Abstract
The role of histamine as a newly recognized sympathetic neurotransmitter has been presented previously, and its postsynaptic effects greatly depended on the activities of sympathetic nerves. Cardiac sympathetic nerves become overactivated under acute myocardial ischemic conditions and release neurotransmitters in large amounts, inducing ventricular arrhythmia. Therefore, it is proposed that cardiac sympathetic histamine, in addition to norepinephrine, may have a significant arrhythmogenic effect. To test this hypothesis, we observed the release of cardiac sympathetic histamine and associated ventricular arrhythmogenesis that was induced by acute ischemia in isolated mouse hearts. Mast cell-deficient mice (MCDM) and histidine decarboxylase knockout (HDC(-/-)) mice were used to exclude the potential involvement of mast cells. Electrical field stimulation and acute ischemia-reperfusion evoked chemical sympathectomy-sensitive histamine release from the hearts of both MCDM and wild-type (WT) mice but not from HDC(-/-) mice. The release of histamine from the hearts of MCDM and WT mice was associated with the development of acute ischemia-induced ventricular tachycardia and ventricular fibrillation. The incidence and duration of induced ventricular arrhythmias were found to decrease in the presence of the selective histamine H(2) receptor antagonist famotidine. Additionally, the released histamine facilitated the arrhythmogenic effect of simultaneously released norepinephrine. We conclude that, under acute ischemic conditions, cardiac sympathetic histamine released by overactive sympathetic nerve terminals plays a certain arrhythmogenic role via H(2) receptors. These findings provided novel insight into the pathophysiological roles of sympathetic histamine, which may be a new therapeutic target for acute ischemia-induced arrhythmias.
Highlights
Previous investigations have shown that endogenous histamine (HA) and HA receptors play highly significant roles in many cardiovascular diseases, such as hypertension [1,2], artherosclerosis [3,4,5] and chronic heart failure [6,7]
The staining of tryptase, a specific marker of mast cells, showed that heart sections from WT and histidine decarboxylase (HDC)–/– mice expressed a number of mast cells (Figures 1A1, C1), but none were found in the hearts of the homozygote of Mast cell–deficient mice (MCDM) (Figure 1B1)
HA-like immunopositive signals were found to be present in Superior cervical ganglions (SCGs) neurons of the same WT mice and homozygote of MCDM (Figures 1A3, B3), but were absent in the HDC–/– mice (Figure 1C3)
Summary
Previous investigations have shown that endogenous histamine (HA) and HA receptors play highly significant roles in many cardiovascular diseases, such as hypertension [1,2], artherosclerosis [3,4,5] and chronic heart failure [6,7]. Several previous reports have suggested that the cardiac endogenous HA originates from mast cells. Cardiac mast cells are degranulated and release HA to induce arrhythmogenesis [8]. The overactivation of cardiac sympathetic nerves in ischemic hearts, as reported in previous studies, further correlates with ischemiainduced ventricular arrhythmias [11,12,13,21,22]. It is rational to speculate that sympathetic HA, in addition to norepinephrine (NE), is released and plays certain pathophysiological roles in ischemia-induced ventricular arrhythmias
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