To determine the possible role that leukotrienes (LTs) may play in the regulation of cerebral blood flow, the responses of cerebral arterioles to LTs and 12-hydroxyeicosatetraenoic acid (12-HETE) were studied in vivo in rabbits equipped with a cranial window for direct observation of the microcirculation. Topical application of LTC, LTD4, or 12-HETE (1.6 × 10−9–3.1 × 10−6 M) neither constricted nor dilated the pial arteries. LTB4 produced only a 5% vasoconstriction at 3.0 × 10−6 M. However, bradykinin induced dose-dependent arteriolar vasodilation and histamine and 5-hydroxytryptamine induced dose-dependent arteriolar vasoconstriction. Although some LTs have potent vasoconstrictor activity in peripheral tissues and 5-lipoxygenase products have been hypothesized to be mediators of vasospasm after subarachnoid hemorrhage, LTB4, LTC4, LTD4, and 12-HETE apparently are unable to induce significant constriction of the cerebral arterioles in the anesthetized rabbit.

SUMMARY. Experiments by others have shown that exogenous bradykinin dilates cerebral arterioles and that the brain contains kininogen and kallikrein, the latter being the enzyme which converts kininogen to bradykinin. The objective of these experiments was to determine if bradykinin produced from endogenous brain kininogen can affect the cerebral microcirculation. Rabbit pial arteriolar diameter was measured with a microscope using the dosed cranial window technique. Topical application of bradykinin (10~8-10~5 M) induced a dose-dependent vasodilation (8-46%) which was completely inhibited by the cydooxygenase enzyme inhibitors indomethadn and medofenamic add. Topical application of 1 U of tissue kallikrein per milliliter of artificial cerebrospinal fluid induced 43% dilation, which could be prevented by local treatment with indomethadn or the proteinase inhibitor aprotinin. The action of aprotinin and indomethadn was specific, since aprotinin did not affect the dilation produced by bradykinin, and indomethadn did not affect dilation produced by adenosine. A second application of kallikrein had no effect on cerebral diameter, yet the arterioles still responded normally to exogenous bradykinin, indicating that the first application of kallikrein depleted brain kininogen. We suggest that activation of brain kallikrein and subsequent formation of kinin from brain kininogen may be important in modulation of cerebral blood flow or generation of cerebral edema. (Circ Res 57: 545-552, 1985)