Sustained normalization of high blood pressure in spontaneously hypertensive rats by implanted hemin pump.
Treatment of established hypertension, especially for prolonged control of this pathogenic process, represents a great challenge. To upregulate the expression of heme oxygenase (HO) to lower blood pressure (BP) of spontaneously hypertensive rats (SHRs), we administered hemin to 12-week-old adult SHRs through subcutaneously implanted osmotic minipumps for 3 consecutive weeks (the hemin protocol). Systolic BP of SHRs was normalized 123+/-2 mm Hg (n=20; P<0.001) and this normalization maintained for 9 months after the removal of hemin pumps. At the end of the hemin protocol, HO-1 expression, HO activity, soluble guanylyl cyclase expression, and cGMP content were all increased, but phosphodiesterase-5 expression was downregulated in the mesenteric arteries. The hemin protocol also reversed SHR-featured arterial eutrophic inward remodeling and decreased expression levels of vascular endothelial growth factor. These changes lasted 9 months after the hemin protocol. Our study, thus, formulates a novel hemin protocol that will not only normalize BP in SHRs with established hypertension but, more importantly, will also provide long-lasting antihypertension protection. Sustained upregulation of HO-1-linked signaling pathways and reversal of vascular remodeling in peripheral blood vessels mediate likely the antihypertensive effect of the hemin protocol.
Wang
Rui
R
Department of Physiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada. rwang@lakeheadu.ca
Shamloul
Rany
R
Wang
Xiaoxia
X
Meng
Qinghe
Q
Wu
Lingyun
L
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure; D001808:Blood Vessels / Q000503:physiopathology; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006162:Guanylate Cyclase / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006427:Hemin / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology*; D007260:Infusion Pumps; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D020033:Protein Isoforms; D042461:Vascular Endothelial Growth Factor A; D006427:Hemin; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D006419:Heme Oxygenase (Decyclizing); D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat; D006162:Guanylate Cyclase; D006152:Cyclic GMP