The role of heme oxygenase and carbon monoxide in the development of hypertension: A mechanistic approach

Endogenous carbon monoxide (CO) is formed by the enzymatic breakdown of heme by the heme oxygenase (HO). Significant increases in CO can be associated with endothelial dysfunction due to a reduction in endothelial nitric oxide synthase (eNOS) and/or depletion in nitric oxide (NO). Studies aimed at investigating the role of HO in water and electrolyte excretion revealed a direct renal tubular role for endogenous CO in regulating sodium excretion in both L-NAME treated and untreated rats. Further, acute administration of angiotensin II (AngII) revealed that AngII increases HO-1 concentration in both heart and kidney and leads to induction of endogenous CO which drives an elevation in blood pressure. Treatment with Zinc deuteroporphyrin 2, 4-bis glycol (ZnDBPG) decreases the blood pressure through the attenuation of HO-1 induction, which in turn decreases carboxyhemoglobin (CoHb). Patients with diabetes mellitus are known to have an increase in respiratory CO levels which could contribute to endothelial dysfunction. Recurrent insulin induced hypoglycemia (RIIH) is an unavoidable risk of conventional therapeutic management of insulin dependent diabetes mellitus (IDDM). We hypothesized that RIIH contributes to endothelial dysfunction and ultimately contributes to hypertension. Studies revealed that insulin induced hypoglycemia in male rats is responsible for diminished blood glucose levels promoting an increase in HO-1 in heart and kidney which drives CO induction and increases blood pressure. Circulating Ang II concentration was increased due to RIIH which contributes to hypertension and end organ damage. Treatment with high zinc diet and ZnDPBG, a HO-1 inhibitor, reduces HO-1 levels and CoHb concentration which produces a significant reduction in blood pressure. The current study confirmed that HO-1 induction was via AngII in that captopril (20 mg/kg) administration significantly lowered the blood pressure and attenuated the induction in HO-1. Our results provide novel evidence demonstrating the role of endogenously formed CO and the potential to promote endothelial dysfunction contributing to hypertension. Overall, the current studies suggest the possible role of HO and CO as a potential mechanism leading to hypertension.