Mechanisms Involved in the Relationship between Low Calcium Intake and High Blood Pressure

Abstract

There is increasing epidemiologic and animal evidence that a low calcium diet increases blood pressure. The aim of this review is to compile the information on the link between low calcium intake and blood pressure. Calcium intake may regulate blood pressure by modifying intracellular calcium in vascular smooth muscle cells and by varying vascular volume through the renin-angiotensin-aldosterone system. Low calcium intake produces a rise of parathyroid gland activity. The parathyroid hormone increases intracellular calcium in vascular smooth muscles resulting in vasoconstriction. Parathyroidectomized animals did not show an increase in blood pressure when fed a low calcium diet as did sham-operated animals. Low calcium intake also increases the synthesis of calcitriol in a direct manner or mediated by parathyroid hormone (PTH). Calcitriol increases intracellular calcium in vascular smooth muscle cells. Both low calcium intake and PTH may stimulate renin release and consequently angiotensin II and aldosterone synthesis. We are willing with this review to promote discussions and contributions to achieve a better understanding of these mechanisms, and if required, the design of future studies.

Keywords: blood pressure; calcium intake; parathyroid function; renin-angiotensin-aldosterone system; vitamin D.

Figure 1

Scheme of the mechanisms involved in the rise of blood pressure in low calcium intake by an increase in peripheral vascular resistance. Low calcium intake decreases plasmatic calcium concentration ([Ca²⁺]_plasma), stimulating the release of parathyroid hormone (PTH) and parathyroid hypertensive factor (PHF), the synthesis of calcitriol, and the activation of the renin–angiotensin–aldosterone system (RAAS). In vascular smooth muscle cells (VSMC), angiotensin II via the angiotensin II type I receptor (AT1R)/Gq/phospholipase C (PLC)/inositol trisphosphate (IP3) pathway, PTH via PTHr-1/Gs/3′,5′-cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA), and calcitriol via adenylate cyclase (AC)/cAMP/PKA and PLC/IP3 signaling pathways increased the intracellular calcium concentration ([Ca²⁺]_i). The rise of [Ca²⁺]_i leads to vasoconstriction, and hence increases in peripheral vascular resistance and blood pressure. The PHF mechanism of action remains unknown. See text for further details.

Figure 2

Scheme of the mechanisms involved in the rise of blood pressure in low calcium intake via an increase in cardiac output. Low calcium intake decreased the plasmatic calcium concentration ([Ca²⁺]_plasma), stimulating PTH and the renin–angiotensin–aldosterone system (RAAS). Both angiotensin II and PTH were increased aldosterone secretion due to the adrenal gland. Aldosterone upregulates epithelial sodium channels (ENaC) in the principal cells of the collecting duct in the kidney, increasing apical membrane permeability for Na⁺, thus Na⁺ and water reabsorption. The rise of extracellular fluid volume (ECF) increased cardiac output and hence blood pressure.

Figure 3

Scheme of the mechanisms involved in the rise of blood pressure due to low calcium intake, namely the link between calciotropic hormones and blood pressure regulators. Low calcium intake: (a) increases calcitriol serum levels, (b) stimulates parathyroid function, and (c) increases renin secretion. Calcitriol may increase cytosolic free calcium concentration ([Ca²⁺]_i) via non-genomic short-term mechanisms. The parathyroid gland secretes parathyroid hormone (PTH) and possibly (dash arrow) the parathyroid hypertensive factor (PHF). Both mediators increase [Ca²⁺]_i, leading to the contraction of the vascular smooth muscle cells (vasoconstriction). Renin release is stimulated both by low extracellular calcium and PTH, activating the renin–angiotensin–aldosterone system (RAAS). In addition, PTH increases angiotensin II and aldosterone synthesis, which also leads to vasoconstriction and increases renal water reabsorption, increasing blood pressure. Aldosterone also increases PTH serum levels (double-headed arrow). See text for further details.