Long-term heme synthesis inhibition: vascular implications
Heme is essential for numerous enzymes involved in the regulation of vascular tone; it is an integral component of nitric oxide synthase and soluble guanylyl cyclase, and is the substrate for heme oxygenase, enzymes critical for vasodilation. Inhibition of heme synthesis is anticipated to result in...
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| Format: | Others |
| Language: | en en |
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2008
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| Online Access: | http://hdl.handle.net/1974/1263 |
| Summary: | Heme is essential for numerous enzymes involved in the regulation of vascular tone; it is an integral component of nitric oxide synthase and soluble guanylyl cyclase, and is the substrate for heme oxygenase, enzymes critical for vasodilation. Inhibition of heme synthesis is anticipated to result in a deficiency in these hemoproteins, causing disturbances in the tissue’s ability to regulate vascular tone. Hypertension is frequently associated with the morbidity of both porphyria and lead poisoning, two conditions wherein heme biosynthesis is disrupted. The hypothesis tested was, that extended pharmacological inhibition of heme synthesis disrupts normal vascular control and induces hypertension.
Rats were treated with SA, a heme synthesis inhibitor, for two weeks; this depleted heme stores of the liver, kidney, spleen and vasculature by up to 62.2%. A significant decrease in hematocrit, hemoglobin, urine nitrate levels, NOS activity and sGC activity were also produced, indicating compromised hemoprotein synthesis and function. Ex vivo studies of blood vessels revealed blunted sensitivity to nitric oxide donors. Lastly, SA treatment produced a significant increase in left ventricular mass, which is indicative of altered cardiac output and blood pressure elevation.
Next, telemetry devices were used to determine in vivo blood pressure and salt-sensitivity of blood pressure of rats treated with SA for 33 days. Hemodynamic changes were minimal, yet there was a mild decrease in pressure over two weeks of SA treatment alone. The change from low to high salt diet in SA rats showed no difference compared to control rats. A small increase was observed in 3 mg/kg L-NAME plus high salt compared to high salt alone, while there was no change at this dose in control animals. Heme tissue and blood content was depleted by up to 47%, but was less than two-week experiments. An increase in kidney medulla NOS activity by 19% was observed in vitro compared to controls.
Initial two-week experiments were consistent with the hypothesis above, as heme depletion impaired in vivo activity of NOS and sGC and altered vasodilator function. Nevertheless, in vivo results did not support the hypothesis as hypertension and salt-sensitivity of blood pressure were not observed. === Thesis (Master, Pharmacology & Toxicology) -- Queen's University, 2008-06-19 12:32:08.686 |
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