RT Journal Article
SR Electronic
T1 Enhanced Hemeoxygenase Activity in the Rostral Ventrolateral Medulla Mediates the Exaggerated Hemin-Evoked Hypotension in the SHR
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.111.183368
DO 10.1124/jpet.111.183368
A1 Noha Nassar
A1 Guichu Li
A1 Aurel Strat
A1 Abdel A. Abdel-Rahman
YR 2011
UL http://jpet.aspetjournals.org/content/early/2011/07/18/jpet.111.183368.abstract
AB In anesthetized normotensive rats, activation of brainstem hemeoxygenase (HO) elicits sympathoinhibition and hypotension. Accordingly, we tested the hypothesis that an attenuated basal or induced HO activity in the rostral ventrolateral medulla (RVLM) contributes to hypertension in the SHR. We measured basal RVLM HO expression and catalytic activity and investigated the effects of intra-RVLM HO activation (hemin) or selective HO-1 inhibition (zinc protoporphyrin IX, ZnPPIX) on MAP, HR and RVLM neuronal norepinephrine (NE) level (index of sympathetic activity) in conscious SHRs and WKY rats. Basal RVLM HO catalytic activity (bilirubin level) and HO-1 expression were significantly higher in the SHR. These neurochemical findings were corroborated by the significantly greater decreases (hemin) and increases (ZnPPIX) in RVLM NE and MAP in the SHR. By contrast, HO-independent CO release in the RVLM (CORM-3) elicited similar MAP reductions in both rat strains. Further, pretreatment with ZnPPIX or the selective nNOS inhibitor N-propyl-L-arginine (NPLA) abrogated the neurochemical (RVLM cGMP) and hypotensive responses caused by hemin. In addition to demonstrating, for the first time, higher basal RVLM HO catalytic activity and HO-1 expression in the SHR, the findings suggest that: (i) the exaggerated hypotension elicited by intra-RVLM HO activation in the SHR is nNOS-dependent, and (ii) in the SHR, the enhanced RVLM HO-nNOS signaling compensates for the reduced expression/activity of the downstream target, soluble guanylyl cyclase (sGC). Together, the findings suggest a protective role for RVLM HO-nNOS pathway against further increases in MAP in the SHR.