Histamine 3 receptor activation reduces the expression of neuronal angiotensin II type 1 receptors in the heart.
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 N(G)-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.
Department of Pharmacology, Weill Cornell Medical College, New York, NY, USA.
Narumi
N
Hashikawa-Hobara
Noel Yan-Ki
NY
Chan
Roberto
R
Levi
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000294:innervation; D017442:Histamine Agonists / Q000494:pharmacology*; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000473:pathology; D009206:Myocardium / Q000378:metabolism*; D009411:Nerve Endings / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009569:Nitric Oxide / Q000494:pharmacology; D016716:PC12 Cells; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis*; D018100:Receptors, Histamine H3 / Q000187:drug effects / Q000502:physiology*; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D017442:Histamine Agonists; D044140:Receptor, Angiotensin, Type 1; D018100:Receptors, Histamine H3; D017923:Sodium-Hydrogen Exchangers; D000804:Angiotensin II; D009569:Nitric Oxide; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate