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.