PT  - JOURNAL ARTICLE
AU  - Nassar, Noha N.
AU  - Li, Guichu
AU  - Strat, Aurel L.
AU  - Abdel-Rahman, Abdel A.
TI  - Enhanced Hemeoxygenase Activity in the Rostral Ventrolateral Medulla Mediates Exaggerated Hemin-Evoked Hypotension in the Spontaneously Hypertensive Rat
AID  - 10.1124/jpet.111.183368
DP  - 2011 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 267--274
VI  - 339
IP  - 1
4099  - http://jpet.aspetjournals.org/content/339/1/267.short
4100  - http://jpet.aspetjournals.org/content/339/1/267.full
SO  - J Pharmacol Exp Ther2011 Oct 01; 339
AB  - In anesthetized normotensive rats, activation of brainstem hemeoxygenase (HO) elicits sympathoinhibition and hypotension. Accordingly, we tested the hypothesis that attenuated basal or induced HO activity in the rostral ventrolateral medulla (RVLM) contributes to hypertension in the spontaneously hypertensive rat (SHR). We measured basal RVLM HO expression and catalytic activity and investigated the effects of intra-RVLM HO activation (hemin) or selective HO isoform 1 (HO-1) inhibition [zinc protoporphyrin IX (ZnPPIX)] on mean arterial pressure (MAP), heart rate, and RVLM neuronal norepinephrine (NE) level (index of sympathetic activity) in conscious SHRs and Wistar Kyoto 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 (CO-releasing molecule 3) elicited similar MAP reductions in both rat strains. Furthermore, pretreatment with ZnPPIX or the selective neuronal nitric-oxide synthase (nNOS) inhibitor N-propyl-l-arginine 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: 1) the exaggerated hypotension elicited by intra-RVLM HO activation in the SHR is nNOS-dependent, and 2) in the SHR, the enhanced RVLM HO-nNOS signaling compensates for the reduced expression/activity of the downstream target, soluble guanylyl cyclase. Together, the findings suggest a protective role for the RVLM HO-nNOS pathway against further increases in MAP in the SHR.