B. Driessen et al., THE FADE OF THE PURINERGIC NEUROGENIC CONTRACTION OF THE GUINEA-PIG VAS-DEFERENS - ANALYSIS OF POSSIBLE MECHANISMS, Naunyn-Schmiedeberg's archives of pharmacology, 350(5), 1994, pp. 482-490
The purinergic response of the guinea-pig vas deferens to long trains
of pulses at high frequency consists of an initial twitch followed by
a much lower plateau. Mechanical, neurochemical and electrophysiologic
al techniques were used to examine the reason for the fade. Mechanical
measurements. In tissues stimulated by trains of 180 pulses/10 Hz and
treated with prazosin to suppress the noradrenergic contraction compo
nent, the response to alpha,beta-methylene ATP and to exogenous ATP wa
s as high during the secondary plateau of the purinergic neurogenic co
ntraction as it was outside electrical stimulation periods; the respon
se to 50 pulses/100 Hz was also unchanged during the low plateau. The
plateau was not increased by reactive blue 2,8-(p-sulphophenyl)theophy
lline, propranolol or capsaicin. Neurochemical measurements. In tissue
s preincubated with [H-3]-noradrenaline, electrical stimulation elicit
ed an overflow of tritium and of ATP. In the absence of drugs as well
as in the presence of prazosin and suramin to suppress contractions, t
he overflow of tritium per pulse decreased slightly in the course of t
rains of 90 pulses/10 Hz; the overflow of ATP per pulse decreased to a
greater extent on average, but the decrease was not statistically sig
nificant. In the presence of prazosin and nifedipine, also to suppress
contractions, the overflow of tritium per pulse again decreased sligh
tly in the course of trains of 105 pulses/10 Hz, but the overflow of A
TP per pulse if anything tended to increase. Electrophysiological meas
urements. Extracellular recording in the presence of prazosin showed t
hat electrical stimulation by 180 pulses/10 Hz elicited excitatory jun
ction currents (EJCs) which facilitated and summated to reach threshol
d for the initiation of action potentials in the smooth muscle cells.
In most tissues, smooth muscle action potentials ceased after a few se
conds although EJCs continued. Intracellular recording in the presence
of prazosin and nifedipine showed that excitatory junction potentials
(EJPs) elicited by 180 pulses/10 Hz facilitated and summated to a pla
teau after about 20 stimuli. The EJPs continued unchanged, and the pla
teau depolarization was maintained, throughout the train. It is conclu
ded that the fade of the purinergic neurogenic contraction is not due
to P-2X-purinoceptor desensitization. It also is not due to a secondar
y relaxation mediated by P-2Y- or P-1-purinoceptors, beta-adrenoceptor
s or a compound originating from primary afferent axons. Moreover, a f
ade of the release of ATP in the course of the pulse train is not resp
onsible for the contraction fade. Rather, the reason is a failure of t
he process by which the smooth muscle cell depolarization triggers act
ion potentials. Inactivation of L-type Ca2+ channels that are under th
e control of released ATP may be the underlying mechanism.