MS-551 protects against ventricular fibrillation in a chronic canine model of sudden cardiac death.

We studied the electrophysiologic and antifibrillatory properties of MS-551 (1,3-dimethyl-6-((2-[N-hydroxy-ethyl)-3-(4-nitrophenyl) propylamino] ethylamino) 2,4(1H,3H) pyrimidinedione hydrochloride) in a conscious canine model of sudden cardiac death. Three to 5 days after surgically induced myocardial infarction (MI: 2-h occlusion of the left anterior descending coronary artery, LAD), animals were subjected to programmed electrical stimulation (PES) to identify those at risk for sudden cardiac death. MS-551 was administered (2.0, 3.0, or 4 x 2.0 mg/kg intravenously, i.v.). Vehicle-treated animals received 0.9% sodium chloride solution for injection. MS-551 (multiple-dose regimen) increased ventricular effective refractory period (VERP) from 112 +/- 4 to 137 +/- 4 ms (p < 0.05) as compared with vehicle treatment, which did not alter VERP (125 +/- 6 to 121 +/- 5 ms). MS-551 prolonged QTc interval from a predrug value of 293 +/- 8 to 333 +/- 18 ms postdrug. The size of surgically induced MI did not differ among groups: 2.0 mg/kg, 23 +/- 4%; 3.0 mg/kg, 28 +/- 2%; 4 x 2.0 mg/kg, 25 +/- 3%; and vehicle, 28 +/- 3% of the left ventricle. Single bolus administration of MS-551 (2.0 or 3.0 mg/kg i.v.) did not confer significant protection against sudden cardiac death. However, repeated administration of MS-551 protected against sudden cardiac death in 8 of 10 dogs as compared with 2 of 12 in the vehicle-treated group (p < 0.05). The data indicate that a multiple-dose regimen of MS-551 provides protection against ischemia-induced ventricular fibrillation (VF) in the postinfarcted heart. The mechanism by which MS-551 achieves its antifibrillatory effect most likely depends on its ability to prolong VERP of myocardium without altering ventricular conduction velocity.

Thrombolytic effects of recombinant fibrolase or APSAC in a canine model of carotid artery thrombosis.

BACKGROUND: Thrombolytic agents used clinically rely on the activation of plasminogen to plasmin. Plasmin possesses multiple actions including increasing thrombin activity and activation of platelets. Thus, after successful thrombolytic therapy, arterial hyperactivity and reocclusion may be the result of a predominant plasmin-induced thrombogenic action at the site of the residual thrombus. Fibrolase, a direct-acting fibrinolytic enzyme from southern copperhead snake venom, induces rapid clot lysis in vitro. Fibrolase does not rely on plasminogen activation or any other bloodborne components for activity and is not inhibited by any of the rapidly acting serine proteinase inhibitors in blood. METHODS AND RESULTS: We investigated the efficacy of fibrolase to lyse an occlusive thrombus formed in the carotid artery of the anesthetized dog. Electrolytic injury was initiated in both the right and left carotid arteries. Thirty minutes after both arteries were occluded, each vessel was infused with either fibrolase (4 mg/kg over 5 minutes) or physiological saline (over 5 minutes). In two separate groups of dogs, anisoylated plasminogen streptokinase activator complex (APSAC) (0.1 U/kg) was infused into the occluded vessel. In the artery infused with fibrolase, five of five dogs exhibited patency within 6 +/- 1 minutes of the infusion (P < .05 versus vehicle-treated artery; Fisher's exact test). In the contralateral carotid artery that received vehicle, the occlusion was maintained throughout the experimental protocol. APSAC alone lysed the thrombus in each vessel within 17 +/- 3 minutes. Five minutes after the end of fibrolase administration and in one of the groups administered APSAC, a glycoprotein (GP)IIb/IIIa antibody, 7E3 (0.8 mg/kg IV), was administered to prevent reocclusion of the patent artery. After 7E3 administration, the vessel treated with fibrolase remained patent in four of five dogs, and six of six APSAC-treated vessels were patent for the remainder of the observation period (2 hours). CONCLUSIONS: These studies demonstrate that local administration of fibrolase lyses a carotid arterial thrombus rapidly without excessive hemorrhage or hemodynamic compromise. The enzyme in combination with antiplatelet therapy (7E3) offers a unique mechanism for clot dissolution and may prove useful as a clinically efficacious alternative to presently used thrombolytic agents or may act in a synergistic manner with plasminogen activators.