Sarpogrelate is a serotonin 2A receptor antagonist, whose effects on cardiovascular disorders are still being evaluated. In collaboration with Dr Dhalla, the author has conducted research on this antagonist for more than 10 years, with 10 articles published on the subject. This particular article summarizes the collaborative published work, clarifies the action of sarpogrelate on myocardial and vascular smooth muscle cells, and describes the beneficial effects of sarpogrelate.
Keywords: 5-HT(2A) receptors, Cardiovascular disorders, Sarpogrelate, Serotonin
Abstract
The present article, dedicated to Dr NS Dhalla on the occasion of the jubilee of his life’s work, is a brief review of articles based on the authors’ studies of sarpogrelate conducted in collaboration with Dr NS Dhalla. These studies on the effects of sarpogrelate on cardiovascular disorders have been ongoing for more than 10 years, and 10 articles have been published to date.
Sarpogrelate is a serotonin (5-HT) 2A receptor antagonist that exerts antiplatelet and antithrombotic effects. The mechanism of its effects on cardiovascular disorders is unclear, but from a pharmacological and clinical viewpoint, it is important to elucidate the action of sarpogrelate on myocardial cells and vascular smooth muscle cells. The present report summarizes 10 articles published in international journals documenting the results of our collaborative research with Dr Dhalla, and describes the beneficial effects of sarpogrelate.
EFFECTS OF SARPOGRELATE ON VASCULAR SMOOTH MUSCLE CELLS
Cellular injury triggers the enhanced release of certain cytokines, including 5-HT, which induce proliferation of vascular smooth muscle cells. Using radioactive thymidine, uridine and phenylalanine in cultured rat aortic smooth muscle cells, it was revealed that 5-HT stimulated the proliferation of smooth muscle cells, and that this proliferation was inhibited by sarpogrelate (1).
To determine whether sarpogrelate inhibits 5HT-induced proliferation of porcine coronary artery smooth muscle cells, cell proliferation and mitotic activity were estimated using cell culture techniques. Sarpogrelate prevented the activation of mitogen-activated protein kinase and downregulated the expression of c-Fos and c-Jun (2).
The effect of 5-HT on Ca2+ concentration in rat aortic smooth muscle cells was examined by fura-2 microfluorometry. 5-HT increased the Ca2+ concentration, and this increase was blocked by sarpogrelate (3).
Sarpogrelate was also found to attenuate 5-HT-mediated increases in intracellular Ca2+ concentration and ischemia-reperfusion injury in the heart. The major effects of sarpogrelate are inhibition of 5-HT-induced platelet aggregation and smooth muscle cell proliferation. Therefore, sarpogrelate could exert antiplatelet, antithrombotic, antiatherosclerotic and antiangial effects (4).
EFFECTS OF SARPOGRELATE ON HEART FUNCTION
Ischemia-reperfusion-induced changes in left ventricular developed pressure, left ventricular end diastolic pressure, rate of pressure development and rate of delay were attenuated by sarpogrelate treatment. Sarpogrelate also decreased ultrastructural damage and increased the level of high-energy phosphate in hearts subjected to ischemia-reperfusion (5).
Sarpogrelate reduced the mortality rate, infarct size and left ventricular end diastolic pressure in rats with myocardial infarction induced by ligation of the left coronary artery (6).
Marked functional disorders in rats with experimental myocardial infarction were associated with depression of sarcoplasmic reticulum Ca2+ uptake and release activities, as well as depression of myofibrillar Ca2+-stimulated ATPase activity. These changes were attenuated by treatment with sarpogrelate (7).
Electrocardiographical, echocardiographical and hemodynamic parameters were measured in rats with heart failure due to myocardial infarction. Treatment of infarcted rats with sarpogrelate improved left ventricular dimensions, fractional shortening, cardiac output, stroke volume, mean arterial pressure and diastolic function. Sarpogrelate decreased the incidence of ventricular arrhythmia and mortality rate. These data indicate that sarpogrelate can prevent remodelling and improve cardiac function in heart failure due to myocardial infarction (8).
Rats were pretreated with sarpogrelate and subsequently given either an adrenaline injection or subjected to coronary occlusion. Electrocardiographical analysis revealed that sarpogrelate pretreatment decreased the incidence and severity of ventricular arrhythmias. Sarpogrelate did not affect the corrected QT interval (9).
