Lack of hemodynamic effects after extended heme synthesis inhibition by succinylacetone in rats.

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 x kg(-1) x day(-1) i.p.) for 14 days, resulting in a marked increase in urinary SA and delta-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.

• Authors: Stephane L Bourque, Carling D Benjamin, Michael A Adams, Kanji Nakatsu
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 333 Issue 1 Pg. 290-6 (Apr 2010) ISSN: 1521-0103 [Electronic] United States
• PMID: 20071481 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Heptanoates
• Receptors, Cytoplasmic and Nuclear
• Heme
• succinylacetone
• Aminolevulinic Acid
• Sodium
• Nitric Oxide Synthase
• Porphobilinogen Synthase
• Guanylate Cyclase
• Soluble Guanylyl Cyclase

Topics

• Aminolevulinic Acid (urine)
• Animals
• Blood Pressure (drug effects)
• Guanylate Cyclase (metabolism)
• Heme (antagonists & inhibitors, biosynthesis)
• Hemodynamics (drug effects)
• Heptanoates (toxicity, urine)
• Hypertension (metabolism, physiopathology)
• Kidney (drug effects, enzymology)
• Male
• Nitric Oxide Synthase (antagonists & inhibitors)
• Organ Specificity
• Porphobilinogen Synthase (antagonists & inhibitors)
• Rats
• Rats, Sprague-Dawley
• Receptors, Cytoplasmic and Nuclear (metabolism)
• Sodium (metabolism)
• Soluble Guanylyl Cyclase