Calcium-sensing receptor (CaR) activation decreases serum
parathyroid hormone (PTH) and Ca2+ 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 (iCa2+), elicited a 90% reduction in PTH, and produced dose-dependent self-limiting increases in MAP (from 119 +/- 6 to 129 +/- 5, 142 +/- 4, and 145 +/- 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 +/- 6 and 18 +/- 6% above baseline, respectively. Hindlimb vascular resistance (HVR) also trended upward (13 +/- 8%). At 3 mg/kg, increases in CVR (38 +/- 10%), MVR (40 +/- 8%), and HVR (39 +/- 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 synthase-dependent NO production subsequent to reductions in blood iCa2+.