Post-ischemic administration of DY-9760e, a novel calmodulin antagonist, reduced infarct volume in the permanent focal ischemia model of spontaneously hypertensive rat

We assessed the effect of a novel calmodulin antagonist, DY-9760e (3-[2-[4- (3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazoly lmethyl)- 1H-indazole dihydrochloride 3.5 hydrate) in a spontaneously hyper tensive rat (SHR) permanent focal cerebral ischemia. In experiment I, the l eft middle cerebral artery was permanently occluded in 62 SHRs. DY-9760e (0 .5 mg kg(-1) h(-1)) or vehicle alone were administered continuously i. v. f or 6 h, beginning 0, 30, or 60 min after the arterial occlusion. The infarc t volume was measured 24 h of ischemia. In experiment II, the effect of DY- 9760e on CBF was assessed in 10 SHRs. Administration without a delay result ed in a mean infarct volume of 166.7 +/- 27 mm(3) (vehicle, n = 10) and 125 .1 +/- 31.8 mm(3) (DY-9760e; n = 9). Administration with a 30 min delay res ulted in a mean infarct volume of 773.2 +/- 32.4 mm(3) (vehicle; n = 12) an d 143.3 +/- 35.3 mm(3) (DY-9760e; n = 11). Dy-9760e significantly reduced t he infarct under these conditions (p < 0.05). The administration with a 60 min delay failed to reduce the infarct. DY-9760e had no effect on the CBF. Continuous i.v. administration of DY-9760e reduced infarct volume in a SHR permanent focal ischemia without affecting ischemic CBF.