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


METHODS
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 Ca(2+) -sensitive receptor related to CaR (GPRC6A), were also tested.


RESULTS
Cinacalcet induced endothelium-independent relaxation (pEC₅₀ 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 (pEC₅₀ 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.


CONCLUSIONS
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.
Division of Basic Medical Sciences, St George's University of London, Cranmer Terrace, London, UK.
Pratish
P
Thakore
W-S Vanessa
WS
Ho
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D057966:Calcimimetic Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D000069449:Cinacalcet; D042783:Endothelial Cells / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology*; D015759:Ionomycin / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000294:innervation / Q000502:physiology; D008642:Mesenteric Veins / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology*; D009952:Ornithine / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*; D013237:Stereoisomerism; D014665:Vasodilator Agents / Q000494:pharmacology*
C506457:(R)-2-(1-(1-naphthyl)ethyl-aminom-ethyl)indole; D057966:Calcimimetic Agents; D020746:Calcium Channels, L-Type; D007211:Indoles; D009281:Naphthalenes; D015221:Potassium Channels; D044169:Receptors, Calcium-Sensing; D014665:Vasodilator Agents; D015759:Ionomycin; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D009952:Ornithine; D002118:Calcium; D000069449:Cinacalcet