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Norepinephrine release from the ischemic heart is greatly enhanced in mice lacking histamine H3 receptors
Motohiro Koyama1, Nahid Seyedi, Wai-Ping Fung-Leung
1Department of Pharmacology, Weill Medical College of Cornell University, New York, New York 10021, USA.
Insights
Histamine H(3) receptors (H(3)Rs) protect the heart during ischemia by reducing norepinephrine release from cardiac sympathetic nerve endings. Mice lacking H(3)Rs showed increased norepinephrine release and impaired protection, highlighting H(3)R
Area of Science:
- Cardiovascular Pharmacology
- Neuroscience
- Receptor Physiology
Background:
- Histamine H(3) receptors (H(3)Rs) are known to regulate norepinephrine (NE) release from cardiac sympathetic nerve endings (cSNE).
- H(3)Rs attenuate NE release in normal and hyperadrenergic states, including myocardial ischemia.
- The role of H(3)R in the ischemic heart was investigated using a newly created H(3)R knockout mouse model.
Purpose of the Study:
- To assess the functional relevance of H(3)Rs in modulating cardiac sympathetic nerve activity during myocardial ischemia.
- To compare NE release and response to receptor activation in wild-type versus H(3)R knockout mice under ischemic conditions.
Main Methods:
- Isolation of cardiac sympathetic nerve endings (cSNE) from wild-type (H(3)R(+/+)) and H(3)R knockout (H(3)R(-/-)) mice.
- Measurement of basal and depolarization-evoked NE release from isolated cSNE.
- Assessment of NE overflow into coronary perfusate in isolated hearts subjected to 20 minutes of ischemia.
- Pharmacological manipulation using H(3)R and adenosine A(1) receptor (A(1)R) agonists.
Main Results:
- Basal NE release was significantly higher (~60%) in H(3)R(-/-) cSNE compared to H(3)R(+/+) cSNE.
- Ischemic hearts from H(3)R(-/-) mice exhibited a 2-fold greater NE overflow than wild-type hearts.
- H(3)R activation attenuated NE release in wild-type hearts during ischemia, an effect absent in H(3)R(-/-) hearts.
- Adenosine A(1) receptors consistently attenuated NE release in both genotypes, indicating a complementary inhibitory mechanism.
Conclusions:
- Histamine H(3) receptors play a crucial role in limiting norepinephrine release from cardiac sympathetic nerve endings during myocardial ischemia.
- The absence of H(3)Rs exacerbates NE overflow during ischemia, suggesting a significant cardioprotective role.
- H(3)Rs and A(1)Rs act as important heteroinhibitory modulators of NE release, with H(3)Rs being particularly vital in ischemic conditions.
Abstract:
We previously reported that histamine H(3) receptors (H(3)Rs) 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 H(3)R provided us with the opportunity to assess the relevance of H(3)R in the ischemic heart. We isolated SNE from hearts of wild-type (H(3)R(+/+)) and knockout (H(3)R(-/-)) mice and found that basal NE release from H(3)R(-/-) cSNE was approximately 60% greater than that from H(3)R(+/+) cSNE. NE exocytosis evoked by K(+)-induced depolarization of cSNE from H(3)R(+/+) mice was attenuated by activation of either H(3)R or adenosine A(1) receptors (A(1)R). In contrast, NE release from cSNE of H(3)R(-/-) was unaffected by H(3)R agonists, but it was still attenuated by A(1)R activation. When isolated mouse hearts were subjected to ischemia for 20 min, NE overflow into the coronaries was 2-fold greater in the H(3)R(-/-) hearts than in those from H(3)R(+/+) mice. Furthermore, whereas stimulation of H(3)R or A(1)R reduced ischemic NE overflow from H(3)R(+/+) hearts by 50%, only A(1)R, but not H(3)R activation, reduced NE release in H(3)R(-/-). Our data demonstrate that NE release from cSNE can be modulated by various heteroinhibitory receptors (e.g., H(3)R and A(1)R) and that H(3)Rs 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 H(3)R on cSNE.