In Vivo evaluation of hemodynamic and gastro‐protective effects of non‐selective cyclooxygenase (COX) inhibitor nitric oxide donors (CINODs)

CINODs offer the potential to provide analgesic and anti‐inflammatory therapy while protecting the gastrointestinal mucosa against the insult that may accompany oral administration of a COX inhibitor. We now report in vivo hemodynamic and gastrointestinal effects of naproxen sodium and the CINODs NMI‐1182 and AZD3582. Gastrointestinal protection was evaluated in fasted Sprague Dawley rats, dosed orally at 10, 20 or 40 mg/kg. Stomachs were removed three hours after dosing and scored for total luminal lesion length. In a separate study, we measured abdominal aortic blood flow (BF) and systemic mean arterial pressure (MAP) in conscious, stroke‐prone spontaneously hypertensive rats (SHR‐SP) following a single oral dose of vehicle (0.5% Methocel), Naproxen (30 mg/kg), NMI‐1182 (30 mg/kg naproxen equivalent) or AZD3582 (30 mg/kg naproxen equivalent). Peripheral vascular resistance (PVR) was calculated as MAP/BF. Gastric lesions were suppressed at both the 20 and 40 mg/kg dose in the NMI‐1182 and AZD3582 groups vs. naproxen treated animals (P <0.001). MAP was significantly lower in the NMI‐1182 group vs. naproxen and AZD3582 (P <0.001). PVR in the NMI‐1182 was decreased relative to the AZD3582‐treated rats (p <0.001). In conclusion, NMI‐1182 and AZD3582 provided improved gastric safety compared to naproxen. NMI‐1182 also demonstrated an improved hemodynamic profile compared to AZD3582, consistent with possible enhancement of systemic nitric oxide bioavailability and potentially greater safety in patients at risk for exacerbation of hypertension. [Supported by NitroMed, Inc]