Effect of tadalafil on neointimal hyperplasia in a rabbit carotid artery anastomosis model.

PURPOSE: Intimal thickening, which results from the response to arterial damage caused by therapeutic interventions or other reasons, is usually called as neointima. Neointimal hyperplasia is a main step in the pathogenesis of late-term restenosis, which is developed after vascular interventions. Reduction in nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling plays a substantial role in the pathogenesis of neointima formation. Phosphodiesterase V is detected in the peripheral coronary and pulmonary vascular smooth muscle cells and in the cardiac tissue. Based on the effects of phosphodiesterase V inhibitors on vascular smooth muscle cells, in the present study, the effect of tadalafil, a new member of phosphodiesterase V inhibitors, on neointimal hyperplasia was investigated in the rabbit carotid artery anastomosis model. MATERIAL AND METHOD: Fourteen male New Zealand white rabbits weighing between 2.5-3 kg, were used. The rabbits were randomly divided into two equal groups; tadalafil group received oral tadalafil (2 mg/kg/day), and PBS group received sterile PBS solution (normal saline; 2 mg/kg/day) for 28 days after the surgery. The right carotid arteries of all rabbits were anastomosed in an end-to-end fashion using 8/0 polypropylene suture. The rabbits were sacrificed at the end of the postoperative period of 28 days. After sacrificing, firstly anastomosis segment on the right carotid artery and secondly a part of the left carotid artery (as control) of each rabbit were removed. Morphometric examination of tissue sections was performed under a light microscope connected to an image capture system. RESULTS: There was a significant difference between the right and left carotid arteries in terms of intimal area and intima/media ratio both in tadalafil and PBS groups (p <0.001 for each). Intimal area and intima/media ratio were increased in the right carotid arteries compared to the left carotid arteries (p <0.001 for each). Besides, when the right carotid arteries of both groups were compared using covariance analysis, it was observed that intimal area and intima/media ratio in the anastomosis site were significantly reduced with tadalafil treatment (p <0.001). CONCLUSION: The present study was promising in terms of tadalafil use as a new agent for the prevention of neointimal hyperplasia, which is the leading cause of late-term graft failure in vascular surgery.

The effects of PPAR-γ agonist pioglitazone on renal ischemia/reperfusion injury in rats.

BACKGROUND: Acute renal failure due to renal ischemia/reperfusion (IR) injury is a significant clinical problem in cardiovascular surgery. Reactive oxygen species and inflammation play essential roles in the pathophysiology of IR injury. Matrix metalloproteinases (MMPs) are enzymes that play important roles in inflammation and mediate extracellular matrix degradation. It is known that peroxisome proliferator-activated receptor-γ agonists have antiinflammatory and antioxidant effects. In the present study, we aimed to investigate the effects of pioglitazone, a synthetic peroxisome proliferator-activated receptor-γ agonist, on MMPs and oxidative stress in a renal IR injury model in rats. MATERIALS AND METHODS: Male Wistar albino rats were divided into three groups: control (n = 7), placebo (n = 7; saline/p.o.), and pioglitazone (n = 7; 5 mg/kg/day/p.o.). In the control group, a right nephrectomy was conducted without left renal IR injury. In the placebo and pioglitazone groups, pretreatments were started 3 d before operation. In both groups, left renal pedicles were clamped for 60 min and then reperfused for 60 min. Paraffinized renal sections were evaluated histopathologically. Furthermore, expressions of MMP-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-2, superoxide dismutase 1 (SOD1), and p47-phox/p67-phox subunits of NADPH oxidase were determined by immunostaining and scoring. RESULTS: In the placebo group, renal IR injury induced diffuse tubular necrosis and intense acute inflammation, but pioglitazone inhibited these effects. MMP-2, MMP-9, and TIMP-2 expression increased in the placebo group. However, while MMP-2 and -9 expression decreased, TIMP-2 expression did not change in the pioglitazone group. p47-phox/p67-phox expression increased in the placebo group, but SOD1 expression did not change. Pioglitazone diminished p47-phox/p67-phox expression, whereas it enhanced SOD1 expression. CONCLUSION: Our results suggest that pioglitazone might be helpful to reduce renal IR injury because of its antiinflammatory and antioxidant effects.

Mesenchymal stem cells ameliorate postpyelonephritic renal scarring in rats.

