Enhanced Hemeoxygenase Activity in the Rostral Ventrolateral Medulla Mediates Exaggerated Hemin-Evoked Hypotension in the Spontaneously Hypertensive Rat

Abstract

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.

Neuronal Nitric Oxide Synthase–Dependent Elevation in Adiponectin in the Rostral Ventrolateral Medulla Underlies G Protein–Coupled Receptor 18–Mediated Hypotension in Conscious Rats

“…Dimethylsulfoxide (DMSO) was used as the vehicle for all kinase inhibitors, whereas saline was the vehicle for NOS inhibitors. DMSO was diluted in artificial cerebrospinal fluid (1:16) and this DMSO/artificial cerebrospinal fluid mixture had no effect on BP, which is consistent with our previous findings (Nassar et al, 2011). The rats in each group (n 5 6 unless otherwise specified) received one of the following treatment combinations (80 nl): 1) DMSO plus vehicle or Abn CBD (n 5 3 each), 2) saline plus vehicle or Abn CBD (n 5 3 each), 3) wortmannin plus vehicle or Abn CBD, 4) PD98059 plus vehicle or Abn CBD, 5) L-NIO plus vehicle or Abn CBD, or 6) NPLA plus vehicle or Abn CBD.…”

“…These surgeries were performed as reported in our previous studies (Zhang and Abdel-Rahman, 2002;Penumarti and Abdel-Rahman, 2014). On the day of the experiment, the arterial catheter was flushed with heparin in saline (200 U/ml), connected to a Gould-Statham (Oxnard, CA) pressure transducer, and the BP of unrestrained rats was measured as mentioned in our previous studies (Nassar et al, 2011;Ibrahim and Abdel-Rahman, 2012a). Expanded Materials and Methods are available in the Supplemental Materials and Methods.…”

Rostral Ventrolateral Medulla EP3 Receptor Mediates the Sympathoexcitatory and Pressor Effects of Prostaglandin E2 in Conscious Rats

“…Five days after the surgical procedures, an ML870 (PowerLab 8/30, AD Instruments, Colorado Springs, CO) system was used to measure BP and heart rate (HR) in conscious unrestrained rats. The data were analyzed and displayed using LabChart (version 7) prosoftware (AD Instruments, Colorado Springs, CO) as in our reported studies (Ibrahim and Abdel-Rahman, 2011;Nassar et al, 2011;Penumarti and Abdel-Rahman, 2014).…”

Enhancement of Rostral Ventrolateral Medulla Neuronal Nitric-Oxide Synthase–Nitric-Oxide Signaling Mediates the Central Cannabinoid Receptor 1-Evoked Pressor Response in Conscious Rats

“…Procedures detailed in our previous studies were used for BP and HR measurements in conscious unrestrained rats Abdel-Rahman, 2011, 2012;Nassar et al, 2011).…”

“…A modified protocol from our recent studies (Nassar et al, 2011;Ibrahim and Abdel-Rahman, 2012) was used to measure phosphorylated and total nNOS. Animals were euthanized, and brains were removed, flash-frozen, and stored at Ϫ80°C until used.…”