TY - JOUR
T1 - Changes in the cytosolic Ca2+ concentration and Ca2+-sensitivity of the contractile apparatus during angiotensin II-induced desensitization in the rabbit femoral artery
AU - Fukai, Masuko
AU - Yamamoto, Hiromichi
AU - Toyofuku, Kazuki
AU - Nishimura, Junji
AU - Hirano, Katsuya
AU - Kanaide, Hideo
PY - 2000/2
Y1 - 2000/2
N2 - 1. To investigate the underlying mechanism for the angiotensin II-induced desensitization of the contractile response during the prolonged stimulation of the vascular smooth muscle, we determined the effects of angiotensin-II on (1) cytosolic Ca2+ concentration ([Ca2+](i)) and tension using fura-2-loaded medial strips of the rabbit femoral artery, (2) 45Ca2+ influx in ring preparations, and (3) Ca2+-sensitivity of the contractile apparatus in α-toxin permeabilized preparations. 2. In the presence of extracellular Ca2+, high concentrations of angiotensin-II elicited biphasic increases in [Ca2+](i) and tension, which consisted of initial transient and subsequent lower and sustained phases. 3. The 45Ca2+ influx initially increased after the application of 10-6 M angiotensin-II, and thereafter gradually decreased. At 20 min after the application, there was a discrepancy between the level of [Ca2+](i) and the extent of 45Ca2+ influx. 4. The relationships between [Ca2+](i) and tension suggested that the angiotensin-II-induced increase in the Ca2+-sensitivity of the contractile apparatus was maintained during the desensitization of smooth muscle contraction. 5. When 10-6 M angiotensin-II was applied during the sustained phase of contraction induced by 118 mm K+-depolarization, at 10 min after the application, the [Ca2+](i) levels were significantly lower and the tension levels were significantly higher than those prior to the application of angiotensin-II. 6. In conclusion, the decrease in [Ca2+](i), which is partially due to the inhibition of the Ca2+ influx, is mainly responsible for the desensitization evoked by high concentrations of angiotensin-II, and angiotensin-II seems to activate additional mechanisms which inhibit Ca2+ signaling during prolonged stimulation.
AB - 1. To investigate the underlying mechanism for the angiotensin II-induced desensitization of the contractile response during the prolonged stimulation of the vascular smooth muscle, we determined the effects of angiotensin-II on (1) cytosolic Ca2+ concentration ([Ca2+](i)) and tension using fura-2-loaded medial strips of the rabbit femoral artery, (2) 45Ca2+ influx in ring preparations, and (3) Ca2+-sensitivity of the contractile apparatus in α-toxin permeabilized preparations. 2. In the presence of extracellular Ca2+, high concentrations of angiotensin-II elicited biphasic increases in [Ca2+](i) and tension, which consisted of initial transient and subsequent lower and sustained phases. 3. The 45Ca2+ influx initially increased after the application of 10-6 M angiotensin-II, and thereafter gradually decreased. At 20 min after the application, there was a discrepancy between the level of [Ca2+](i) and the extent of 45Ca2+ influx. 4. The relationships between [Ca2+](i) and tension suggested that the angiotensin-II-induced increase in the Ca2+-sensitivity of the contractile apparatus was maintained during the desensitization of smooth muscle contraction. 5. When 10-6 M angiotensin-II was applied during the sustained phase of contraction induced by 118 mm K+-depolarization, at 10 min after the application, the [Ca2+](i) levels were significantly lower and the tension levels were significantly higher than those prior to the application of angiotensin-II. 6. In conclusion, the decrease in [Ca2+](i), which is partially due to the inhibition of the Ca2+ influx, is mainly responsible for the desensitization evoked by high concentrations of angiotensin-II, and angiotensin-II seems to activate additional mechanisms which inhibit Ca2+ signaling during prolonged stimulation.
KW - Angiotensin-II
KW - Cytosolic calcium concentration
KW - Desensitization
KW - Vascular smooth muscle
UR - http://www.scopus.com/inward/record.url?scp=0033622024&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033622024&partnerID=8YFLogxK
U2 - 10.1038/sj.bjp.0703092
DO - 10.1038/sj.bjp.0703092
M3 - Article
C2 - 10711340
AN - SCOPUS:0033622024
SN - 0007-1188
VL - 129
SP - 425
EP - 436
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 3
ER -