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NO release and the opening of K+ATP channels mediate vasodilator responses to histamine in the cat
1Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
Insights
Histamine causes vasodilation in cat hindlimbs primarily through H1 receptors, involving nitric oxide and cGMP. H1 activation also utilizes ATP-sensitive potassium channels, distinct from H2 and H3 receptor pathways.
Area of Science:
- Pharmacology
- Physiology
- Cardiovascular Research
Background:
- Histamine receptors (H1, H2, H3) play diverse roles in vascular function.
- The specific mechanisms of histamine-induced vasodilation in the feline hindlimb are not fully elucidated.
Purpose of the Study:
- To investigate the histamine receptor subtypes involved in feline hindlimb vasodilation.
- To determine the intracellular signaling pathways mediating these responses, including nitric oxide and ion channels.
Main Methods:
- Administered histamine and selective receptor agonists (HTMT, dimaprit, R(-)-alpha-methylhistamine) and antagonists (pyrilamine, cimetidine, thioperamide) in a constant-flow cat hindlimb preparation.
- Utilized nitric oxide synthase and phosphodiesterase inhibitors (zaprinast), K+ channel blockers (tetraethylammonium), cyclooxygenase inhibitors (meclofenamate), and K+ATP channel antagonists (U-37883A).
- Measured changes in hindlimb perfusion pressure to assess vascular responses.
Main Results:
- Histamine, H1, H2, and H3 agonists all induced dose-dependent decreases in perfusion pressure (vasodilation).
- H1 receptors were the primary mediators of histamine's vasodilatory effect, with partial involvement of H2 and H3.
- Responses involved nitric oxide release and increased cyclic guanosine monophosphate (cGMP), modulated by tetraethylammonium-sensitive mechanisms.
- H1-receptor-mediated vasodilation was additionally linked to ATP-sensitive potassium (K+ATP) channel opening.
Conclusions:
- The feline hindlimb vascular bed expresses functional H1, H2, and H3 receptors.
- Histamine-induced vasodilation is predominantly mediated via H1 receptors, involving nitric oxide/cGMP pathways and K+ATP channels.
- H3 receptor activation does not mediate histamine's vasodilatory effects in this model, despite the presence of H3 receptors.
Abstract:
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.