Abstract 5218: Corrin-mediated Activation of Nitric Oxide Receptor and Its Cardiovascular Consequences

Soluble guanylyl cyclase (sGC) is the recognized receptor for nitric oxide (NO) messenger molecule. In addition to NO, several allosteric regulators, which do not produce NO, can activate sGC heme-dependently or independently. Earlier studies recognized that tetrapyrrole protoporphyrin IX can actively replace sGC heme moiety or bind to the heme-deficient sGC, resulting in a robust activation of sGC ability to produce cGMP from GTP. We investigated the effects of various tetrapyrroles on the ability of sGC to generate cGMP in vitro. Our data demonstrated that not only various protoporphyrins but some corrins can activate sGC. Pro-vitamin B12 dicyanocobinamide (CN2-Cbi) was the most efficient among tested compounds. CN2-Cbi-dependent activation of sGC was synergistically enhanced by BAY41–2272, a heme-dependent allosteric regulator of sGC. CN2-Cbi and several other corrins, including vitamin B12, induces a dose-dependent relaxation on isolated rat aorta rings. Tested corrins were equally effective in endothelium competent or endothelium denuded rings. Effective concentrations of CN2-Cbi were significantly improved with BAY41–2272, and relaxation was achieved even with micromolar CN2-Cbi. Therefore, data are consistent with direct activation of sGC by CN2-Cbi. Following ex-vivo relaxation by CN2-Cbi, we monitored blood pressure (BP) in anesthetized rats in response to CN2-Cbi. CN2-Cbi (5 mg/kg bolus) induced a modest and transient decrease in BP while 15 mg/kg showed a more marked and prolonged response. Decreased BP was associated with increased cardiac output, suggesting vascular relaxation. CN2-Cbi combined with 100 μ g/kg BAY41–2272 induced a more profound and prolonged decrease in BP. Following U-46619, a thromboxane analogue to induce systemic and pulmonary hypertension, combined CN2-Cbi/BAY41–2272 was also effective in restoring systemic and pulmonary pressures to baseline. These data suggest that CN2-Cbi (or corrin)-mediated activation of sGC may be an alternative approach to regulate sGC activity and vascular function. Data indicate that derivatives of vitamin B12 may be used for regulation of BP in normal and hypertensive conditions as part or treatment regimens or dietary supplements.