Transplantation/immunologyPenehyclidine hydrochloride ameliorates renal ischemia–reperfusion injury in rats
Introduction
Renal ischemia–reperfusion (I/R) injury is a complex pathophysiological process, which develops in diverse clinical situations, such as trauma, shock, sepsis, and various surgical procedures. Renal I/R injury is a major cause of acute kidney injury, a potentially life-threatening condition associated with high mortality and morbidity [1], [2]. The mechanisms underlying ischemic acute renal injury involve local elevations in proinflammatory chemokines and cytokines and alterations in tubule cell metabolism, leading to the generation of reactive oxygen species (ROS). Consequently, excess ROS production causes lipid peroxidation, DNA mutation, and initiation of apoptotic and necrotic cascades, resulting ultimately in cell death [3], [4], [5], [6], [7].
Penehyclidine hydrochloride (PHC)—3-(2-hydroxyl-2-cyclopentyl-2-phenyl-ethoxy) quinuclidine (Fig. 1) [8], [9]—is a selective anticholinergic agent, which was developed by the Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, People's Republic of China. It has been widely used as an anesthetic premedication and as a treatment for smooth muscle spasm [10], [11], [12]. Previous studies in animals have shown that PHC reduces inflammation [13], [14] and oxidative stress [13] and inhibits the p38 and extracellular signal–regulated kinase signaling pathways [15]. PHC also attenuated renal or gastrointestinal damage caused by bilateral hind limb I/R by suppressing the inflammatory response and the release of oxygen-free radicals [16], [17], [18]. More recently, PHC has been shown to attenuate cerebral I/R injury in rats [19]. However, its effect on renal I/R injury remains unknown. Thus, the aim of this study was to evaluate the effects of PHC on renal I/R injury in adult Sprague–Dawley rats and elucidate the underlying mechanisms.
Section snippets
Chemicals and reagent
PHC injection (1 mg/1 mL) was purchased from List Pharmaceutical (Chengdu, China).
Animal preparation and drug administration
Adult, male Sprague–Dawley rats (180–220 g) were provided by Laboratory Animal Center of Peking University Health Science Center. Rats were housed at 27°C and were given rodent chow and tap water ad libitum. All procedures were approved by the Ethics Committee of Experimental Animals of The Peking University Health Science Center and were performed in accordance with the Guide for the Care and Use of Laboratory
PHC ameliorates I/R-induced renal dysfunction
Compared with the sham controls, the I/R group showed significantly increased BUN and SCr levels after 1 h, and the levels peaked 24 h after reperfusion (P < 0.01). Pretreatment with PHC reduced BUN and SCr levels at all time points (P < 0.01) (Fig. 2).
PHC treatment decreases histopathologic damage to tubules
Compared with the normal tubular histology in the sham group, tubular dilatation, swelling, luminal congestion, and nuclear pyknosis were observed 3 and 12 h after renal reperfusion in the kidneys from the I/R group, and histopathology was even
Discussion
When the blood flow is interrupted, renal warm ischemia occurs. A hypoxic state ensues and causes the local accumulation of anaerobic metabolites and free radicals. Renal dysfunction and cellular degeneration occur in the renal tissue. After blood flow is restored, an oxidant burden occurs because of decrease of molecular oxygen and increase of hydrogen peroxide, which induces the majority of the damage to renal tissues. Renal tissue I/R induces the production of inflammatory factor, such as
Acknowledgment
This work was supported by the National Natural Science Foundation of China (grant 30950018) and the Beijing Natural Science Foundation (grant 7113174).
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2020, Journal of Surgical ResearchCitation Excerpt :Penehyclidine hydrochloride (PHC), a well-known hyoscyamus reagent, has limited M2 receptor–mediated circulatory side effects compared with additional hyoscyamine.15,16 Prior studies revealed that PHC has diverse biological properties, including pulmonary defensive, antiinflammation, and antioxidant effects, among others.17-19 PHC has been useful in lung defense and management, cardiac and cerebral disorders, and diverse neurodegenerative disorders in animal models.19-22
Penehyclidine hydrochloride preconditioning provides pulmonary and systemic protection in a rat model of lung ischaemia reperfusion injury
2018, European Journal of PharmacologyPenehyclidine hydrochloride preconditioning provides cardiac protection in a rat model of myocardial ischemia/reperfusion injury via the mechanism of mitochondrial dynamics mechanism
2017, European Journal of PharmacologyCitation Excerpt :More importantly, its application almost does not cause M2 receptor-associated side effects to cardiovascular system (Shen et al., 2009; Han et al., 2005; Zhan et al., 2007). Previous findings have demonstrated that PHC preconditioning is a promising therapeutic agent in the treatment I/R-induced renal dysfunction, cerebral injury, pulmonary disease by inhibiting cell apoptosis and alleviating oxidative stress (Wang et al., 2014; Yu and Wang, 2013; Ma et al., 2013). However, its role and related mechanisms in myocardial I/R injury are elusive.
Cardioprotective time-window of Penehyclidine hydrochloride postconditioning: A rat study
2017, European Journal of PharmacologyCitation Excerpt :In recent years, with the exploration of organ-protective effects in I/R injury, PHC has attracted much attention. Animal studies have shown that PHC offers organ-protective effects, such as neuroprotective (Ma et al., 2013; Yu and Wang, 2013), lung protective, (Zhan et al., 2015) and renal protective (Wang et al., 2014). We previously reported that high dose (1 mg/kg) of PHC preconditioning protects against I/R injury in rat hearts in vivo (Lin et al., 2015).