Limits...
Sildenafil citrate increases myocardial cGMP content in rat heart, decreases its hypertrophic response to isoproterenol and decreases myocardial leak of creatine kinase and troponin T.

Hassan MA, Ketat AF - BMC Pharmacol. (2005)

Bottom Line: The results showed that daily intraperitoneal administration of sildenafil per se for 10 days was without noticeable adverse effects on survival or myocardium.When sildenafil was injected daily, one hour before isoproterenol, survival was significantly improved and the myocardium didn't show significant hypertrophy or cell injury.At the same time, cGMP was found to possess a positive correlation with myocardial creatine kinase activity that reflects the efficiency of the energy utilization processes in the myocardium.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology, Faculty of Medicine, University of Alexandria, Egypt. madiha2000x@hotmail.com

ABSTRACT

Background: Cardiac hypertrophy is a major risk factor for morbidity and mortality in a number of cardiovascular diseases. Consequently, the signaling pathways that inhibit cardiac hypertrophy are currently receiving much interest. Among them, nitric oxide (NO), signaling via cGMP and cGMP-dependent protein kinase I, has been recognized as a negative regulator of cardiac hypertrophy. The present study investigated the in-vivo effect of sildenafil as a phosphodiestrase-5A (PDE-5A) inhibitor on the hypertrophic response of rat heart to isoproterenol and the relation of this effect to the level of myocardial cGMP and integrity of the constitutive nitric oxide synthase (cNOS) activity.

Results: The results showed that daily intraperitoneal administration of sildenafil per se for 10 days was without noticeable adverse effects on survival or myocardium. Conversely, daily subcutaneous administration of isoproterenol for 10 days caused significant myocardial hypertrophy, cell injury and decline in survival. When sildenafil was injected daily, one hour before isoproterenol, survival was significantly improved and the myocardium didn't show significant hypertrophy or cell injury. Interestingly, sildenafil was accompanied by significant rise in myocardial cGMP level, a parameter which was found in the present study to possess a significant negative correlation with cardiac hypertrophy and leak of cardiac troponin T into serum. At the same time, cGMP was found to possess a positive correlation with myocardial creatine kinase activity that reflects the efficiency of the energy utilization processes in the myocardium. However, in rats given Nomega-nitro-L-arginine (L-NNA) as a competitive inhibitor of cNOS, sildenafil failed to show any favorable effect on survival or the myocardial injury parameters used to assess isoproterenol-induced injury.

Conclusion: The present study suggests that increased cardiac cGMP level by sildenafil have a cardioprotective effect probably through acting as a post-receptor negative regulator of cardiac sympathetic responsiveness. Integrity of NOS function was an essential prerequisite for sildenafil's mediated cardioprotection encountered in the present study.

Show MeSH

Related in: MedlinePlus

Kaplan-Meier analysis of 10 days survival among 70 rats classified into vehicle (group I, n= 10; solid line), isoproterenol (group II, n = 15; thick dotted intermediate curve), isoproterenol/ sildenafil (group III, n = 15; thick dashed curve), sildenafil/vehicle(group IV, n = 15; solid line) and sildenafil/isoproternol/ Nω-nitro-L-arginine (group V, n = 15; thin dash-dot line to the left). Significant improvement in survival rate was found by log-rank test in group III compared to groups II and V (P < 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC1131906&req=5

Figure 1: Kaplan-Meier analysis of 10 days survival among 70 rats classified into vehicle (group I, n= 10; solid line), isoproterenol (group II, n = 15; thick dotted intermediate curve), isoproterenol/ sildenafil (group III, n = 15; thick dashed curve), sildenafil/vehicle(group IV, n = 15; solid line) and sildenafil/isoproternol/ Nω-nitro-L-arginine (group V, n = 15; thin dash-dot line to the left). Significant improvement in survival rate was found by log-rank test in group III compared to groups II and V (P < 0.05).

Mentions: To address this issue, the present study examined the cardioprotective effect of sildenafil in a rat model of ventricular hypertrophy and myocardial cell injury induced by the β-adrenergic agonist isoproterenol. The model is characterized by technical simplicity, excellent reproducibility and an acceptable level of mortality [8]. Previous studies in rats revealed that isoproterenol induced a dose-dependent increase in ventricular end diastolic pressure and global wall stress that were associated with compensatory hypertrophy and repair fibrosis [5,9]. However, in the present study, the following parameters were assessed: rate of survival among experimental groups, heart coefficient, myocardial cGMP level, myocardial creatine kinase activity and serum level of cardiac troponin T (cTnT). In addition, the role of constitutive NOS was examined by adding the NOS inhibitor Nω-nitro-L-arginine (L-NNA) to drinking water of a group of sildenafil and isoproternol treated rats.


