Abstract
In severe myocardial ischemia, histamine 3 (H3) receptor activation affords cardioprotection by preventing excessive norepinephrine release and arrhythmias; pivotal to this action is the inhibition of neuronal Na+/H+ exchanger (NHE). Conversely, angiotensin II, formed locally by mast cell-derived renin, stimulates NHE via angiotensin II type 1 (AT1) receptors, facilitating norepinephrine release and arrhythmias. Thus, ischemic dysfunction may depend on a balance between the NHE-modulating effects of H3 receptors and AT1 receptors. The purpose of this investigation was therefore to elucidate the H3/AT1 receptor interaction in myocardial ischemia/reperfusion. We found that H3 receptor blockade with clobenpropit increased norepinephrine overflow and arrhythmias in Langendorff-perfused guinea pig hearts subjected to ischemia/reperfusion. This coincided with increased neuronal AT1 receptor expression. NHE inhibition with cariporide prevented both increases in norepinephrine release and AT1 receptor expression. Moreover, norepinephrine release and AT1 receptor expression were increased by the nitric oxide (NO) synthase inhibitor NG-methyl-l-arginine and the protein kinase C activator phorbol myristate acetate. H3 receptor activation in differentiated sympathetic neuron-like PC12 cells permanently transfected with H3 receptor cDNA caused a decrease in protein kinase C activity and AT1 receptor protein abundance. Collectively, our findings suggest that neuronal H3 receptor activation inhibits NHE by diminishing protein kinase C activity. Reduced NHE activity sequentially causes intracellular acidification, increased NO synthesis, and diminished AT1 receptor expression. Thus, H3 receptor-mediated NHE inhibition in ischemia/reperfusion not only opposes the angiotensin II-induced stimulation of NHE in cardiac sympathetic neurons, but also down-regulates AT1 receptor expression. Cardioprotection ultimately results from the combined attenuation of angiotensin II and norepinephrine effects and alleviation of arrhythmias.
Footnotes
This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Grant HL034215]; and a Pharmaceutical Research Manufacturers of America Foundation predoctoral fellowship.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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ABBREVIATIONS:
- NE
- norepinephrine
- ANG
- angiotensin
- AT1R
- ANG II type 1 receptor
- H3R
- histamine 3 receptor
- H4R
- histamine 4 receptor
- I/R
- ischemia/reperfusion
- l-NMA
- NG-methyl-l-arginine
- NHE
- Na+/H+ exchanger
- NO
- nitric oxide
- PKC
- protein kinase C
- PMA
- phorbol 12-myristate β-acetate
- TBS
- Tris-buffered saline
- NGF
- nerve growth factor
- ANOVA
- analysis of variance
- ACE2
- angiotensin I converting enzyme 2
- CBP
- clobenpropit
- EXP3174
- 2-n-butyl-4-chloro-1-((2′-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) imidazole-5-carboxylic acid
- HOE642
- 4-isopropyl-3-methylsulfonylbenzoyl-guanidine methanesulfonate.
- Received September 6, 2011.
- Accepted October 18, 2011.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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