TY - JOUR T1 - Histamine H3-receptor activation reduces the expression of neuronal angiotensin AT1-receptors in the heart JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.111.187765 SP - jpet.111.187765 AU - Narumi Hashikawa-Hobara AU - Noel Yan-Ki Chan AU - Roberto Levi Y1 - 2011/01/01 UR - http://jpet.aspetjournals.org/content/early/2011/10/19/jpet.111.187765.abstract N2 - In severe myocardial ischemia, histamine 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 AT1-receptors, facilitating norepinephrine release and arrhythmias. Thus, ischemic dysfunction may depend on a balance between the respective 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 an 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 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 nitric oxide 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 downregulates AT1R expression. Cardioprotection ultimately results from the combined attenuation of angiotensin II and norepinephrine effects and alleviation of arrhythmias. ER -