Monitoring circulatory heme level in hemin therapy for lowering blood pressure in rats.
Hemin and other heme derivatives, e.g. heme-L-lysinate (HLL) and heme-L-arginate, have been used extensively to upregulate expression of heme oxygenase and production of endogenous carbon monoxide. Hemin administration has been shown to markedly decrease high blood pressure in spontaneously hypertensive rats (SHR), but not in normotensive Wistar-Kyoto or Sprague Dawley (SD) rats. While methodology to measure serum heme levels has been established long ago, metabolism of the injected hemin or heme derivatives when used to lower blood pressure has not been investigated. In this study, metabolism of hemin or HLL after injected into the rat was monitored by measuring changes in circulatory heme levels. SHR (12-20 weeks old) had significantly higher blood pressure than age-matched SD rats. In both strains, serum heme level was negligible. Hemin or HLL injection (15 mg/kg/day, i.p.) for 5-13 days significantly lowered blood pressure of 12-weeks SHR. High blood pressure was not lowered in SHR older than 20 weeks until hemin or HLL injection period was beyond 5 days. This anti-hypertensive effect of hemin and HLL was synchronized with an increase in serum heme level, from undetectable to 4.3 micromol/l. On the other hand, hemin or HLL had no effect on blood pressure of age-matched SD rats, despite serum heme level rose to the same extent as in the treated SHR. There was no significant difference between hemin and HLL injections in terms of changes in blood pressure and serum heme level in all rats. Our study for the first time correlated changes in serum heme levels with blood pressure levels after injection of hemin or HLL in SHR and SD rats. Hemin and HLL had similar effects on blood pressure change and serum heme level. By determining serum heme levels following the administration of hemin or HLL, we can better understand mechanisms for the blood pressure lowering effect of hemin therapy. Application of this heme monitoring technology will also pave the way for clinical application of hemin therapy in treatment of different types of hypertension pathologies.
Shamloul
R
R
Department of Physiology, University of Saskatchewan, Saskatoon, Canada.
Wang
R
R
D000818:Animals; D000959:Antihypertensive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006418:Heme / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use; D006427:Hemin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006973:Hypertension / Q000188:drug therapy*; D008239:Lysine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley
D000959:Antihypertensive Agents; C106087:heme lysinate; D006418:Heme; D006427:Hemin; D008239:Lysine