Sildenafil Citrate (Viagra) Does Not Cause Structural Changes in the Arterial Wall But Modulates Renal Artery Vascular Tone in Atherosclerosis-Induced Male Rabbits
Background: Phosphodistrase type 5 (PDE-5) inhibitors are shown to improve vasomotor aspect of endothelial dysfunction through modulatory effects on nitric oxide NO-cyclic guanosine monophosphate (NO-cGMP) mediated responses. However, the effects of PDE-5 inhibitors on the progression of atherosclerosis and blood flow alteration need further evaluation. Aim: To investigate in atherosclerosis-induced male rabbits, whether a selective PDE-5 inhibitor (sildenafil), can prevent atherosclerosis progression or modulate blood flow in the aorta and renal arteries. Materials and Methods: Eighteen local domestic healthy male rabbits were randomly divided into three groups of six each. Group I, were fed a normal chow (oxiod) diet, for 12 weeks and served as a control. Group II, were fed with an atherogenic diet, for 12 weeks. Group III, rabbits that were fed with cholesterol enriched diet for six weeks, were treated with oral sildenafil 5mg/kg/day, for a further six weeks. All rabbits were subjected to ultrasound/Doppler study of the abdominal aorta, renal artery and intrarenal arteries, along with oxidative stress measurements. Autopsy of the aortic arch sectioning for histopathology was done at the end of the study. Results: Treatment with sildenafil resulted in non-significant reduction (P>0.05) in aortic diameter and intima-media thickness (IMT); sildenafil elicited an atherosclerotic effect that did not reach the significant level (P>0.05). There was no significant change ( p>0.05) in aortic flow peaked systolic velocity (PSV), end diastolic velocity (EDV), pulsatility index (PI) , and resistive index (RI). Sildenafil caused significant reductions (P<0.05) in renal artery and intra-renal artery PSV, EDV, PI and RI. Conclusion: Sildenafil neither resulted in significant structural changes in the atherosclerotic aortic wall, nor caused alteration in the arterial blood flow. Sildenafil exerted a significant relaxant effect on the atherosclerotic renal artery and intra -renal arteries. These findings may have a clinical implication favoring the use of PDE-5 inhibitors (Sildenafil) in the treatment of patients with atherosclerosis and renal hypertension.
Sildenafil, PDE-5, Atherosclerosis, Hypercholestrolemic Rabbits, Doppler, Renal Artery, Intra-Renal Arteries Blood Flow
Cheitlin MD, Hutter AM, Brindis RG, Ganz P, Kaul S, Russell RO, Zusman RM. Use of Sildenafil (Viagra) in Patients With Cardiovascular Disease. Circulation 1999; 99: 168-177.
Lau LC, Adaikan PG. Mechanisms of direct relaxant effect of sildenafil, tadalafil and vardenafil on corpus cavernosum. Eur J Pharmacol 2006; 541(3):184-190.
Tessier DJ, Komalavilas P, McLemore E, Thresher J, and Brophy CM. Sildenafil- induced vasorelaxation is associated with increases in the phosphorylation of the heat shock-related protein 20 (HSP20).Journal of Surgical Reaserch 2004; 118 (1): 21-25.
Gillies H.C., Roblin D., and Jackson G.: Coronary and systemic hemodynamic effects of sildenafil citrate: from basic science to clinical studies in patients with cardiovascular disease. International Journal of Cardiology, 2002; 86: 131–141.
Park J.W., Mrowietz C., Chung N., and Jung F.: Sildenafil improves cutaneous microcirculation in patients with coronary artery disease: a monocentric, prospective, double-blind, placebo-controlled, randomized cross-over study. Clin Hemorheol Microcirc, 2004; 31(3):173-183.
Fries R., Shariat K., Wilmowsky H. V, and Böhm M.: Sildenafil in the Treatment of Raynaud’s Phenomenon Resistant to Vasodilatory Therapy. Circulation, 2005; 112: 2980-2985.
Jackson G., Montorsi P., and Cheitlin M.D.: Cardiovascular safety of sildenafil citrate (Viagra): an updated perspective. Urology, 2006; 68(3): 47-60.
Ishikura F., Beppu S., Hamada T., Khandheria B.K., Seward J.B., and Nehra A.: Effects of Sildenafil Citrate (Viagra) Combined With Nitrate on the Heart. Circulation, 2000; 102: 2516-2553.
