PT  - JOURNAL ARTICLE
AU  - Stephane L. Bourque
AU  - Carling D. Benjamin
AU  - Michael A. Adams
AU  - Kanji Nakatsu
TI  - Lack of Hemodynamic Effects After Extended Heme Synthesis Inhibition by Succinylacetone in Rats
AID  - 10.1124/jpet.109.162966
DP  - 2010 Apr 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 290--296
VI  - 333
IP  - 1
4099  - http://jpet.aspetjournals.org/content/333/1/290.short
4100  - http://jpet.aspetjournals.org/content/333/1/290.full
SO  - J Pharmacol Exp Ther2010 Apr 01; 333
AB  - 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.