Abstract 311: Nifedipine Attenuates Abdominal Aortic Aneurysm in Ang II-infused hph-1 Mice

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Abstract

We have previously shown that angiotensin II (Ang II) perfusion of hph-1 mice results in development of severe abdominal aortic aneurysm (AAA, 79% within 2 wks) that is associated sudden death and regulation of blood pressure. This phenotype can be completely attenuated by recoupling of eNOS with oral folic acid (FA) administration, which restores eNOS cofactor tetrahydrobiopterin (H4B) bioavailability via restoration of endothelial H4B salvage enzyme dihydrofolate reductase (DHFR). In view of the unclear relationship between blood pressure and AAA formation, we investigated the potential effects of L-type calcium channel blocker (CCB) Nifedipine (Nif) on AAA formation using the Ang II infused hph-1 model. Six-month old hph-1 mice were infused with Ang II (0.7 mg/kg/day) for 2 wks using Alzet osmotic pumps. The animals were fed Nif chew (20 mg/kg/day) two days prior to Ang II infusion and throughout the study period of 2 wks. Of note, the incidence rate of AAA dropped from 79% to 21% (2 out of 13). The Ang II induced hypertension (telemetry) and expansion of abdominal aorta (ultrasound) in hph-1 mice were abolished by Nif diet. Increased aortic reactive oxygen species (ROS) production (DHE) was also attenuated by Nif administration. L-NAME sensitive superoxide production, reflective of eNOS uncoupling activity, was measured by electron spin resonance (ESR). Treatment with Nif restored eNOS function completely, resulting in -2.49± 0.71 fold change in L-NAME sensitive superoxide production. Our previous data demonstrated extensive eNOS uncoupling activity (>10 fold) in Ang II-infused hph-1 mice that is attenuated by restoration of endothelial DHFR function (Hypertension 2012). Nif treatment also markedly improved NO bioavailability (ESR) by 2.42± 0.23 fold. These data demonstrate that an oral treatment of Nif is effective in correcting eNOS dysfunction to attenuate AAA formation. Although it does not differentiate the contributions from attenuation of oxidative stress and blood pressure lowering, it once again suggests that eNOS uncoupling can an important mediator of AAA formation.

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