S. Amerini et al., THAPSIGARGIN INHIBITS THE RESPONSE TO ACETYLCHOLINE AND SUBSTANCE-P BUT DOES NOT INTERFERE WITH THE RESPONSES TO ENDOTHELIUM-INDEPENDENT AGENTS, Journal of cardiovascular pharmacology, 28(1), 1996, pp. 82-88
We investigated the influence of the Ca2+-ATPase inhibitor thapsigargi
n (TG) on the vasorelaxant response to different endothelium-dependent
and endothelium-independent relaxing agents in an isolated thoracic a
orta preparation of the rabbit, precontracted by norepinephrine (NE).
Pretreatment with 100 mu M L-arginine methyl ester (L-NAME) an inhibit
or of nitric oxide (NO) synthesis, completely prevented acetylcholine
(ACh)-induced relaxation; the inactive stereoisomer D-NAME did not mod
ify the effect of ACh. The exposure of the preparations to 1 mu M TG i
nduced a slowly developing slight increase in the basal tension during
30-min contact. The same concentration of TG also slightly reduced th
e response to the subsequent administration of NE. The antagonist effe
ct of TG on the ACh response was concentration dependent in the range
between 0.1 and 10 mu M. A 30-min pretreatment with 1 mu M TG appeared
to be sufficient to induce a consistent antagonism of the ACh (0.01-1
0 mu M) concentration-relaxant effect curve, since an increase to 60 m
in did not produce a further significant increment in the degree of th
e antagonist effect. The concentration-dependent relaxation induced by
substance P (SP 0.1-3 nM) was also significantly antagonized by 1 mu
M TG. The effect of the calcium ionophore A23187 (0.01-1 mu M was redu
ced by the Ca2+-ATPase inhibitor only at the higher concentrations tes
ted (0.3-1 mu M) However, a 30-min contact time with 1 mu M TG was com
pletely ineffective in antagonizing the concentration-relaxant respons
e curves to the two nitrovasodilators sodium nitroprusside (SNP 0.1-10
0 mu M) and nitroglycerin (NTG 1-300 nM) and to the cyclic GMP analogu
e 8-Bromo-cyclic GMP (3-100 mu M). The effects of the beta-adrenocepto
r agonist isoprenaline (ISO 0.1-10 mu M) and of the direct adenylate c
yclase activator forskolin (FK 0.01-10 mu M) were also completely unaf
fected by 1 mu M TG. These results demonstrate that TG affects the res
ponse to agents that induce an endothelium-dependent relaxation throug
h receptor-dependent calcium mobilization. However, they do not suppor
t the hypothesis that sarcoplasmic pump activity is essential for the
development of a vasorelaxant response to endothelium-independent agen
ts.