Abstract

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.