Systemic Activation of the Calcium Sensing Receptor Produces Acute Effects on Vascular Tone and Circulatory Function in Uremic and Normal Rats: Focus on Central versus Peripheral Control of Vascular Tone and Blood Pressure by Cinacalcet

Abstract

Calcium-sensing receptor (CaR) activation decreases serum parathyroid hormone (PTH) and Ca 2ϩ and, despite long-term reductions in mean arterial blood pressure (MAP), may produce acute hypertension in rats, an effect we hypothesized was mediated by constriction of multiple vascular beds. Rats were subjected to 5/6 nephrectomy (NX) or no surgery (Normal); at 7 to 8 weeks, uremia animals were anesthetized and instrumented to record MAP and regional blood flow (carotid, mesenteric, and hindlimb). Cinacalcet [N-(1-naphthalen-1-ylethyl)-3-[3-(trifluoromethyl)phenyl]-propan-1-amine; 1, 3, and 10 mg/ kg; 30 min/dose] was infused over 90 min. In NX rats, cinacalcet dose-dependently decreased ionized calcium (iCa 2ϩ ), elicited a 90% reduction in PTH, and produced dose-dependent selflimiting increases in MAP (from 119 Ϯ 6 to 129 Ϯ 5, 142 Ϯ 4, and 145 Ϯ 3 mm Hg at the end of each infusion). At 1 mg/kg, carotid vascular resistance (CVR) and mesenteric vascular resistance (MVR) increased to 16 Ϯ 6 and 18 Ϯ 6% above baseline, respectively. Hindlimb vascular resistance (HVR) also trended upward (13 Ϯ 8%). At 3 mg/kg, increases in CVR (38 Ϯ 10%), MVR (40 Ϯ 8%), and HVR (39 Ϯ 14%) were exacerbated; at 10 mg/kg, values remained at or near these levels. The effects of cinacalcet in Normal rats were similar to NX and were attenuated by ganglionic blockade with hexamethonium at low doses but remained significantly elevated at higher doses. Thus, CaR activation acutely increases MAP in uremic and nonuremic rats, responses that occur in parallel to vasoconstriction in multiple vascular beds through both a central and peripheral mechanism of action. Moreover, subsequent mechanistic studies suggest that increases in MAP produced by cinacalcet may be mediated by reduced tonic NO synthasedependent NO production subsequent to reductions in blood iCa 2ϩ .

Enhanced Ca 2+ -Sensing Receptor Function in Idiopathic Pulmonary Arterial Hypertension

“…In addition, CaSR is expressed in vascular smooth muscle cells from rat subcutaneous artery 52 , aorta 53 , pulmonary artery 16, 17 , gerbil spiral modiolar artery 54 , human renal artery 55 , aorta 55, 56 , and internal mammary artery 57 , as well as in endothelial cells from rat mesenteric artery, porcine coronary artery 58 , and human aorta 19 . Activation of CaSR in vascular smooth muscle cells increases [Ca 2+ ] and induces vasoconstriction 17, 54, 56 cyt ; therefore, CaSR is involved in regulating myogenic tone, peripheral vascular resistance 52 , and arterial blood pressure 59, 60 . Recent observations demonstrate that the CaSR in vascular smooth muscle cells contributes to regulating cell proliferation and apoptosis through the MEK1/ERK1/2 and PLC signaling pathways 17, 53, 55 , and expression of CaSR is involved in the regulation of mouse lung development 61 .…”

Novel regulatory aspects of the extracellular Ca2+-sensing receptor, CaR

“…In rats in which uremia was experimentally induced to mimic chronic kidney disease, acute CaR activation with calcimimetics caused an initial increase in blood pressure (which was also present in sham-operated rats), that only in uremic rats was followed by a marked and sustained depression of the mean arterial blood pressure [98]. The long-term effects of calcimimetics have been ascribed to a reduction in blood pressure downstream of a decline in tonic NO production, which occurs as a consequence of the decrease in serum [Ca 2+ ] o evoked by the calcimimetics [44].…”

Novel Role of the Calcium-Sensing Receptor in Blood Pressure Modulation

“…10 In addition to the long-term reductions in blood pressure, the calcimimetics induce acute hypertension in both uremic and normal rats. 10,81 Thus, the calcimimetics cause an initial blood pressure increase in normal and uremic rats, which is followed by a marked and sustained hypotensive effect in uremic rats. The mechanisms for the actions of the calcimimetics and calcium on the blood pressure remain to be elucidated but may be through direct effects by the presence of the CaR on the endothelium cells and perivascular nerves or indirect through the kidney or parathyroid glands.…”