Abstract
Hypertyrosinemia (HT) is a life-threatening condition caused in large part by the buildup of tyrosine metabolites and their derivatives. One such metabolite is succinylacetone (SA), a potent irreversible inhibitor of heme biosynthesis. Heme is a key component of numerous enzymes involved in arterial blood pressure (BP) regulation, including nitric-oxide synthase (NOS) and its downstream mediator soluble guanylyl cyclase (sGC). Because NOS and sGC are important regulators of cardiovascular function, we hypothesized that inhibition of heme supply to these enzymes by SA would result in the induction of a measurable hypertensive response. Male Sprague-Dawley rats were treated with SA (80 mg · kg−1 · day−1 i.p.) for 14 days, resulting in a marked increase in urinary SA and δ-aminolevulinic acid (P < 0.001 for both parameters) and decreased heme concentrations in kidney, liver, spleen, and vascular tissues (P < 0.05 for all parameters). After SA treatment, systemic nitrite/nitrate excretion was reduced by 72% (P < 0.001), and renal NOS and sGC activities were decreased by 32 (P < 0.05) and 38% (P < 0.01), respectively. SA administration also compromised the ex vivo sensitivity of aorta to endothelium-dependent and -independent vasodilation. Despite these effects, SA treatment failed to induce any changes in BP, as assessed by radiotelemetry. Moreover, BP profiles in the SA-treated animals were less responsive to altered sodium intake. The present results demonstrate that extended inhibition of heme synthesis with SA affects hemoenzyme function, albeit without consequent effects on BP regulation and sodium excretion.
Footnotes
- Received October 23, 2009.
- Accepted January 12, 2010.
S.L.B. and C.D.B. contributed equally to this study.
This work was supported by the Canadian Institutes of Health Research [Grants MOP-68993, MOP-74521]. S.L.B. is a recipient of the Canadian Hypertension Society/Pfizer/Canadian Institutes of Health Research's Research and Development Doctoral Award. C.D.B. is a recipient of the Canadian Institutes of Health Research-Gasotransmitter Research and Training Master's Award.
This study was presented, in part, in Benjamin CD, Bourque SL, Adams MA, and Nakatsu K (2008) Long-term inhibition of heme synthesis: vascular implications, at the 19th Annual Scientific Meeting of the Ontario Hypertension Society; 2008 May 2–4; Alliston, ON, Canada.
Parts of this study were included in Bourque SL (2009) The Long-Term Cardiovascular and Behavioral Consequences of Maternal Iron Restriction During Gestation in Rat Offspring, Ph.D. thesis, Queen's University, Kingston, ON, Canada; and Benjamin CD (2008) Long-Term Heme Synthesis Inhibition: Vascular Implications; M.Sc thesis, Queen's University, Kingston, ON, Canada.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.162966.
-
ABBREVIATIONS:
- BP
- arterial blood pressure
- δ-ALA
- δ-aminolevulinic acid
- HT
- hypertyrosinemia
- NO
- nitric oxide
- NOS
- NO synthase
- SA
- succinylacetone
- sGC
- soluble guanylyl cyclase
- MAP
- mean arterial pressure
- l-NAME
- N-nitro-l-arginine methyl ester
- SNP
- sodium nitroprusside
- PE
- phenylephrine
- ACh
- acetylcholine
- MAHMA-NONOate
- methylamine hexamethylene methylamine NONOate.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|