Migraine Therapy

Canine and rabbit vascular contractile responses to serotonergic agonists have been used to predict antimigraine efficacy for several antimigraine agents, including sumatriptan. The purpose of the present study was to establish the assumed predictive value of contractile responses in canine and rabbit saphenous veins to contractile efficacy for a series of agonists in human cerebral and coronary arteries and to understand better the receptors mediating such responses. The canine and rabbit saphenous veins contracted similarly (both qualitatively and quantitatively) to series of structurally diverse serotonergic agonists, suggesting that the receptors mediating serotonin-induced contractility in these tissues were similar. In addition, the contractile potency (estimated as EC50 values) for these structurally diverse serotonergic agonists in either the rabbit or canine saphenous vein significantly correlated with contractile potency for these agonists in human cerebral arteries. Thus, to the extent that contractile responsiveness of human cerebral arteries may predict antimigraine agents, contractile responses of the rabbit and/or canine saphenous vein may be useful surrogates for antimigraine efficacy. In addition, the contractile potency for this series of serotonergic agonists in the rabbit or canine saphenous vein significantly correlated with contractile potency of these agonists in human coronary arteries. These data suggest that the use of the saphenous vein to identify potent vasoconstrictors will also reveal agents capable of contracting human coronary arteries, a liability for using this approach to evaluate promising antimigraine therapies.

Increased myosin light chain kinase content in sensitized canine saphenous vein

Our previous studies revealed that smooth muscle from sensitized canine saphenous vein (SCSV) demonstrated greater active shortening capacity, maximum shortening velocity, and prolonged relaxation vis-a-vis the control muscle. These changes could be responsible for the in vivo hyperreactivity of venous smooth muscle observed in anaphylactic shock. Because smooth muscle cross-bridge cycling is regulated by myosin light chain kinase (MLCK)-dependent phosphorylation of the 20-kDa myosin light chain (MLC20), we studied MLC20 and MLCK phosphorylation in homogenates of SCSV and veins from littermate control dogs. We found that phosphorylation of MLC20 in SCSV homogenate was higher (42.26 +/- 5.10%) compared with control homogenates (26.69 +/- 3.30%; P < 0.05); MLCK content was significantly higher in SCSV homogenates [0.169 +/- 0.019 (SE) mu g/mg protein] than in control homogenates (0.075 +/- 0.004 mu g/mg protein; P < 0.05). Total MLCK activity increased from 6.16 +/- 0.60 x 10(-5) nmol Pi x mg fresh weight of tissue-1 x min-1 in control homogenates to 12.50 +/- 2.50 x 10(-5) nmol Pi x mg fresh weight of tissue-1 x min-1 in sensitized homogenates (P < 0.05). Specific MLCK activity was, however, similar in sensitized and control homogenates. The results of our study suggest that elevation of MLCK content in the homogenate could account for the increased contractility of the SCSV in anaphylactic shock.