Neurogenic Dural Protein Extravasation Induced by Meta-Chlorophenylpiperazine (Mcpp) Involves Nitric Oxide and 5-HT2B Receptor Activation

Cephalalgia ◽  
2003 ◽  
Vol 23 (2) ◽  
pp. 117-123 ◽  
Author(s):  
KW Johnson ◽  
DL Nelson ◽  
DK Dieckman ◽  
DB Wainscott ◽  
VL Lucaites ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Receptor Antagonist ◽  
Receptor Activation ◽  
Trigeminal System ◽  
Nitric Oxide Synthase Inhibitor ◽  
Protein Extravasation ◽  
Plasma Protein Extravasation ◽  
Synthase Inhibitor ◽  
Oxide Synthase ◽  
Stimulation Of

The compound m-chlorophenylpiperazine (mCPP), which is known to trigger migraine-like head pain in some subjects, was evaluated for its ability to induce dural plasma protein extravasation (PPE) in guinea pigs. Intravenous mCPP dose-dependently increased PPE. This effect was inhibited by non-selective 5-HT2 receptor antagonists (methysergide, LY53857, LY215840), by a peripherally restricted 5-HT2 receptor antagonist (xylamidine) and by a 5-HT2B selective receptor antagonist (LY202146). These data suggests that peripheral 5-HT2B receptors mediate mCPP-induced PPE. The nitric oxide synthase inhibitor L-NAME and 5-HT1 agonist sumatriptan also blocked mCPP-induced PPE, suggesting a role for nitric oxide (NO) and the trigeminal system, respectively. NO release has been linked to activation of the 5-HT2B receptor on the vascular endothelium. However, LY202146 did not block PPE induced by electrical stimulation of the trigeminal ganglion. These data are consistent with activation of peripheral 5-HT2B receptors initiating PPE and the theory that selective 5-HT2B antagonists might be effective prophylactic therapies for migraine.

NO release and the opening of K+ATP channels mediate vasodilator responses to histamine in the cat

1997 ◽  
Vol 273 (2) ◽  
pp. H928-H937 ◽  
Author(s):  
H. C. Champion ◽  
P. J. Kadowitz
Keyword(s):  
Nitric Oxide ◽  
Phosphodiesterase Inhibitor ◽  
Receptor Activation ◽  
K Channel ◽  
Flow Conditions ◽  
Nitric Oxide Synthase Inhibitor ◽  
Vascular Bed ◽  
H3 Receptor ◽  
Synthase Inhibitor ◽  
Oxide Synthase

Responses to histamine were investigated in the hindlimb vascular bed of the cat under constant-flow conditions. Injections of histamine, the H1 agonist HTMT, the H2 agonist dimaprit, and the H3 agonist R(-)-alpha-methylhistamine caused dose-related decreases in hindlimb perfusion pressure. Pyrilamine reduced the responses to histamine and HTMT by approximately 80%, whereas cimetidine reduced the responses to histamine by 20% and to dimaprit by approximately 50%. The H3-receptor antagonist thioperamide reduced the responses to R(-)-alpha-methylhistamine by approximately 60% but was without effect on the other histamine agonists. These data suggest the presence of H1, H2, and H3 receptors in the hindlimb vascular bed of the cat, that histamine acts, for the most part, by stimulating H1 receptors, and that H3-receptor activation is not involved in mediating the responses to histamine. The responses to histamine and the H1-, H2-, and H3-receptor agonists were significantly reduced by a nitric oxide synthase inhibitor and enhanced in duration by the guanosine 3', 5'-cyclic monophosphate (cGMP)-selective phosphodiesterase inhibitor zaprinast, suggesting that the responses are mediated, in part, by the release of nitric oxide and an increase in cGMP levels. The responses to histamine agonists but not to nitric oxide donors were significantly reduced by the nonselective K(+)-channel antagonist tetraethylammonium. The responses to histamine and the H1, H2, and H3 agonists were not affected by the cyclooxygenase inhibitor meclofenamate. The responses to histamine and HTMT are also reduced 30-50% by U-37883A, an ATP-sensitive K+ (K+ATP)-channel antagonist, at a time when the responses to the H2 and H3 agonists were unaltered. The present data suggest that vasodilation of the hindlimb vascular bed in response to H1-, H2-, and H3-receptor activation is mediated by a tetraethylammonium-sensitive mechanism that is associated with the release of nitric oxide and an increase in cGMP levels. These data further suggest that the response to H1-receptor activation is mediated by the complementary, yet independent, release of nitric oxide and the opening of a K+ATP channel.

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