Bhalla A., Singh R., Gautam C.S., and Sachdev A.: Sildenafil Citrate In Diabetics With Hypertension And Erectile Dysfunction. The Internet Journal of Internal Medicine, 2003; 1528-8382.
Gross G.J. Sildenafil and Endothelial Dysfunction in Humans. Circulation, 2005; 111: 721-723.
Ferreira-Melo SE, Yugar-Toledo JC, Coelho OR, De Luca IM, Tanus-Santos JE, Hyslop S, Irigoyen MC, Moreno H Jr. Sildenafil reduces cardiovascular remodeling associated with hypertensive cardiomyopathy in NOS inhibitor-treated rats. Eur J Pharmacol. 2006; 542(1-3):141-147.
Patrizi R, Leonardo F, Pelliccia F, Chierchia SL, Galetta P, Cerquetani E, Frascà F, Fini M, Rosano GM. Effect of sildenafil citrate upon myocardial ischemia in patients with chronic stable angina in therapy with beta-blockers. Ital Heart J. 2-001; 2: 841-844.
Hassan MA, Ketat AF. 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. BMC Pharmacol, 2005; 5: 10 doi:10.1186/1471-2210-5-10.
Swissa M, Ohara T, Lee MH, Kaul S, Shah PK, Hayashi H, Chen PS, Karagueuzian HS. Sildenafil-nitric oxide donor combination promotes ventricular tachyarrhythmias in the swine right ventricle. Am J Physiol Heart Circ Physiol. 2002 May;282(5):H1787-92.
Narayanasawamy M, Wright KC, and Kandarpa K. Animal Models for Atherosclerosis, Restenosis, and Endovascular Graft Research: J. vascular interventional radiology, 2000; 11: 5-17.
Quesenberry KE. and Carpenter JW. Ferrets, Rabbits and Rodents: Clinical Medicine and Surgery, Saunders. 2004: St. Louis.
Victor et al., 1996) [ Victor PM, Hulst V, Baalen J, Kool LS. Renal Artery Stenosis. Endovascular Flow Wire Study for Validation of Doppler U.S. Radiology 1996; 200: 165-168.
Stary HC, Chandler AB, Robert E. Dinsmore, Fuster V, Glagov S, Insull JrW, Rosenfeld ME, . Schwartz CJ , . Wagner WD, Wissler RW. A Definition of Advanced Types of Atherosclerotic Lesions and a Histological Classification of Atherosclerosis. A Report From the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Associatio Circulation. 1995; 92: 1355-1374.
Fadhil G Al-Amran, Akeel AMH Zwain, Najah R Hadi, and Ahmed M Al-Mudhaffer. Autonomic cerebral vascular response to sildenafil in diabetic patient. Diabetology & Metabolic Syndrome 2012, 4:2 doi:10.1186/1758-5996-4-2
Mayne ST. Antioxidant nutrient and chronic disease: use of biomarker of exposure and oxidative stress status in epidemiologic research. J nutrition, 2003; 133;933-940.
Engelmann B. Changes of membrane phospholipid composition of human erythrocytes in hyperlipidemias. Increased phosphatidyl -choline and reduced sphingomyelin in patients with elevated levels of triacylglycerol-rich lipoproteins. Biochim. Biophys. Acta., 1992; 1165: 32–37.
Lange W. H.: Statistics techniques in business and economics. 2002; McGraw Hill/Irwin, eleventh edition, pp. 408.
David A. Kass, Champion, HC, Beavo JA. Review. Phosphodiesterase Type 5 Expanding Roles in Cardiovascular R egulation. Circulation Research. 2007; 101: 1084-1095.
Zhao L, Mason NA, Morrell NW, Kojonazarov B, Sadykov A, Maripov A, Mirrakhimov MM, Aldashev A, Wilkins MR. Sildenafil inhibits hypoxia-induced pulmonary hypertension. Circulation. 2001; 104: 424–428.
McConnell MV, Aikawa M, Maier SE, Ganz P, Libby P, Lee RT. MRI of Rabbit Atherosclerosis in Response to Dietary Cholesterol Lowering . Arteriosclerosis, Thrombosis, and Vascular Biology. 1999; 19: 1956-1959.
