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Anti-inflammatory and cardioprotective effects of tadalafil in diabetic mice
Amit Varma1, Anindita Das, Nicholas N Hoke
1Division of Cardiology, Department of Internal Medicine, VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia, USA.
Background:
Insulin resistance impairs nitric oxide (NO) bioavailability and obesity promotes a state of chronic inflammation and damages the vascular endothelium. Phosphodiesterase-5 inhibitors restore NO signaling and may reduce circulating inflammatory markers, and improve metabolic parameters through a number of mechanisms. We hypothesized that daily administration of the PDE-5 inhibitor, tadalafil (TAD) will attenuate inflammation, improve fasting plasma glucose and triglyceride levels, body weight, and reduce infarct size after ischemia/reperfusion injury in obese, diabetic mice.
Methods:
Twenty leptin receptor null (db/db) mice underwent treatment with TAD (1 mg/Kg) or 10% DMSO for 28 days. Body weight and fasting plasma glucose levels were determined weekly. Upon completion, hearts were isolated and subjected to 30 min global ischemia followed by 60 min reperfusion in a Langendorff model. Plasma samples were taken for cytokine analysis and fasting triglyceride levels. Infarct size was measured using computer morphometry of tetrazolium stained sections. Additionally, ventricular cardiomyocytes were isolated and subjected to 40 min of simulated ischemia and reoxygenation. Necrosis was determined using trypan blue exclusion and LDH release assay and apoptosis was assessed by TUNEL assay after 1 h or 18 h of reoxygenation, respectively.
Results:
Treatment with TAD caused a reduction in infarct size in the diabetic heart (23.2 ± 1.5 vs. 47.8 ± 3.7%, p<0.01, n = 6/group), reduced fasting glucose levels (292 ± 31.8 vs. 511 ± 19.3 mg/dL, p<0.001) and fasting triglycerides (43.3 ± 21 vs. 129.7 ± 29 mg/dL, p<0.05) as compared to DMSO, however body weight was not significantly reduced. Circulating tumor necrosis factor-α and interleukin-1β were reduced after treatment compared to control (257 ± 16.51 vs. 402.3 ± 17.26 and 150.8 ± 12.55 vs. 264 ± 31.85 pg/mL, respectively; P<0.001) Isolated cardiomyocytes from TAD-treated mice showed reduced apoptosis and necrosis.
Conclusion:
We have provided the first evidence that TAD therapy ameliorates circulating inflammatory cytokines and chemokines in a diabetic animal model while improving fasting glucose levels and reducing infarct size following ischemia-reperfusion injury in the heart.
Insights
Tadalafil (TAD) treatment reduced heart infarct size, fasting glucose, and triglycerides in diabetic mice. This phosphodiesterase-5 inhibitor also decreased inflammatory markers and protected heart cells from damage.
Area of Science:
- Cardiovascular Research
- Metabolic Disorders
- Pharmacology
Background:
- Insulin resistance and obesity cause inflammation, impairing nitric oxide (NO) bioavailability and damaging the vascular endothelium.
- Phosphodiesterase-5 inhibitors (PDE-5 inhibitors) can restore NO signaling and reduce inflammatory markers.
- Tadalafil (TAD), a PDE-5 inhibitor, may improve metabolic parameters and reduce inflammation.
Purpose of the Study:
- To investigate the effects of daily tadalafil (TAD) administration on inflammation, glucose and triglyceride levels, body weight, and ischemia/reperfusion injury in obese, diabetic mice.
- To determine if TAD can attenuate inflammation and improve metabolic parameters in a diabetic animal model.
Main Methods:
- Twenty leptin receptor null (db/db) mice were treated with TAD (1 mg/Kg) or DMSO for 28 days.
- Fasting glucose, triglycerides, and body weight were measured weekly. Hearts were subjected to ischemia/reperfusion injury.
- Cardiac infarct size, plasma cytokine levels, and cardiomyocyte apoptosis/necrosis were assessed.
Main Results:
- TAD treatment significantly reduced infarct size (23.2% vs. 47.8%), fasting glucose (292 vs. 511 mg/dL), and triglycerides (43.3 vs. 129.7 mg/dL).
- Circulating tumor necrosis factor-α and interleukin-1β levels were reduced in TAD-treated mice.
- Isolated cardiomyocytes from TAD-treated mice exhibited decreased apoptosis and necrosis.
Conclusions:
- TAD therapy ameliorates circulating inflammatory cytokines in a diabetic animal model.
- TAD improves fasting glucose levels and reduces infarct size following ischemia-reperfusion injury.
- This study provides the first evidence for TAD's beneficial effects in a diabetic heart model.
