The responses of segments of rabbit basilar and ear arteries to high K+ (K+, 45 mM), norepinephrine (NE, 10(-5) and 10(-7) M), and 5-hydroxytryptamine (5-HT, 10(-7) M) were tested before and after their incubation in calcium (Ca2+)-free Krebs solution for times varying from 2.5 to 60 min. The time course of evolution of the responses to K+ with Ca2+-free conditions in both vessels could be represented by a monoexponential curve. The rates of decline of the responses of amines in the ear artery were similar to K+ at first but then fell off at a slower rate. The decline in K+ contraction and the fast initial decline of the NE contraction may relate to the speed of removal of extracellular calcium, whereas the final slower NE decline reflects depletion of an intracellular pool. In the basilar artery, the NE and K+ response declined in a similar manner, whereas the 5-HT contraction showed a fast and a slow component of decline. These results for the maintained agonist response were confirmed using the Ca2+ influx antagonist, 3-methoxyverapamil (D 600). In addition, a D 600-insensitive phasic contraction was observed in both arteries. These results suggest that the steady-state NE contraction in the basilar artery is almost entirely dependent on loosely bound extracellular Ca2+. This is in contrast to the ear artery, where an additional tightly bound or intracellular Ca2+ pool is used. This source is present in the basilar artery but contributes only to a D 600-insensitive phasic component.

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SUMMARY In vitro studies suggest that cerebrovascular contraction is more dependent on the influx of calcium to smooth muscle than general systemic arteries. The present study tested the in vivo effects of a calcium influx blocker (nimodipine) on cerebral blood flow and metabolism in 16 baboons. The l33 xenon clearance technique was used together with careful control of EEG and blood gases. With normal blood gases intravenous nimodipine infusion (1 /xg/kg/min) produced an 18% increase in cerebral blood flow with no alteration in cerebral oxidative metabolism or blood pressure. Higher doses (above 10 ^.g/kg/min) resulted in a decreased arterial blood pressure and a return to control cerebral flow. Infusion of the dose producing maximal increase in flow, decreased the cerebral reactivity to altered PCO 2 (n = 5). These results suggest that nimodipine may be a relatively selective cerebrovascular dilator. Stroke Vol 15, No 3, 1984PREVIOUS IN VITRO studies suggest that the smooth muscle of the cerebral resistance vessels is more heavily dependent for contraction on the influx of calcium from the extracellular fluid than other general systemic blood vessels.' 2 Thus, it seems probable that, pharmacologic agents which prevent the movement of calcium into the smooth muscle would preferentially reduce cerebrovascular constriction leaving intact general systemic vascular tone. The drug nimodipine has proven effective in vitro in antagonizing cerebral vascular contractions to agonists such as 5-hydroxytryptamine, norepinephrine and high K + solutions. 3 The present study tested, in vivo, the effects of various doses of nimodipine on resting cerebral blood flow. The dose which showed the largest cerebral flow increase was then used to determine the action on the cerebrovascular constriction resulting from, 5-hydroxytryptamine infusion in the hypercapnic animal 4 and hyperventilation to lower the PCO 2 . 3 Methods and MaterialsAdult baboons (Papio 8-12 kg) were sedated with intramuscular phencyclidene (Sernylan, 10 mg/kg) or ketamine (5 mg/kg). They were then transported to the laboratory where full anesthesia was induced with sodium pentobarbital (Nembutal, 20 mg/kg i.v.). The animals were intubated and after succinyl choline (20 mg i.v.) were ventilated using a positive pressure respirator. The rate and depth of ventilation were adjusted so that the animals showed approximately 5% CO 2 in end tidal expiratory air (CO 2 measured continuously from the endotracheal tube) using a Goddard capnograph. The depth of anesthesia was monitored throughout using a single lead EEG and this was maintained showing a rhythm of 8-10 Hz using a ventilation gas mixture of 70% N 2 O in oxygen and supple-

Cerebral blood flow (CBF) was measured in 20 baboons by the intra-arterial xenon-133 injection method. The CBF responses to intra-arterial infusions of noradrenaline (NA) were determined. These responses were normally found to be vasodilator and mediated by beta adrenoreceptors. After infusion of substances blocking extraneuronal uptake of NA or opening of the blood-brain barrier, this vasodilation was either abolished or converted to an alpha-receptor mediated vasoconstriction. This suggests that normally the cerebral circulation is protected against noradrenergic vasoconstriction by mechanisms reducing the concentration of NA in the tunica media to below threshold for alpha-adrenoreceptor stimulation.

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