Acute Blood Pressure Effects and Chronic Hypotensive Action of Calcimimetics in Uremic Rats

Abstract

A previous study in subtotally nephrectomized (SNX) rats suggested beneficial effects of the calcimimetic R-568 beyond the control of mineral metabolism. This study analyzed potential blood pressure (BP)-lowering effects of R-568. Male SpragueDawley rats received two-stage subtotal nephrectomy or sham operation. Telemetry devices were inserted into the abdominal aorta, and BP was measured every 5 min. R-568 (20 mg/kg per d) or solvent was infused for 4 wk followed by once-daily subcutaneous injections for 2 wk. Total body sodium was measured by neutron activation analysis. The uremia-induced increase of mean arterial pressure from baseline to day 42 in SNX solvent rats (103 ؎ 5 to 128 ؎ 14 mmHg, P ‫؍‬ 0.006) was attenuated by R-568 (104 ؎ 5 to 111 ؎ 8 mmHg; P < 0.0001 for difference of slopes). The circadian rhythm was abrogated in SNX rats and not restored by R-568. In sham-operated rats, R-568 had only a minor transient antihypertensive effect. R-568 injection induced a transient rise of mean arterial pressure by 23 ؎ 4 and 26 ؎ 10 mmHg in sham and SNX rats but only by 9 ؎ 3 and 10 ؎ 5 mmHg in solvent-treated rats (P < 0.01 versus baseline and solvent versus R-568). Plasma angiotensinconverting enzyme activity and aldosterone levels were similar; food intake and physical activity did not differ throughout the study. In healthy rats, total body sodium was higher after 14 d of R-568 compared with solvent infusion (37.1 ؎ 4 versus 32.5 ؎ 1.4 mmol/kg; P ‫؍‬ 0.01). The calcimimetic R-568 causes an initial BP increase in sham-operated and uremic rats, which in uremic rats is followed by a marked and sustained antihypertensive effect.

Interstitial fibrosis and microvascular disease of the heart in uremia: amelioration by a calcimimetic

“…Within the limitation of the method, the intervention failed to significantly affect blood pressure. The effect of calcimimetics on blood pressure that had been observed in this laboratory using telemetry 25 was not observed in this study using tail plethysmography (in the long-term experiment), but was seen by intra-aortic measurement 2 h after dose in a shortterm setting. Therefore, the effect on BP is apparently rather transient.…”

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

“…9,10 Similar effects on blood pressure were achieved by parathyroidectomy, and administration of NPS R-568 did not intensify the hypotensive effect of the parathyroidectomy. Accordingly, administration of a calcilytic NPS-2143 increases blood pressure in normotensive rats in the presence of parathyroid glands.…”

Hypertensive effect of calcilytic NPS 2143 administration in rats

“…Furthermore, the calcimimetic NPS R-568 caused the marked and sustained antihypertensive effect in uraemic rats (Odenwald et al 2006). Therefore, it might be presumed that the inactivation of CaR by cacilytics leads to increased blood pressure in normotensive rats.…”