Hs. Allawi et al., EFFECT OF 7-NITRO INDAZOLE ON NEUROTRANSMISSION IN THE RAT VAS-DEFERENS - MECHANISMS UNRELATED TO INHIBITION OF NITRIC-OXIDE SYNTHASE, British Journal of Pharmacology, 113(1), 1994, pp. 282-288
1 The effect of the nitric oxide synthase (NOS) inhibitor, 7-nitro ind
azole (7-NI), on sympathetic and purinergic neurotransmission in the r
at isolated vas deferens preparation has been studied. 2 7-NI (50-200
mu M) caused a dose- and frequency-dependent inhibition of the phasic
(predominantly purinergic) contractile response of the rat vas deferen
s to electrical (field) stimulation (100 V, 0.5 ms). Greatest inhibiti
on occurred at lower frequencies of stimulation (0.1-10 Hz). The susta
ined tonic contractile response (predominantly noradrenergic) was inhi
bited only at a high frequency of stimulation (60 Hz) and only at the
highest concentration of 7-NI studied (200 mu M). 3 7-NI (100 mu M) si
gnificantly reduced the contractile response of the vas deferens to ex
ogenous ATP (20 mu M-5 mM) and the stable P-2X purinoceptor agonist, a
lpha,beta-methylene ATP (2.5 and 25.0 mu M) but was without effect on
contractions due to noradrenaline (0.1-50 mu M) indicating a lack of a
ntagonist effect on post-junctional alpha(1) adrenoceptors. 4 The effe
ct of 7-NI (100 mu M) on the phasic contractile response to field stim
ulation (0.1 and 2.0 Hz) was unaffected by preincubation of preparatio
ns with yohimbine (1.0 mu M) or propranolol (0.01-10.0 mu M) indicatin
g the absence of involvement of alpha(2)- or beta-adrenoceptors in thi
s response. 5 7-NI (50-600 mu M) caused dose-related inhibition of con
tractions elicited by addition of a depolarizing concentration of KCl
(64 mM). 6 The effect of 7-NI (100 mu M) on the phasic contractile res
ponse to held stimulation (0.1 and 2.0 Hz) was unaffected by preincuba
tion of preparations with L-arginine (1 mM). Neither L-arginine (1 mM)
nor N-G nitro L-arginine methyl ester (L-NAME, 100 mu M) affected the
response of the vas deferens to field stimulation at 0.1 or 2.0 Hz. N
itric oxide synthase (NOS) enzyme activity, measured as the conversion
of [H-3]-L-arginine to [H-3]-citrulline, was not detectable in rat va
s deferens homogenates. 7 7-NI preferentially inhibits the purinergic
component of the response of the rat vas deferens to held stimulation.
The mechanism of action of 7-NI is not known but is not related to NO
S inhibition. It seems likely that 7-NI combines an antagonist action
at smooth muscle cell P-2X-purinoceptors with the ability to inhibit t
he cellular influx of calcium ions. Although these hitherto unrecorded
effects of 7-NI occur at relatively high concentrations, the effects
described may contribute to the pharmacological effects of this NOS in
hibitor.