of balloon angioplasty in both vessels. Our results indicate that an orally active and potent antagonist of the ETAreceptor inhibits cell proliferation and synthesis of extracellular matrix in pigs and may provide an important therapeutic approach to the prevention of restenosis.

A specific inhibitor of thromboxane A2(TxA2) synthesis, CGS-13080, was studied during acute myocardial ischemia (MI) in cats. To define more clearly the mechanism of action of CGS-13080, we also studied its effects on isolated cat coronary arteries, in vitroaggregation of cat platelets, and production of thromboxane B2(TxB2) from cat platelet-rich plasma (PRP). MI cats that received the vehicle for CGS-13080 exhibited a significant increase in plasma concentration of TxB2. This was accompanied by increases in the ST segment of the electrocardiogram, specific activity of plasma creatine kinase (CK), and loss of CK activity and amino-nitrogen from the ischemic myocardium. In contrast, TxB2concentrations, plasma and tissue CK activities, and myocardial amino-nitrogen concentration in MI cats treated with CGS-13080 were not significantly different from those in sham MI cats that had received the drug. In vitro, CGS-13080 did not inhibit contraction of cat coronary arteries produced by a stable TxA2analog and did not inhibit aggregation of cat PRP induced by arachidonic acid (AA). However, production of TxB2by cat platelets treated with AA was completely inhibited by this agent. Thus, specific inhibition of TxA2synthesis without thromboxane receptor antagonism can exert a protective effect on the myocardium during ischemia in cats.