Mechanisms underlying the neurokinin A-induced contraction of the pregnant rat myometrium.
1. Using fura-PE3 fluorimetry and alpha-toxin permeabilization, the characteristics of the contractile responses to neurokinin A (NKA) were determined in the pregnant rat myometrium. 2. NKA induced contractions in rat myometrium in a concentration-dependent manner. There were no significant differences in the maximum contractions and EC(50) values between the pregnant and non-pregnant myometrium, however, the contraction of only the former was greatly enhanced in the presence of phosphoramidon (PPAD), an endopeptidase inhibitor. 3. In the pregnant myometrium, NKA induced sustained increases in [Ca(2+)](i) and tension in normal physiological saline solution, while only small transient increases in [Ca(2+)](i) and tension were observed in Ca(2+)-free solution. 4. Both diltiazem (10 microM) and SK-F 96365 (10 microM) significantly inhibited the NKA-induced elevations of [Ca(2+)](i) and tension. The effects were additive when these drugs were used together. 5. NKA induced a significant leftward shift of the [Ca(2+)](i)-tension curve obtained by changing the external Ca(2+) (0 - 2.5 mM) during depolarization with high K(+) solution. This Ca(2+)-sensitizing effect by NKA was also observed in the alpha-toxin permeabilized myometrium. 5. These results indicated that in the pregnant rat myometrium: (1) the responsiveness to NKA increased, although it was masked by the increase in the endopeptidase activity; (2) NKA induced contractions of the myometrium by increasing both [Ca(2+)](i) and the myofilament Ca(2+) sensitivity and (3) The NKA-induced [Ca(2+)](i) elevation was partly due to the intracellular Ca(2+) release and mainly due to the Ca(2+) influx, which was thought to be through both voltage dependent calcium channels and non-specification channels.
Shintani
Y
Y
Department of Molecular Cardiology, Research Institute of Angiocardiology, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Nishimura
J
J
Niiro
N
N
Hirano
K
K
Nakano
H
H
Kanaide
H
H
D000818:Animals; D002118:Calcium / Q000378:metabolism; D004110:Diltiazem / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D015288:Neurokinin A / Q000494:pharmacology*; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000502:physiology*; D051381:Rats; D011921:Rats, Inbred WKY; D014590:Uterine Contraction / Q000187:drug effects*
D007093:Imidazoles; D015288:Neurokinin A; D004110:Diltiazem; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D002118:Calcium