The effects of an intracellular calcium antagonist HA 1077 on delayed cerebral vasospasm in dogs

Abstract

The effectiveness of calcium antagonists on a chronic cerebral vasospasm after an SAH is still under debate. Calcium channel blockers such as nimodipine, nifedipine etc. can dilate spastic arteries by intrathecal administration, but not by systemic (iv or po) use. HA 1077 is a novel and potent calcium antagonist vasodilator which is considered to act by employing different mechanisms from the usual calcium channel blockers since it inhibits 1. calcium ionophore A 23187 induced contraction in arterial strips and 2. phenylephrine induced contraction in calcium free media, suggesting that its site of action is in the intracellular space. HA 1077 is water soluble and relatively stable in light. In the present study, the efficacy of HA 1077 was evaluated on dogs by using the spiral arterial strips in vitro and by angiography in vivo. In the arterial strips from the control dogs, a 50% relaxation of KCl (15 mM) induced contraction was obtained by a 10(-6) M HA 1077 for the "intracranial" basilar and middle cerebral arteries, while a 10(-5) M was needed to obtain the same effect for the "extracranial" common carotid and vertebral arteries, indicating that HA 1077 is more effective for the intracranial arteries. A vasospasm was produced by the "two haemorrhage" model of Varsos et al. The average angiographic diameter of the basilar artery was reduced to 60% of the control on SAH day 7. Intravenous infusion of HA 1077 (0.5-3 mg/kg/30 min) significantly dilated the spastic basilar artery (up to 20-30%), for over 2 hours. A fall in the systemic BP remained less than 20% during this time.(ABSTRACT TRUNCATED AT 250 WORDS)