Abstract
In severe myocardial ischemia, histamine 3 (H&sub3;) 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&sub1;) receptors, facilitating norepinephrine release and arrhythmias. Thus, ischemic dysfunction may depend on a balance between the NHE-modulating effects of H&sub3; receptors and AT&sub1; receptors. The purpose of this investigation was therefore to elucidate the H&sub3;/AT&sub1; receptor interaction in myocardial ischemia/reperfusion. We found that H&sub3; 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&sub1; receptor expression. NHE inhibition with cariporide prevented both increases in norepinephrine release and AT&sub1; receptor expression. Moreover, norepinephrine release and AT&sub1; 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&sub3; receptor activation in differentiated sympathetic neuron-like PC12 cells permanently transfected with H&sub3; receptor cDNA caused a decrease in protein kinase C activity and AT&sub1; receptor protein abundance. Collectively, our findings suggest that neuronal H&sub3; receptor activation inhibits NHE by diminishing protein kinase C activity. Reduced NHE activity sequentially causes intracellular acidification, increased NO synthesis, and diminished AT&sub1; receptor expression. Thus, H&sub3; 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&sub1; receptor expression. Cardioprotection ultimately results from the combined attenuation of angiotensin II and norepinephrine effects and alleviation of arrhythmias.