Tadalafil, a Long-Acting Inhibitor of PDE5, Improves Pulmonary Hemodynamics and Survival Rate of Monocrotaline-Induced Pulmonary Artery Hypertension in Rats

Sawamura, Fusae; Kato, Momoko; Fujita, Kazuhisa; Nakazawa, Takahiro; Beardsworth, Anthony

doi:10.1254/jphs.09110fp

Cited by 44 publications

(43 citation statements)

References 39 publications

(30 reference statements)

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“…15 Sawamura et al suggested that tadalafil is effective in the treatment of the late phase of pulmonary arterial hypertension through relaxation of pulmonary arteries in lungs. 16 In addition, the acute effect of tadalafil as a reno protective agent was demonstrated in experimental renal ischemia/reperfusion injury model in the rat. 17 More recently, Wang et al demonstrated that tadalafil is effective and safe for the treatment of diabetic neuropathy as it increases regional blood flow in the sciatic nerve tissue and improves peripheral nerve function in type II diabetic mice.…”

Section: Discussionmentioning

confidence: 99%

Protective effect of tadalafil in diabetic nephropathy induced rat model

Elhawary

Allah

2017

Int J Basic Clin Pharmacol

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INTRODUCTIONDiabetes mellitus (DM) is a major global health problem that causes several micro-and macro-vascular complications. Among these is diabetic nephropathy (DN). DN is the main cause of end-stage renal disease and is associated with a high morbidity and mortality. It develops due to a complex interaction between metabolic and haemodynamic pathophysiological factors, which lead to renal damage. In the earliest stage of DN, patient usually presents with an increase in urinary albumin excretion (microalbuminuria) which progress to macroalbuminuria (more than 300 mg in a 24-hour collection) and later renal insufficiency. 1Among the various mechanisms involved in the pathogenesis of diabetic nephropathy, abnormalities in renal nitric oxide (NO) generation has attracted a lot of attention. NO is postulated to play a protective role towards ischemic injuries of vascular tissues including renal vascular endothelium, an action mediated via cyclic guanosine monophosphate (cGMP) which initiates renal vascular smooth muscle relaxation.2 NO plays numerous physiological roles in the kidney, including control of renal and glomerular hemodynamics, dilates both the ABSTRACT Background: Among various mechanisms involved in the pathogenesis of diabetic nephropathy (DN), abnormalities in renal nitric oxide (NO) generation has attracted a lot of attention. Tadalafil, a competitive inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 commonly used in the treatment of erectile dysfunction was suggested to play a potential prophylactic role for DN. However, this role has not been fully elucidated. The present study was designed to explore the potential beneficial effect of low-dose tadalafil on the progression of diabetic nephropathy in streptozotocin (STZ) induced diabetic rat model. Methods: After injection of STZ and verifying establishment of diabetes, rats were divided into 4 groups: control, diabetic-control, tadalafil-treated nondiabetic, and tadalafil-treated diabetic groups. Biochemical and hemodynamic parameters affecting the renal function such as blood glucose level, serum level of urea and creatinine, renal blood flow, urine volume, urinary albumin excretion, Na+ and K+ excretion, renal level of nitrite and nitrate, plus renal tissues antioxidant parameters (total antioxidant capacity, superoxide dismutase activity and glutathione content) were detected 8 weeks after administration of tadalafil. Histopathological and electron microscopy examination were performed. Results: Our results demonstrated that tadalafil attenuated the glycemic, renal biochemical, microscopic and ultramicroscopic changes/injuries caused by STZ-induced diabetes. Tadalafil could effectively increase renal blood flow and ameliorate glomerular basement membrane thickening. Conclusions: From the results it can be concluded that tadalafil protects rats against streptozotocin-induced DN possibly, in part, through its effect on renal nitric oxide level and its antioxidant activity.

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Section: Discussionmentioning

confidence: 99%

Protective effect of tadalafil in diabetic nephropathy induced rat model

Elhawary

Allah

2017

Int J Basic Clin Pharmacol

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“…From previous studies, the dose of tadalafil which achieved therapeutic effects varied from 0.5 to 10 mg/kg/day in different experimental works (Oh et al 2008;Ko et al, 2009;Sawamura et al, 2009). It was found that doses of 0.5 and 10 mg/kg tadalafil in rats simulate human doses of 2.5 and 40 mg/day, respectively (Sawamura et al, 2009).…”

Section: Experimental Designmentioning

confidence: 99%

“…It was found that doses of 0.5 and 10 mg/kg tadalafil in rats simulate human doses of 2.5 and 40 mg/day, respectively (Sawamura et al, 2009). Therefore, the doses of 1, 5 and 10 mg/kg per day of tadalafil were chosen in the study.…”

Section: Experimental Designmentioning

confidence: 99%

Evaluation of the colo-protective effects of tadalafil in an experimental model of ulcerative colitis in rats

Labib¹,

Abdelzaher²,

Shaker³

et al. 2017

Afr. J. Pharm. Pharmacol.

