Clentiazem protects against chronic cerebral vasospasm in rabbit basilar artery.

Abstract

Background and Purpose: Experiments were carried out in rabbits to determine whether clentiazem (8-chlorodiltiazem), a cerebrovascular-selective calcium channel blocker, administered 24 hours before subarachnoid hemorrhage influenced the subsequent cerebral vasospasm.Methods: Subarachnoid hemorrhage was induced by multiple injections of blood into the prepontine cisterns of 35 male New Zealand White rabbits, and clentiazem (5 nig/kg) was administered 4 times daily until sacrifice. Cerebral artery diameter was assessed in vivo by angiography. Functional features of basilar arteries were measured using conventional in vitro methodology.Results: Clentiazem reduced the angiographic narrowing seen on days 2 and 5 from 35% and 34%, respectively (sham control, 1.42+0.31 mm [n=22]), to 8% and 11%, respectively, and prevented the narrowing (32%) that occurred on day 9. Narrowing in the untreated rabbits was only partly reversed by papaverine; all narrowing in clentiazem-treated animals was papaverine sensitive. Clentiazem prevented or reduced many of the changes in the basilar artery caused by the subarachnoid hemorrhage. Of particular relevance to arterial narrowing were the increased wall stiffness, the transient spontaneous changes in wall force, and the reduction in relaxation to acetylcholine. Reduction of the changes in wall force induced by agonists and by stimulation of intramural sympathetic nerves was observed.Conclusions: The vascular damage associated with chronic cerebral vasospasm is related to calcium entry into the smooth muscle and endothelial cells, and possibly sympathetic nerve terminals, through calcium channels sensitive to clentiazem, which suggests that clentiazem may be of value in the management of chronic cerebral vasospasm. (Stroke 1991;22:1409-1413)

Standard intracranialin vivoanimal models of delayed cerebral vasospasm

“…3, Panel C1). 33,[48][49][50][51][52][53][54][55][56][57][58] The double injection method generates a slightly more delayed onset of vasospasm, with a peak onset between day 4 and day 6 after initial hemorrhage (Fig. 3, Panel C2).…”

Effect of clot removal on cerebrovascular contraction after subarachnoid hemorrhage in the monkey: Pharmacological study

“…However, the maximal contraction to KC1 was not changed [12,15] after SAH. On the other hand, it was reported that the contractions to 5-HT, NE, and KC1 were suppressed in rabbit SAH, using the same method, due to increased wall stiffness and transient spontaneous changes in wall force [16]. In cat SAH, induced by the same method, the rings of posterior communicating arteries displayed a supersensitivity to 5-HT and NE, 3 days after SAH.…”

“…In rabbit SAH, the vasodilation to ACh was not significantly reduced and that to ATP was significantly attenuated in the rings of basilar arteries contracted with 5-HT, 2 days after SAH produced by a single blood injection into the major cistern [12], while both ACh-and ATPinduced relaxation was suppressed in the same arteries 4 days after SAH by two successive blood injections [37]. The relaxation to ACh was significantly depressed after SAH in the same arterial rings pretreated with histamine [16]. In dog SAH produced by the doublehemorrhage method, the endothelium-dependent relaxation to arginine vasopressin was abolished and that to thrombin was significantly reduced, and the endothelium-independent relaxation to papaverine was preserved in the rings of basilar arteries contracted with uridine triphosphate, 8 days after SAH [25].…”

Cerebral Artery Remodeling in Rodent Models of Subarachnoid Hemorrhage

“…This model is considered to be relatively well developed and is broadly accepted. Some studies reported matrix remodeling of cerebral arteries in different species following experimental SAH and proposed that a main cause of vasospasm is the increased rigidity of the artery wall [38,39,40,41]. However, carotid artery blood flow measurements in rats revealed no reduction in flow after 3 days, which would be expected from a state of vasospasm of the brain vasculature.…”

“…Vorkapic et al [39] found increased artery wall stiffness of basilar arteries in the rabbit double hemorrhage model. Kim et al [38] studied mechanical properties of basilar arteries in dogs induced by two cisternal injections of autologous blood.…”