Key result
The calcimimetic R-568 significantly blunted renin release in vitro and reduced stimulated plasma renin activity in vivo (e.g., from 3.1 to 2.1 ng/ml/h in isoproterenol-treated rats, P<0.05).
Absolute Event Rate: 2.1% vs 3.1%
p-value: p=<0.05
The calcimimetic R-568 blunts renin release in vitro and in vivo in rats, suggesting calcium-sensing receptors play a regulatory role in renin release.
Supports calcium-sensing receptor role in renin release; hypothesis-generating for calcimimetics in human hypertension.
OBJECTIVES: Calcium-sensing receptors (CaSRs) have been localized in the juxtaglomerular apparatus where they may contribute to the regulation of renin release. In the present study, we investigated the in-vitro and in-vivo effects of the calcimimetic R-568 on renin release. METHODS: In vitro, the effect of calcimimetics on renin release was assessed by incubating freshly isolated rat juxtaglomerular cells with or without R-568 (1 and 10 mumol/l) in serum-free medium in the presence or absence of forskolin or CaCl2. In vivo, we measured the impact of R-568 (20 ng/min intravenously) on the acute changes in plasma renin activity (PRA) induced by either a 90 min infusion of the angiotensin-converting enzyme inhibitor captopril, or the beta-receptor agonist isoproterenol, or of a vehicle in or after a furosemide challenge in conscious Wistar rats. RESULTS: In vitro, R-568 dose-dependently blunted renin release, but also reduced the increase in renin due to forskolin (P < 0.01). Both isoproterenol and enalapril increased in vivo PRA to 3.1 +/- 0.3 and 3.7 +/- 0.5 ng Ang I/ml per h, respectively (P < 0.01), compared with vehicle (1.5 +/- 0.2 ng Ang I/ml per h). R-568 significantly reduced PRA to 2.1 +/- 0.1 ng/ml per h in isoproterenol-treated rats and to 1.6 +/- 0.2 ng/ml per h in enalapril-treated rats (P < 0.05). In low-salt treated animals, acute infusion of furosemide increased PRA from 8.7 +/- 3.2 to 18.6 +/- 2.3, whereas R-568 partially blunted this rise to 11.2 +/- 1.5 (P = 0.02). In vivo, R-568 significantly lowered serum calcium and PTH1-84, but the drug-induced changes in PRA were independent of the changes in calcium and parathyroid hormone. CONCLUSION: After the recent discovery of CaSRs in juxtaglomerular cells of mice, our results confirm the presence of such receptors in rats and demonstrate that these receptors modulate renin release both in vitro and in vivo. This suggests that CaSRs play a role as a regulatory pathway of renin release.
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Maillard et al. (2009) studied this question. Calcimimetic R-568 vs. Vehicle / without R-568 was evaluated on Plasma renin activity (PRA) in isoproterenol-treated rats (p=<0.05). The calcimimetic R-568 significantly blunted renin release in vitro and reduced stimulated plasma renin activity in vivo (e.g., from 3.1 to 2.1 ng/ml/h in isoproterenol-treated rats, P<0.05).
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