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Ulcerative colitis is a serious premalignant condition with a confusing multifactorial pathogenesis. It should warrant all attention by researchers, for exploration of new prophylactic or therapeutic drugs targeting its pathophysiology. The current study was conducted to study the possible role of tadalafil and its potential actions in ulcerative colitis rat model, induced by acetic acid. Forty eight male Wistar albino rats were classified into 6 groups: control group, acetic acid (AA)-ulcerated group, AA-ulcerated + tadalafil (1 mg/kg/day), AA-ulcerated + tadalafil (5 mg/kg/day), AA-ulcerated + tadalafil (10 mg/kg/day) and AA-ulcerated + sulfasalazine 100 mg/kg/day groups. Tissue malondialdehyde (MDA), superoxide dismutase (SOD) and myeloperoxidase (MPO) were determined. Also, caspase-3 gene expression was measured as an indicator of apoptosis. Histopathological examination of the colonic tissue was also done. In addition, serum levels of interleukin (IL)-1β and tumour necrosis factor (TNF)-α were measured. In AA-ulcerated group, there was significant elevation in tissue MDA levels and MPO activity with upregulation of caspase 3 gene expression. Meanwhile, AA caused decreases in the SOD activities. Also, AA induced elevation in the serum IL-1β and TNF-α levels. Pretreatment with tadalafil in doses of 1, 5 and 10 mg/kg/days guarded against changes in these parameters. Its effects were dose-dependent. According to the results, pretreatment with tadalafil in doses of 1, 5 and 10 mg/kg/day exerted dosedependent beneficial effects against AA-induced damage of the colon, possibly by exerting antiinflammatory and antioxidant effects. Also, reduction of apoptosis proved to be one of the contributing protective mechanisms of actions.

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“…14,15) Four weeks after MCT treatment, systemic arterial pressure (SAP) and right ventricular systolic pressure (RVSP) were measured. Measurements of SAP and RVSP were initiated when stable pressures were recorded for more than 5 min.…”

Section: Cigarette Smoke Extract (Cse)+lps-induced Copd Model In Guinmentioning

confidence: 99%

Pharmacological Profile of GPD-1116, an Inhibitor of Phosphodiesterase 4

Nose

Kondo

Shimizu

et al. 2016

Biological & Pharmaceutical Bulletin

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We have previously reported that GPD-1116, an inhibitor of phosphodiesterase (PDE) 4, exhibits antiinflammatory effects in a model of cigarette smoke-induced emphysema in senescence-accelerated P1 mice. In the present study, we further characterized the pharmacological profile of GPD-1116 in several experiments in vitro and in vivo. GPD-1116 and its metabolite GPD-1133 predominantly inhibited not only human PDE4, but also human PDE1 in vitro. Moreover, GPD-1116 was effective in several disease models in animals, including acute lung injury, chronic obstructive pulmonary disease (COPD), asthma and pulmonary hypertension; the effective doses of GPD-1116 were estimated to be 0.3-2 mg/kg in these models. With regard to undesirable effects known as class effects of PDE4 inhibitors, GPD-1116 showed suppression of gastric emptying in rats and induction of emesis in dogs, but showed no such suppression of rectal temperature in rats, and these side effects of GPD-1116 seemed to be less potent than those of roflumilast. These results suggested that GPD-1116 could be a promising therapeutic agent for the treatment of inflammatory pulmonary diseases. Furthermore, the inhibitory effects of GPD-1116 for PDE1 might be associated with its excellent pharmacological profile. However, the mechanisms through which PDE1 inhibition contributes to these effects should be determined in future studies. Key words phosphodiesterase; naphthyridine; pulmonary inflammationEnzymes of the cyclic nucleotide phosphodiesterase (PDE) family hydrolyze both cAMP and cGMP. PDE isozymes have been grouped into 11 classes according to their substrate specificity and biochemical features.1) Because inhibition of PDE activity increases intracellular concentrations of cyclic nucleotides by suppressing these degradation to 5′-nucleotides and alters intracellular signal transduction, the PDE family has been recognized as promising targets for therapeutic drugs. For example, inhibitors of PDE3 and PDE5 have actually been used in medicinal therapy for acute heart failure, erectile dysfunction and pulmonary hypertension.1-4) Furthermore, inhibition of PDE4 results in excellent anti-inflammatory effects under experimental conditions, 1,2,5) and an inhibitor of PDE4, roflumilast, has recently emerged as a therapeutic drug for the treatment of chronic obstructive pulmonary disease (COPD). 6)We have previously reported that GPD-1116, a novel PDE4 inhibitor created by ASKA Pharmaceutical, can attenuate the development of cigarette smoke-induced emphysema in senescence-accelerated P1 mice 7) ; however, other pharmacological characteristics of GPD-1116, such as the selectivity toward PDE isozymes and the effects of GPD-1116 in animal models of other pulmonary diseases, have not yet been clarified. In the present study, we clarified more extensive pharmacological profiling of GPD-1116 in several experiments in vitro and in vivo. MATERIALS AND METHODSAnimals Male CD Sprague-Dawley (SD) rats, male Hartley guinea pigs and female Beagle dogs were obtained from Charles Rive...

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Tadalafil, a Long-Acting Inhibitor of PDE5, Improves Pulmonary Hemodynamics and Survival Rate of Monocrotaline-Induced Pulmonary Artery Hypertension in Rats

Cited by 44 publications

References 39 publications

Protective effect of tadalafil in diabetic nephropathy induced rat model

Protective effect of tadalafil in diabetic nephropathy induced rat model

Evaluation of the colo-protective effects of tadalafil in an experimental model of ulcerative colitis in rats

Pharmacological Profile of GPD-1116, an Inhibitor of Phosphodiesterase 4

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