In rats with diabetes induced by streptozotocin injection, decreased serum insulin as well as increased serum glucose, cholesterol and triglyceride levels were observed, and were associated with increases in blood pressure and heart/body weight ratio. Impaired cardiac performance in diabetic rats was evident in terms of decreases in heart rate, left ventricular developed pressure and other parameters. Treatment of diabetic rats with sarpogrelate attenuated these changes. The expression of the membrane glucose transporter GLUT-4 was depressed in the diabetic heart; this alteration of GLUT-4 was partially prevented by sarpogrelate. These results suggest that sarpogrelate may improve cardiac function in diabetes by promoting the expression of membrane glucose transporters (10).
REFERENCES
- 1.Sharma SK, Zahradka P, Chapman D, Kumamoto H, Takeda N, Dhalla NS. Inhibition of serotonin-induced vascular smooth muscle cell proliferation by sarpogrelate. J Pharmacol Exp Ther. 1999;290:1475–81. [PubMed] [Google Scholar]
- 2.Sharma SK, Del Rizzo DF, Zahradka P, et al. Sarpogrelate inhibits serotonin-induced proliferation of porcine coronary artery smooth muscle cells: Implications for long-term graft patency. Ann Thorac Surg. 2001;71:1856–64. doi: 10.1016/s0003-4975(01)02599-1. [DOI] [PubMed] [Google Scholar]
- 3.Saini HK, Sharma SK, Zahradka P, Kumamoto H, Takeda N, Dhalla NS. Attenuation of the serotonin-induced increase in intracellular calcium in rat aortic smooth muscle cells by sarpogrelate. Can J Physiol Pharmacol. 2003;81:1056–63. doi: 10.1139/y03-108. [DOI] [PubMed] [Google Scholar]
- 4.Saini HK, Takeda N, Goyal RK, Kumamoto H, Ameja AS, Dhalla NS. Therapeutic potentials of sarpogrelate in cardiovascular disease. Cardiovasc Drug Rev. 2004;22:27–54. doi: 10.1111/j.1527-3466.2004.tb00130.x. [DOI] [PubMed] [Google Scholar]
- 5.Temsah RM, Kumamoto H, Takeda N, Dhalla NS. Sarpogrelate diminishes changes in energy stores and ultrastructure of the ischemic-reperfused rat heart. Can J Physiol Pharmacol. 2001;79:761–7. [PubMed] [Google Scholar]
- 6.Brasil D, Temsah RM, Kumar K, Kumamoto H, Takeda N, Dhalla NS. Blockade of 5-HT(2A) receptors by sarpogrelate protects the heart against myocardial infarction in rats. J Cardiovasc Pharmacol Ther. 2002;7:53–9. doi: 10.1177/107424840200700i108. [DOI] [PubMed] [Google Scholar]
- 7.Sanganalmath SK, Babick AP, Barta J, Kumamoto H, Takeda N, Dhalla NS. Antiplatelet therapy attenuates subcellular remodeling in congestive heart failure. J Cell Mol Med. 2008;12:1728–38. doi: 10.1111/j.1582-4934.2007.00197.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Sanganalmath SK, Barta J, Takeda N, Kumamoto H, Dhalla NS. Antiplatelet therapy mitigates cardiac remodeling and dysfunction in congestive heart failure due to myocardial infarction. Can J Physiol Pharmacol. 2008;86:180–9. doi: 10.1139/Y08-005. [DOI] [PubMed] [Google Scholar]
- 9.Barta J, Sanganalmath SK, Kumamoto H, Takeda N, Edes I, Dhalla NS. Antiplatelet agents sarpogrelate and cilostazol affect experimentally-induced ventricular arrhythmias and mortality. Cardiovasc Toxicol. 2008;8:127–35. doi: 10.1007/s12012-008-9019-x. [DOI] [PubMed] [Google Scholar]
- 10.Goyal RK, Elimban V, Xu YJ, Kumamoto H, Takeda N, Dhalla NS. Mechanism of sarpogrelate action in improving cardiac function in diabetes. J Cardiovasc Pharmacol Ther. 2010. (In press). [DOI] [PubMed]