Contractile Effects in Vitro

Melatonin acts on cerebrovascular receptors to modulate smooth muscle contractility, as shown in studies of rat cerebral arteries, pressurized in vitro (24,3955). Melatonin decreased lumen diameter of middle cerebral artery segments in a concentration-dependent manner (EC50 = 2.7 nM, Figure 1). This effect was inhibited by luzindole, a competitive melatonin receptor antagonist, and by pertussis toxin pre-treatment (24).

The magnitude of the constrictor response to melatonin appears to depend on the level of arterial pressure; in vitro responses were greater at higher levels of transmural pressure (24). When compared with other vasoconstrictors at the same pressure, the effects of melatonin were modest relative to those of serotonin, but similar in nature to those of tetraethylammonium (TEA) and charybdotoxin, two blockers of the large conductance, calcium-activated potassium (BKca) channel (24). Smooth muscle BKca channels play an important role in determining arterial tone and are activated at the membrane potentials found in pressurized cerebral arteries (42). In this preparation, melatonin-induced contractions were attenuated in the presence of either TEA or charybdotoxin, but unaffected by apamin, an inhibitor of small conductance Kca

Figure 1. Representative tracing of the vasoconstrictor effect of melatonin (MLT). Increasing concentrations of melatonin decrease the lumen diameter of a segment of rat middle cerebral artery, pressurized to 60 mm Hg in vitro. (PSS, physiological salt solution) From Ref. 24, with permission.

channels. Melatonin also reversed dilations by NS-1619, an activator of BK channels. Based on these findings, it was proposed that melatonin-induced constriction involves closure of BKra channels, perhaps through inhibition of the cyclic AMP-protein kinase A pathway (24).

We have obtained preliminary evidence that melatonin also has a direct vasodila-tory effect in cerebral arteries (13; Figure 2). In a small pressurized branch of rat middle cerebral artery (<180 ^m diameter), melatonin (1-100nM) induced an increase in lumen diameter that was reversibly blocked by luzindole, which antagonizes both mt1 and MT2 melatonin receptors. At this point, the factors determining whether dilation

Figure 2. The vasodilator effect of melatonin (MLT). In this segment of rat middle cerebral artery, mela-tonin increased lumen diameter (A). Subsequent exposure to luzindole inhibited the effect of melatonin (B), which returned following washout of luzindole (C).

or contraction is elicited by melatonin are not known, but possibilities include the presence of different receptor subtypes and/or different receptor distributions in various cerebral arteries.

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