Constrictor Effects in Vitro

In most isolated preparations of rat tail artery, melatonin does not produce contraction by itself but potentiates the action of other vasoconstrictors (25,35,50,53, Figure 3). However, in pressurized tail arteries from juvenile rats, melatonin could directly constrict the vessel segments (21),similar to what is seen in pressurized cerebral arteries (24). In perfused, non-pressurized tail arteries, melatonin also caused contraction following the addition of NS-1619 to open BK channels (25). We have hypothesized that the varying nature of in vitro responses to melatonin may reflect different resting states of the isolated arterial preparations (25). Evidence suggests the effect of melatonin may depend on factors such as membrane potential, open state of potassium channels, and/or levels of cyclic AMP production (9,24,25). Consequently, significant changes in these factors, in vitro or in vivo, would influence the ability of melatonin to elicit a response.

Our initial study to pharmacologically characterize functional melatonin responses indicated that mt1/MT2-like melatonin receptors mediate potentiation of tail



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Figure 3. Melatonin (100 nM) potentiates the contractile effect of adrenergic nerve stimulation in an isolated, perfused segment of rat tail artery. Representative tracing shows increase in arterial pressure in response to increasing frequencies of adrenergic nerve stimulation (Hz). From Ref. 25, with permission.

artery constriction (35). This conclusion was based on the relative potencies of 2-iodomelatonin, melatonin and N-acetylserotonin and competitive inhibition by luzin-dole, a known melatonin receptor antagonist (34). The constrictor response in tail artery has been further characterized using a naphthalenic series of mti/MT2 agonists, partial agonists and antagonists and a pair of indole-based stereoisomers, (+) and (-)AMMTC (50). These findings also suggest that melatonin is acting on mti/MT2-like melatonin receptors to increase vascular tone.

Most of the drugs tested to date, however, do not discriminate between the mti and MT2 melatonin receptor subtypes. The affinity of luzindole for recombinant human mtj receptors is only about 15-fold lower than its affinity for the recombinant mtj subtype (18). However, the Kb estimated for luzindole in the rat tail artery (3 x 10-7 M; 35,36) correlates well with the affinity of this antagonist for the recombinant mti subtype (17,18). We also find the relative agonist potency of 6-Cl-melatonin to be consistent with the mt1 subtype, i.e, it is ten-fold less potent than melatonin (36). Constrictor effects of melatonin are not inhibited by 4-P-ADOT (4-phenyl-2-acetamidote-tralin) at concentrations selective for the MT2 receptor (10-8M) nor are they mimicked by the selective MT3 agonist, MCA-NAT (5-methoxy-carbonyl-amino-N-acetyltryptamine) (36). These data, together with the finding of mt1 mRNA in tail artery smooth muscle (40), suggest that mt1 receptors mediate vasoconstriction. The development of a selective mt1 antagonist, however, is needed to confirm this hypothesis.

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Sleeping Sanctuary

Salvation For The Sleep Deprived The Ultimate Guide To Sleeping, Napping, Resting And  Restoring Your Energy. Of the many things that we do just instinctively and do not give much  of a thought to, sleep is probably the most prominent one. Most of us sleep only because we have to. We sleep because we cannot stay awake all 24 hours in the day.

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