RT Journal Article
SR Electronic
T1 Norepinephrine Release from the Ischemic Heart Is Greatly Enhanced in Mice Lacking Histamine H<sub>3</sub> Receptors
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 378
OP 382
DO 10.1124/mol.63.2.378
VO 63
IS 2
A1 Motohiro Koyama
A1 Nahid Seyedi
A1 Wai-Ping Fung-Leung
A1 Timothy W. Lovenberg
A1 Roberto Levi
YR 2003
UL http://molpharm.aspetjournals.org/content/63/2/378.abstract
AB We previously reported that histamine H3 receptors (H3Rs) are present in cardiac sympathetic nerve endings (cSNE) of animals and humans, where they attenuate norepinephrine (NE) release in normal and hyperadrenergic states, such as myocardial ischemia. The recent creation of a transgenic line of mice lacking H3R provided us with the opportunity to assess the relevance of H3R in the ischemic heart. We isolated SNE from hearts of wild-type (H3R+/+) and knockout (H3R−/−) mice and found that basal NE release from H3R−/− cSNE was ∼60% greater than that from H3R+/+ cSNE. NE exocytosis evoked by K+-induced depolarization of cSNE from H3R+/+ mice was attenuated by activation of either H3R or adenosine A1 receptors (A1R). In contrast, NE release from cSNE of H3R−/− was unaffected by H3R agonists, but it was still attenuated by A1R activation. When isolated mouse hearts were subjected to ischemia for 20 min, NE overflow into the coronaries was 2-fold greater in the H3R−/− hearts than in those from H3R+/+ mice. Furthermore, whereas stimulation of H3R or A1R reduced ischemic NE overflow from H3R+/+ hearts by 50%, only A1R, but not H3R activation, reduced NE release in H3R−/−. Our data demonstrate that NE release from cSNE can be modulated by various heteroinhibitory receptors (e.g., H3R and A1R) and that H3Rs are particularly important in modulating NE release in myocardial ischemia. Inasmuch as excessive NE release is clinically recognized as a major cause of arrhythmic cardiac dysfunction, our findings reveal a significant cardioprotective role of H3R on cSNE. The American Society for Pharmacology and Experimental Therapeutics