Functional and Morphologic Characterizations of the Diabetic Mouse Corpus Cavernosum: Comparison of a Multiple Low-Dose and a Single High-Dose Streptozotocin Protocols

Abstract

Introduction With the advent of genetically modified mice, it seems particularly advantageous to develop a mouse model of diabetic erectile dysfunction. Aim To establish a mouse model of type I diabetes by implementation of either multiple low-dose streptozotocin (STZ) protocol or single high-dose STZ protocol and to evaluate morphologic alterations in the cavernous tissue and subsequent derangements in penile hemodynamics in vivo. Methods Eight-week-old C57BL/6J mice were divided into three groups: a control group, a group administered the multiple low-dose STZ protocol (50 mg/kg × 5 days), and a group administered the single high-dose STZ protocol (200 mg/kg). Main Outcome Measures After 8 weeks, erectile function was measured by electrical stimulation of the cavernous nerve. The penis was then harvested and stained with hydroethidine (in situ analysis of superoxide anion), TUNEL, or antibodies to nitrotyrosine (marker of peroxynitrite formation), PECAM-1, smooth muscle α-actin, and phospho-eNOS. Penis specimens from a separate group of animals were used for phospho-eNOS and eNOS western blot or cGMP determination. Results Erectile function was significantly less in diabetic groups than in control group. The generation of superoxide anion and nitrotyrosine and the number of apoptotic cells in both cavernous endothelial and smooth muscle cells were significantly higher in diabetic groups than in control group. Cavernous tissue phospho-eNOS and cGMP expression and the number of endothelial and smooth muscle cells were lower in diabetic groups than in control group. Both diabetic models resulted in similar structural and functional derangements in the corpus cavernosum; however, the mortality rate was higher in mice receiving single high-dose of STZ than in those receiving multiple low-doses. Conclusion The mouse model of type I diabetes is useful and technically feasible for the study of the pathophysiologic mechanisms involved in diabetic erectile dysfunction.

Inhibition of Ninjurin 1 restores erectile function through dual angiogenic and neurotrophic effects in the diabetic mouse

“…evaluated the expression of PECAM-1 by immunohistochemical analysis. In agreement with the results of previous studies in STZ-induced diabetic rats (20)(21)(22) and mice (14), the cavernous endothelial area was significantly lower in untreated or IgGtreated diabetic mice than in control mice. Intracavernous injection of high-dose Ninj1-neutralizing antibody (2.5 μg/20 μL) induced complete recovery of the PECAM-1 + endothelial area in the corpus cavernosum of diabetic mice.…”

“…Diabetes was induced by i.p. injections of multiple low doses of STZ (50 mg/kg body weight in 0.1 M citrate buffer, pH 4.5) for 5 d consecutively as previously described (20). Eight weeks after diabetes was induced, the mice were anesthetized with ketamine (100 mg/kg) and xylazine (5 mg/kg) i.m.…”

Arachidonate 12/15-Lipoxygenase–Induced Inflammation and Oxidative Stress Are Involved in the Development of Diabetic Cardiomyopathy

“…Same dose of saline was injected as a control. High-dose STZ-induced model has been established as a diabetes model and recognized as a useful model of diabetic cardiomyopathy (13,20). There was no difference in blood pressure and heart rate among the four groups under normal or STZ-induced high glucose conditions.…”

Optimizingin vivogene transfer into mouse corpus cavernosum by use of surface electroporation

“…On the basis of these initial results, we also examined the efficacy of electroporation-mediated gene delivery into the penis in diabetic mice, in which diabetes was induced in 2-month-old male mice by intraperitoneal injections of streptozotocin (50 mg/kg) for 5 days consecutively as previously described [24]. At 8 weeks after the induction of diabetes, pCMV-Luc (100 µg/40 µL) was injected into the corpus cavernosum of diabetic mice.…”

“…Intracavernous pressure (ICP) and systemic blood pressure were measured during electrical stimulation of the cavernous nerve as previously described [24]. Bipolar platinum wire electrodes were placed around the cavernous nerve.…”