OBJECTIVE: To evaluate the efficiency of mesenchymal stem cells in ameliorating renal scarring in a rat pyelonephritis model. METHODS: Three groups each, including 8 Sprague-Dawley rats were formed: Group 1 = sham operated (4 were given mesenchymal stem cells); group 2 = pyelonephritis induced by Escherichia coli; and group 3 = pyelonephritis and mesenchymal stem cells. Rats not given mesenchymal stem cells in group 1 and 4 rats in groups 2 and 3 were sacrificed on the eighth day for evaluation of inflammation, and the remaining rats were sacrificed at the sixth week to determine renal scarring along with migration of mesenchymal stem cells to renal tubules and differentiation to tubular cells expressing aquaporin-1. RESULTS: Rats in group 3 had lower scores of both acute (8th day) and chronic (6th week) histopathological alterations compared with rats in group 2. By contrast, although rats in group 3 were shown to have mesenchymal stem cells expressing aquaporin-1 in their renal tubules, these cells were not detected in kidney tissue of mesenchymal stem cells-treated sham rats. CONCLUSION: These results indicate that mesenchymal stem cells migrated to renal tissues and ameliorated renal scarring in this rat model of pyelonephritis.

The effects of PPARγ agonist rosiglitazone on neointimal hyperplasia in rabbit carotid anastomosis model.

BACKGROUND: Neointimal hyperplasia involving smooth muscle cell (SMC) proliferation, migration and extracellular matrix (ECM) degradation is an important component of atherosclerosis. It develops as a response to vascular injury after balloon angioplasty and vascular graft placement. Matrix metalloproteinases (MMPs) induce SMC proliferation, migration and contribute to intimal hyperplasia by degrading ECM. PPARγ agonists inhibit SMC proliferation, migration and lesion formation. In this study, we aimed to investigate the effects of PPARγ agonist rosiglitazone on neointimal hyperplasia and gelatinase (MMP-2 and MMP-9) expressions in rabbit carotid anastomosis model. METHODS: New Zealand white rabbits (n = 13, 2.7-3.2 kg) were divided into placebo and treatment groups. Right carotid artery (CA) was transected and both ends were anastomosed. Treatment group (n = 6) received rosiglitazone (3 mg/kg/day/p.o.) and placebo group (n = 7) received PBS (phosphate buffered saline, 2.5 ml/kg/day/p.o.) for 4 weeks postoperatively. After the sacrification, right and left CAs were isolated. Morphometric analyses and immunohistochemical examinations for gelatinases were performed. RESULTS: Intimal area (0.055 ± 0.005 control vs 0.291 ± 0.020 µm(2) anastomosed, p < 0,05) and index (0.117 ± 0.002 control vs 0.574 ± 0.013 anastomosed, p < 0,01) significantly increased in anastomosed arteries compared to control arteries from placebo group. However, in rosiglitazone-treated group, intimal area (0.291 ± 0.020 PBS vs 0.143 ± 0.027 rosiglitazone, p < 0,05) and index (0.574 ± 0.013 PBS vs 0.263 ± 0.0078 rosiglitazone, p < 0,01) significantly decreased. Furthermore, gelatinase immunopositivity was found to have significantly increased in anastomosed arteries from placebo group and decreased with rosiglitazone treatment. CONCLUSIONS: These results suggest that rosiglitazone may prevent neointimal hyperplasia, which is the most important factor involved in late graft failure, by inhibiting gelatinase enzyme expression.

The beneficial effects of tadalafil on renal ischemia-reperfusion injury in rats.

Acute renal failure due to ischemia-reperfusion (I/R) injury is a common complication in cardiovascular surgery. We determined the influence of tadalafil on renal injury in a renal I/R model in rats. For this purpose, 21 male Wistar albino rats were separated into 3 groups: sham, placebo and tadalafil. A right nephrectomy was performed, and the left renal pedicles were occluded for 60 min and reperfused for 60 min in the placebo and tadalafil groups. A single dose of tadalafil (10 mg/kg) through an orogastric tube was administered to the tadalafil group. Tubular atrophy with acute inflammation in renal histology, total oxidant status (TOS) and total antioxidant status (TAS) were determined in tissue homogenates. Compared to the tadalafil group, tubular atrophy and acute inflammation was significant in the placebo group. TAS levels were significantly higher in the tadalafil group compared to the placebo (p = 0.01) and sham groups (p = 0.04). While TOS levels were significantly higher in the placebo group (p = 0.03), tadalafil did not significantly alter the TOS levels. The beneficial effects of tadalafil can be attributed to its protective effects on renal tubular cells and inhibition of leukocyte infiltration in renal tissue. We think that tadalafil treatment has an important role in reducing renal injury resulting from renal I/R.