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Review
. 2011 Oct;164(3):884-93.
doi: 10.1111/j.1476-5381.2011.01317.x.

The calcium-sensing receptor and calcimimetics in blood pressure modulation

Sanela Smajilovic  1 , Shozo Yano, Reza Jabbari, Jacob Tfelt-Hansen
Affiliations
Review

The calcium-sensing receptor and calcimimetics in blood pressure modulation

Sanela Smajilovic et al. Br J Pharmacol. 2011 Oct.

Abstract

Calcium is a crucial second messenger in the cardiovascular system. However, calcium may also be an extracellular first messenger through a G-protein-coupled receptor that senses extracellular concentration (Ca(2+)(o)), the calcium-sensing receptor (CaR). The most prominent physiological function of the CaR is to maintain the extracellular Ca(2+) level in a very tight range by regulating the circulating levels of parathyroid hormone (PTH). This control over PTH and Ca(2+) levels is partially lost in patients suffering from primary and secondary hyperparathyroidism. Allosteric modulators of the CaR (calcimimetics) are the first drugs in their class to become available for clinical use and have been shown to successfully treat certain forms of primary and secondary hyperparathyroidism. In addition, several studies suggest beneficial effects of calcimimetics on cardiovascular risk factors associated with hyperparathyroidism. Although a plethora of studies demonstrated the CaR in heart and blood vessels, exact roles of the receptor in the cardiovascular system still remain to be elucidated. However, several studies point toward a possibility that the CaR might be involved in the regulation of vascular tone. This review will summarize the current knowledge on the possible functions of the CaR and calcimimetics on blood pressure regulation.

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Figures

Figure 1
Figure 1
Signalling pathways activated by calcium-sensing receptor (CaR). CaR is activated by Ca2+o, calcimimetics and numerous other agents. Please refer to text for detailed information. Black and blue arrows signify stimulation and red arrows signify inhibition. Abbreviations: arachidonic acid (AA), adenylate cyclase (AC), protein kinase B (AKT), activating transcription factor-2 (ATF-2), adenosine trisphosphate (ATP), cyclic adenosine monophosphate (cAMP), extracellular regulated kinase (ERK), alpha subunit of i and q subtype of the heterotrimeric G proteins (Gi and Gq11), inositol-1,4,5-triphosphate (IP3), Jun amino terminal kinase (JNK), mitogen-activated protein kinase (MAPK), MAPK kinase (MEK), p38 MAPK (p38), phosphatidylinositol 4-kinase (PI4K), phosphatidylinositol 3-kinase (PI3K), protein kinase C (PKC), phosphatidylinositol-4,5-biphosphate (PIP2) and stress-activated protein kinase ERK kinase 1 (SEK1).
Figure 2
Figure 2
Calcium ion homeostasis is tightly regulated by the calcium-sensing receptor (CaR). During fasting state, trivial decrease in serum Ca2+ is sensed by the CaR expressed on the parathyroid gland, kidney and bone (dotted line). Low Cao2+ level (black arrows) stimulates parathyroid hormone (PTH) secretion from the parathyroid gland (solid line), thereby activating bone resorption and renal reabsorption of Ca2+. PTH-induced synthesis of active vitamin D stimulates Ca2+ absorption from the intestine. Thus, serum Ca2+ level should be normalized to the basal level. In contrast, at postprandial state, serum Ca2+ elevated by its absorption from the gastrointestinal tract is sensed by the CaR of these tissues (dotted line). High Cao2+ level suppresses PTH secretion from the parathyroid gland (solid line), followed by the suppression of Ca2+ mobilization from the other tissues and recovery to the basal Cao2+ level.
Figure 3
Figure 3
Mechanisms of blood pressure regulation by extracellular calcium and/or calcium-sensing receptor (CaR). Relationships between the change in Ca2+o and blood pressure may be resulted from: (i) hormonal effects, including renin, parathyroid hormone (PTH) and unidentified factor; (ii) effect of Ca2+o on vascular tone, which is not related to the CaR; (iii) direct effect of the CaR on vascular tone; (iv) drug specific effect, which is independent of PTH, Ca2+o and the CaR; (v) vascular calcification; and (vi) other mechanisms such as through the sympathetic nervous system. Calcilytics and elevated Ca2+o decrease the CaR activity, followed by elevating PTH (and maybe parathyroid-derived hypertensive factor), renin and activating vascular tone and possibly sympathetic nerve to lead an elevation of blood pressure (black arrows). On the other hand, calcimimetics and decreased Ca2+o increase the CaR activity, followed by the opposite response (white arrows). AT II, angiotensin II.
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