Gl. Raymond et Ir. Wendt, FORCE AND INTRACELLULAR CA2-MEDIATED RELAXATION OF RAT ANOCOCCYGEUS MUSCLE AND THE EFFECTS OF CYCLOPIAZONIC ACID( DURING CYCLIC NUCLEOTIDE), British Journal of Pharmacology, 119(5), 1996, pp. 1029-1037
1 Simultaneous recordings of tension and [Ca2+](i) were made in rat an
ococcygeus muscle strips to investigate possible mechanisms involved d
uring cyclic nucleotide-mediated relaxation. Relaxation of pre-contrac
ted muscles was induced by sodium nitroprusside (SNP) or forskolin and
the effects of cyclopiazonic acid (CPA) on these responses were exami
ned. 2 In muscles pre-contracted with 0.2 mu M phenylephrine addition
of SNP (10 mu M) caused a rapid and near complete relaxation of force.
This was accompanied by a decrease in [Ca2+](i), however, this was no
t of a comparable magnitude to the decrease in force. The level of [Ca
2+](i) in muscles relaxed with SNP was shown to be associated with sub
stantially higher force levels in the absence of SNP. Forskolin (10 mu
M) caused a slower, essentially complete relaxation which was associa
ted with a proportional decrease in [Ca2+](i). 3 In muscles pretreated
with SNP or forskolin subsequent responses to phenylephrine were atte
nuated with both force and [Ca2+](i) rising slowly to attain eventuall
y levels similar to those observed when the relaxant was applied to pr
e-contracted muscles. 4 Exposure of the muscles to the sarcoplasmic re
ticulum Ca2+-ATPase inhibitor, CPA (10 mu M), resulted in a sustained
increase in [Ca2+](i) which, in most cases, was not associated with an
y force development. The relaxation and decrease in [Ca2+](i) in respo
nse to both SNP and forskolin were attenuated and substantially slowed
in the presence of CPA. Overall the extent of this attenuation was gr
eater for SNP. For both SNP and forskolin, CPA attenuated the decrease
in [Ca2+](i) to a greater extent than the decrease in force. In some
cases, SNP-mediated relaxation in the presence of CPA was observed wit
h almost no detectable change in [Ca2+](i). 5 The results suggest that
, in the rat anococcygeus muscle under normal circumstances, a lowerin
g of [Ca2+](i) can fully account for the relaxation induced by forskol
in but not for that induced by SNP, where mechanisms independent of ch
anges in [Ca2+](i) appear to contribute. Whilst Ca2+ sequestration int
o the sarcoplasmic reticulum plays a role in the relaxation mediated b
y both SNP and forskolin other Ca2+ lowering mechanisms may also be in
volved, especially in the response to forskolin.