Evidence for the Nitric Oxide Pathway as a Potential Mode of Action in Fenoldopam-induced Vascular Injury

Abstract

Fenoldopam, a dopaminergic DA1 agonist, induces vasodilatation via nitric oxide (NO), and this may be associated with mesenteric arterial injury. NO is produced from the enzymatic action of nitric oxide synthase (NOS), which is regulated by the shear-stress mediating protein caveolin-1. Profound vasodilatation and accompanied decreased shear are early events that could initiate vascular injury. Therefore, it is of interest to determine the role of caveolin-1 and the NO pathway in fenoldopam-induced vascular injury. At sites of fenoldopam-induced mesenteric arterial injury, decreased caveolin-1 expression and apoptosis were prominent immunohistochemical findings. An additional finding at these sites of injury were loss and/or reduced expression of caveolin-1 regulated structural proteins, connexin-43, (gap junction) ZO-1, and claudin (tight junctions). Because functional loss of caveolin-1 is associated with increased NOS activity and vasodilatation via NO, studies were conducted to show a NO donor produced vascular lesions in the mesenteric arteries morphologically similar to those induced by fenoldopam. Moreover, the incidence and severity of fenoldopam-induced vascular injury were reduced when an NOS inhibitor or a scavenger of NO-generated free radicals were coadministered with fenoldopam. Collectively, these data suggest that caveolin-1 and its regulated NO pathway may play an important role in vasodilatory drug-induced vascular injury.

The Role of eNOS Phosphorylation in Causing Drug-induced Vascular Injury

“…As we had some unexpected deaths in the SIN-1 and L-NAME combinations with nicorandil, these arms of the study had to be terminated early so we could not assess the effect of SIN-1 and L-NAME for this drug. The effect of fenoldopam in inducing vascular injury has been well documented (Brott, Richardson, and Louden 2012;Kerns et al 1989); however, in our hands, fenoldopam alone induced mild vascular injury, and these differences may reflect difference in the dosing regimens used between the studies. Interestingly, the combination of fenoldopam and SIN-1 produced a more than additive effect than fenoldopam or SIN-1 alone ( Figure 5D).…”

The Relationship of Glucokinase Activator–induced Hypoglycemia with Arteriopathy, Neuronal Necrosis, and Peripheral Neuropathy in Nonclinical Studies

“…42, No. 4, 2014 EFFECTS OF GLUCOKINASE ACTIVATORS 705 alterations in NO signaling may be an important feature in the vascular injury observed in this study since recent reports indicate a link between endothelial nitric oxide synthase and vascular injury in mesenteric arteries (Sheth et al 2011;Brott, Richardson, and Louden 2012). Acute hypoglycemia can also induce the release of potent vasoconstrictors such as endothelin which may have a role in vascular injury (Chow and Heller 2012;Wright et al 2007).…”

Pathomorphological Examination of Patients with the Simultaneous Rupture of Dissecting Intracranial Vertebral and Intraperitoneal Arteries: Involvement of Segmental Arterial Mediolysis in Intracranial Artery Dissection

“…15) Furthermore, a short-acting dopamine D1 receptor agonist, fenoldopam, caused experimental IPA dissection. 16) These findings suggest that angiopathy related to a rapid increase in the blood pressure in vivo is involved in the development of SAM. We previously reported the presence of medial defect/ necrosis prior to IVA dissection.…”