Diabetes-induced cerebrovascular dysfunction: Role of poly(ADP-ribose) polymerase Denise M. Arrick, Glenda M. Sharpe, Hong Sun, William G. Mayhan ⁎ Department of Cellular and Integrative Physiology 985850 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA Received 20 June 2006; revised 25 July 2006; accepted 1 August 2006 Available online 18 September 2006 Abstract Our goal was to identify the role of poly(ADP-ribose) polymerase (PARP) in cerebrovascular dysfunction in Type 1 diabetes mellitus (T1D). In a first series of studies, rats were assigned to nondiabetic and diabetic (streptozotocin; 50 mg/kg IP) groups. Two to three months after injection of streptozotocin, we examine in vivo responses of pial arterioles to nitric oxide synthase (NOS)-dependent (adenosine diphosphate (ADP), acetylcholine and histamine) and -independent (nitroglycerin) agonists. After the initial examination of reactivity to the agonists, we treated pial arterioles acutely with an inhibitor of PARP (PJ-34; 1 μM), and then we again examined responses to the agonists. In a second series of studies, we examine superoxide production (lucigenin chemiluminescence) by parietal cortex tissue in nondiabetic and diabetic rats. We found that dilation of pial arterioles in response to ADP, acetylcholine and histamine, but not to nitroglycerin, was impaired in diabetic compared to nondiabetic rats. In addition, although PJ-34 did not alter responses in nondiabetic rats, PJ-34 alleviated T1D-induced impairment of NOS-dependent vasodilation. We also found that basal production of superoxide was increased in diabetic compared to nondiabetic rats and that PJ-34 decreased this basal production of superoxide. Our findings suggest that T1D impairs NOS-dependent reactivity of cerebral arterioles by a mechanism that appears to be related to the formation of superoxide via activation of PARP. © 2006 Elsevier Inc. All rights reserved. Keywords: Adenosine diphosphate; Acetylcholine; Histamine; Nitroglycerin; Type I diabetes; Brain; Nitric oxide; Rats; PJ-34; PARP; Arterioles; Microcirculation Introduction Whereas it is apparent that oxidative stress plays a key role in Type 1-diabetes (T1D)-induced vascular dysfunction, the precise mechanisms remain uncertain. Poly(ADP-ribose) poly- merases (PARPs) are an important set of nuclear enzymes that appears to be involved in the response of the cell to DNA injury/ DNA strand breaks (Chiarugi, 2002; Pieper et al., 1999a,b). These enzymes, of which PARP-1 is most abundant, normally function in DNA repair, but extensive activation of PARP can promote cellular dysfunction and/or cell death via mechan- isms involving depletion of NAD+ and ATP within the cell (Chiarugi, 2002; Pieper et al., 1999a,b). Because oxidative stress can induce the activation of PARP and because oxidative stress is increased in T1D, it is conceivable that PARP activation may contribute to vascular dysfunction during T1D. Several studies have suggested that PARP activation is increased in T1D. Zheng et al. (2004) found an increase in poly (ADP-riboxyl)ation in the retina from diabetic rats. Using an immunohistochemical staining method, investigators Pacher et al. (2002) and Garcia Soriano et al. (2001a,b) reported an increase in the activation of PARP in the heart of diabetic rats and the aorta of diabetic mice, respectively. In addition to an increase in the activation of PARP by T1D, Szabo and his colleagues (Garcia Soriano et al., 2001a,b; Pacher et al., 2002) have reported that inhibition of PARP restores impaired endothelial dysfunction of the thoracic aorta in mice. However, no studies to our knowledge have examined the role of PARP activation in impaired responses of resistance arterioles, in general, and/or cerebral resistance arterioles, specifically, during T1D. Thus, the first goal of this study was to determine whether inhibition of PARP could influence impaired nitric oxide synthase (NOS)-dependent responses of pial arterioles observed in diabetic rats. Our second goal was to examine whether inhibition of PARP could influence superoxide production by parietal cortex tissue. Microvascular Research 73 (2007) 1 – 6 www.elsevier.com/locate/ymvre ⁎ Corresponding author. Fax: +1 402 559 4438. E-mail address: wgmayhan@unmc.edu (W.G. Mayhan). 0026-2862/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.mvr.2006.08.001