Histamine 3 receptor activation reduces the expression of neuronal angiotensin II type 1 receptors in the heart

In severe myocardial ischemia, histamine 3 (H?) 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 (AT?) receptors, facilitating norepinephrine release and arrhythmias. Thus, ischemic dysfunction may depend on a balance between the NHE-modulating effects of H? receptors and AT? receptors. The purpose of this investigation was therefore to elucidate the H?/AT? receptor interaction in myocardial ischemia/reperfusion. We found that H? receptor blockade with clobenpropit increased norepinephrine overflow and arrhythmias in Langendorff-perfused guinea pig hearts subjected to ischemia/reperfusion. This coincided with increased neuronal AT? receptor expression. NHE inhibition with cariporide prevented both increases in norepinephrine release and AT? receptor expression. Moreover, norepinephrine release and AT? receptor expression were increased by the nitric oxide (NO) synthase inhibitor N(G)-methyl-L-arginine and the protein kinase C activator phorbol myristate acetate. H? receptor activation in differentiated sympathetic neuron-like PC12 cells permanently transfected with H? receptor cDNA caused a decrease in protein kinase C activity and AT? receptor protein abundance. Collectively, our findings suggest that neuronal H? receptor activation inhibits NHE by diminishing protein kinase C activity. Reduced NHE activity sequentially causes intracellular acidification, increased NO synthesis, and diminished AT? receptor expression. Thus, H? 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 AT? receptor expression. Cardioprotection ultimately results from the combined attenuation of angiotensin II and norepinephrine effects and alleviation of arrhythmias.