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Calcium-sensing receptor and calcimimetics in the cardiovascular system

 

Sanela Smajilovic

Summary

Calcium is a crucial signal molecule in the cardiovascular system. Calcium (Ca2+) acts as a second messenger via changes in intracellular Ca2+ levels through the actions of calcium channels and pumps. However, it is now well know that calcium may also be an extracellular first messenger through a G-protein-coupled receptor that senses extracellular Ca2+ concentration, the calciumsensing receptor (CaR). The CaR is one of the key players in extracellular calcium homeostasis, but besides being expressed in the major organs involved in calcium homeostasis, the parathyroid gland, kidney and intestine, the CaR has also been found to be functionally expressed in other tissues. Although several studies demonstrated the CaR in heart and blood vessels, exact roles of the receptor in the cardiovascular system still remain to be elucidated. This PhD thesis describes data from our in vitro and ex vivo studies on the expression and function of the CaR in heart and aorta from rats.
We found a functional CaR to be expressed in rat neonatal ventricular  cardiomyocytes in cell culture and to downregulate DNA synthesis in these cells, indicating that the CaR might be protective against cardiac hypertrophy. We also demonstrated the presence of the CaR in cultured rat aortic vascular smooth muscle cells and showed a stimulating effect of extracellular calcium on cell proliferation. However, we were not able to demonstrate that extracellular calcium exerted its effects through the CaR. Although we found the CaR to be expressed in cultured vascular smooth muscle cells, immunohistochemical staining of rat aortic tissue sections showed the CaR mainly in the endothelium but not in the medial layer of the vessel. These discrepant results are probably due to difference between cell culture systems versus tissue specimens, demonstrating the importance of using different models in research. We also investigated the effects of a CaR agonist, calcimimetic AMG 073, on contractility of the rat aorta by wire myography, and found it to induce vasodilation of pre-contracted aorta, an effect that might be, at least partly, mediated by the CaR.
In conclusion, we demonstrated the presence of the CaR in the neonatal ventricular cardiomyocytes and aorta, and showed a vasodilating effect of the calcimimetic AMG 073 on the pre-contracted aorta. These results support the emerging picture that the CaR may be of importance in the heart physiology and blood pressure regulation.