Vascular actions of calcimimetics: role of Ca2+-sensing receptors versus Ca2+ influx through L-type Ca2+ channels

BACKGROUND AND PURPOSE The calcimimetic, (R)-N-(3-(3-(trifluoromethyl)phenyl)propyl)-1-(1-napthyl)ethylamine hydrochloride (cinacalcet), which activates Ca2+-sensing receptors (CaR) in parathyroid glands, is used to treat hyperparathyroidism. Interestingly, CaR in perivascular nerves or endothelial cells is also thought to modulate vascular tone. This study aims to characterize the vascular actions of calcimimetics. EXPERIMENTAL APPROACH In rat isolated small mesenteric arteries, the relaxant responses to the calcimimetics, cinacalcet and (R)-2-[[[1-(1-naphthyl)ethyl]amino]methyl]-1H-indole hydrochloride (calindol) were characterized, with particular emphasis on the role of CaR, endothelium, perivascular nerves, K+ channels and Ca2+ channels. Effects of L-ornithine, which activates a Ca2+-sensitive receptor related to CaR (GPRC6A), were also tested. KEY RESULTS Cinacalcet induced endothelium-independent relaxation (pEC(50) 5.58 +/- 0.07, E-max 97 +/- 6%) that was insensitive to sensory nerve desensitization by capsaicin or blockade of large-conductance Ca2+-activated K+ channels by iberiotoxin. Calindol, another calcimimetic, caused more potent relaxation (pEC(50) 6.10 +/- 0.10, E-max 101 +/- 6%), which was attenuated by endothelial removal or capsaicin, but not iberiotoxin. The negative modulator of CaR, calhex 231 or changes in [Ca2+](o) had negligible effect on relaxation to both calcimimetics. The calcimimetics relaxed vessels precontracted with high [K+](o) and inhibited Ca2+ influx in endothelium-denuded vessels stimulated by methoxamine, but not ionomycin. They also inhibited contractions to the L-type Ca2+ channel activator, BayK8644. L-ornithine induced small relaxation alone and had no effect on the responses to calcimimetics. CONCLUSION AND IMPLICATIONS Cinacalcet and calindol are potent arterial relaxants. Under the experimental conditions used, they predominantly act by inhibiting Ca2+ influx through L-type Ca2+ channels into vascular smooth muscle, whereas Ca2+-sensitive receptors (CaR or GPRC6A) play a minor role.