LAUSR

Vasoinhibin is a potent antiangiogenic protein that blocks the activation of endothelial nitric oxide synthase (eNOS) in response to vascular endothelial growth factor, bradykinin, and acetylcholine (ACh). In this regard, VIAN‐c4551, a new synthetic vasoinhibin analog, has therapeutic potential for targeting angiogenesis in oncology and ophthalmology. Given that cardiovascular actions are common complications of antiangiogenic drugs and eNOS inhibitors, this multidisciplinary study investigated the cardiovascular safety of VIAN‐c4551. Administered acutely, VIAN‐c4551 inhibited ACh‐induced eNOS phosphorylation/activation in cultured endothelial cells and in lung tissue treated in vivo, as well as the ACh‐induced relaxation of rat aortic segments. However, daily intravenous (i.v.) injections of VIAN‐c4551 (1 or 3 mg kg−1) for 5 days failed to significantly modify the vasodepressor responses to ACh and the baseline values of blood pressure in anesthetized rats (intact, vagotomized, or pithed). Furthermore, daily i.v. injections of 1 mg kg−1 VIAN‐c4551 (for 5 days) did not alter: (i) blood pressure or heart rate values in awake rats; (ii) cardiac autonomic and histological outcomes in anesthetized animals; or (iii) inflammatory (tumor necrosis factor‐α [TNF‐α] and interleukin‐6 [IL‐6]) and apoptotic (caspase‐3) markers. Although VIAN‐c4551 inhibited ACh‐induced eNOS activation in vitro and in vivo and vasorelaxation in ex vivo assays, in vivo experiments consistently showed no significant cardiovascular effects produced by this synthetic peptide. Thus, VIAN‐c4551 appears to be cardiovascularly safe for targeting angiogenesis‐related diseases.