Pasterkamp G., Kleijn DPV. and Cornelius-Borst C. Arterial remodeling in atherosclerosis, restenosis and after alteration of blood flow: potential mechanisms and clinical implications. Cardiovascular Research 2000; 5: 843-852.
Armstrong ML, Heistad DD, Marcus ML, Megan MB, Piegors DJ. Structural and hemodynamic responses of peripheral arteries of macaque monkeys to atherogenic diet. Arteriosclerosis 1985; 5: 336-346.
Kristek F, Koprodova R, Cebova M. long term effect of early administered sildenafil and NO donar on cardiovascular system of SHR. J physiol. and Pharmacol. 2007; 58, 1, 33-43.
Polak K, Wimpissinger B, Berisha F, Georgopoulos M, Schmetterer L. Effects of Sildenaﬁl on Retinal Blood Flow and FlickerInduced Retinal Vasodilatation in Healthy Subjects. Investigative Ophthalmology & Visual Science, November 2003, Vol. 44, No. 11.
Morano S, Mandosi E, Fallarino M, Gatti A,Tiberti C, Sensi M, Gandini L, Buchetti B, Lenti L, Jannini EA, Lenzi A. Antioxidant Treatment Associated with Sildenafil Reduces Monocyte Activation and Markers of Endothelial Damage in Patients with Diabetic Erectile Dysfunction: A Double-Blind, Placebo-Controlled Study. e u r o p e a n u r o l o g y 2 0 0 7; 52, 1 7 6 8 – 1 7 7 6.
Ali Erdogan, Doerte Wiebke Luedders, Benedikt Manuel Muenz, Christian Alexander Schaefer, Harald Tillmanns, Johannes Wiecha, Christoph, Ruediger Wolfram Kuhlmann. Sildenafil Inhibits the Proliferation of Cultured Human Endothelial Cells. InternatIonal journal of BIomedIcal science, JUNE, 2007; vol. 3 No., p 94-97 2.
Heller R, Polack T, Gräbner R, Till U. Nitric oxide inhibits proliferation of human endothelial cells via a mechanism independent of cGMP. Atherosclerosis 1999; 144: 49.
Kocakoc E, Ardicoglu A, Bozgeyik Z, Kiris A, Yuzgec V, and Ogur E. Effects of sildenafil on major arterial blood flow using duplex sonography. Journal of Clinical Ultrasound, 2005; 33(4): 173-175.
Knopp RH. Drug Treatment of Lipid Disorders. N Engl J Med. 1999; 341:498-511.
Bozgeyik Z, Berilgen S, Ozdemir H, Tekatas A, Ogur E. Evaluation of the Effects of Sildenafil Citrate (Viagra) on Vertebral Artery Blood Flow in Patients with Vertebro-Basilar Insufficiency. Korean J Radiol 2008;9:477-480
Degirmenci B, Acar M, Albayrak R, Haktanir A, Yucel A, Gecici O. Effects of sildenafil citrate (Viagra) on renal arteries: an evaluation with Doppler ultrasound. Urol Int. 2006;77(2):170-172.
Serhatlioglu S, Kiris A, Kocakoc E, Canpolat I, Bozgeyik Z, Han MC. Evaluation of the effects of sildenafil citrate (Viagra) on canine renal artery, carotid and aortic blood flow with the aid of color Doppler sonography. Urol Int. 2003;71(1):103.
Dishy V, Harris PA, Pierce R, Prasad HC, Sofowora G, Bonar HL, Wood HA, Stein CM: Sildenafil does not improve nitric oxide-mediated endothelium-dependent vascular responses in smokers. British Journal of Clinical Pharmacology 2004, 57(2):209-212.
Lledó-García E, Subirá-Ríos D, Rodríguez–Martínez D, Dulín E, Alvarez-Fernández E, Hernández-Fernández C, Cañizo-López JFD. Sildenafil as a Protecting Drug for Warm Ischemic Kidney Transplants: Experimental Results. The Journal of Urology 2009; (182),1222-1225.
Medeiros PJ, Neto AV, Lima FP, Azevedo IM, Leão LR , Medeiros AC . Effect of sildenafil in renal ischemia/reperfusion injury in rats. Acta Cir Bras. 2010 Dec; 25(6):490-5.