Effect of the Calcimimetic, Cinacalcet, on Regional Vascular Resistance and Blood Ionized Calcium in Uremic and Normal Rats

Abstract

Cinacalcet (CIN) decreases serum PTH and Ca in ESRD patients with SHPT and also produces acute elevations in blood pressure (BP) in uremic rats. To test the hypothesis that CIN produces acute hypertension through vasoconstriction of multiple vascular beds, the regional hemodynamic effects of CIN were delineated in anesthetized rats and correlated to changes in BP and iCa2+. Male SD rats were subjected to 5/6 nephrectomy (NX) or no surgery (Normal); at 7–8 weeks uremia rats were instrumented to record BP, heart rate and regional blood flow (carotid, mesenteric, hindlimb). CIN (1, 3, 10 mg/kg; 30 min/dose) or VEH was infused over 90 min. Change from baseline in CIN vs. VEH was analyzed by repeated measures ANOVA, Dunnett’s (∗p<0.05). In NX, CIN decreased iCa2+ from 1.22±0.02 mmol/L at baseline to 1.10±0.02∗, 0.97±0.02∗ and 0.91±0.03∗ mmol/L and produced increases in BP (from 119±6 mmHg to 129±5, 142±4∗, and 145±3∗ mmHg at the end of each infusion). At 1 mg/kg carotid (CVR) and mesenteric (MVR) vascular resistance increased to 16±6%∗ above baseline (VEH=3±2%) and 18±6∗% above baseline (VEH= −1±2%), respectively. Hindlimb (HVR) vascular resistance trended upward to 13±8% above baseline (VEH = −2±2%). 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 CIN on iCa2+, BP and VR in Normal rats were similar to NX. Thus, at doses producing reductions in iCa2+ CIN acutely increases BP in uremic and non-uremic rats, responses that occur in parallel to vasoconstriction in vascular beds fed by the carotid, mesenteric, and hindlimb arteries.