Sildenafil citrate increases myocardial cGMP content in rat heart, decreases its hypertrophic response to isoproterenol and decreases myocardial leak of creatine kinase and troponin T.

Hassan MA, Ketat AF - BMC Pharmacol. (2005)

Kaplan-Meier analysis of 10 days survival among 70 rats classified into vehicle (group I, n= 10; solid line), isoproterenol (group II, n = 15; thick dotted intermediate curve), isoproterenol/ sildenafil (group III, n = 15; thick dashed curve), sildenafil/vehicle(group IV, n = 15; solid line) and sildenafil/isoproternol/ Nω-nitro-L-arginine (group V, n = 15; thin dash-dot line to the left). Significant improvement in survival rate was found by log-rank test in group III compared to groups II and V (P < 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1131906&req=5

Figure 1: Kaplan-Meier analysis of 10 days survival among 70 rats classified into vehicle (group I, n= 10; solid line), isoproterenol (group II, n = 15; thick dotted intermediate curve), isoproterenol/ sildenafil (group III, n = 15; thick dashed curve), sildenafil/vehicle(group IV, n = 15; solid line) and sildenafil/isoproternol/ Nω-nitro-L-arginine (group V, n = 15; thin dash-dot line to the left). Significant improvement in survival rate was found by log-rank test in group III compared to groups II and V (P < 0.05).
Mentions: To address this issue, the present study examined the cardioprotective effect of sildenafil in a rat model of ventricular hypertrophy and myocardial cell injury induced by the β-adrenergic agonist isoproterenol. The model is characterized by technical simplicity, excellent reproducibility and an acceptable level of mortality [8]. Previous studies in rats revealed that isoproterenol induced a dose-dependent increase in ventricular end diastolic pressure and global wall stress that were associated with compensatory hypertrophy and repair fibrosis [5,9]. However, in the present study, the following parameters were assessed: rate of survival among experimental groups, heart coefficient, myocardial cGMP level, myocardial creatine kinase activity and serum level of cardiac troponin T (cTnT). In addition, the role of constitutive NOS was examined by adding the NOS inhibitor Nω-nitro-L-arginine (L-NNA) to drinking water of a group of sildenafil and isoproternol treated rats.

Bottom Line: The results showed that daily intraperitoneal administration of sildenafil per se for 10 days was without noticeable adverse effects on survival or myocardium.When sildenafil was injected daily, one hour before isoproterenol, survival was significantly improved and the myocardium didn't show significant hypertrophy or cell injury.At the same time, cGMP was found to possess a positive correlation with myocardial creatine kinase activity that reflects the efficiency of the energy utilization processes in the myocardium.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology, Faculty of Medicine, University of Alexandria, Egypt. madiha2000x@hotmail.com

ABSTRACT

Background: Cardiac hypertrophy is a major risk factor for morbidity and mortality in a number of cardiovascular diseases. Consequently, the signaling pathways that inhibit cardiac hypertrophy are currently receiving much interest. Among them, nitric oxide (NO), signaling via cGMP and cGMP-dependent protein kinase I, has been recognized as a negative regulator of cardiac hypertrophy. The present study investigated the in-vivo effect of sildenafil as a phosphodiestrase-5A (PDE-5A) inhibitor on the hypertrophic response of rat heart to isoproterenol and the relation of this effect to the level of myocardial cGMP and integrity of the constitutive nitric oxide synthase (cNOS) activity.

Results: The results showed that daily intraperitoneal administration of sildenafil per se for 10 days was without noticeable adverse effects on survival or myocardium. Conversely, daily subcutaneous administration of isoproterenol for 10 days caused significant myocardial hypertrophy, cell injury and decline in survival. When sildenafil was injected daily, one hour before isoproterenol, survival was significantly improved and the myocardium didn't show significant hypertrophy or cell injury. Interestingly, sildenafil was accompanied by significant rise in myocardial cGMP level, a parameter which was found in the present study to possess a significant negative correlation with cardiac hypertrophy and leak of cardiac troponin T into serum. At the same time, cGMP was found to possess a positive correlation with myocardial creatine kinase activity that reflects the efficiency of the energy utilization processes in the myocardium. However, in rats given Nomega-nitro-L-arginine (L-NNA) as a competitive inhibitor of cNOS, sildenafil failed to show any favorable effect on survival or the myocardial injury parameters used to assess isoproterenol-induced injury.

Conclusion: The present study suggests that increased cardiac cGMP level by sildenafil have a cardioprotective effect probably through acting as a post-receptor negative regulator of cardiac sympathetic responsiveness. Integrity of NOS function was an essential prerequisite for sildenafil's mediated cardioprotection encountered in the present study.

Show MeSH
Related in: MedlinePlus