Dual presynaptic effects of 5-hydroxytryptamine on peripheral noradrenergic synapses

The aim of the present experiments was to study the effects of 5-hydroxytryptamine (5-HT) on the responses to postganglionic stimulation of two models of the peripheral sympathetic nervous system: the isolated nictitating membrane of the cat and the guinea-pig isolated atria. In the nictitating membrane of the cat, 5-HT (0.1 microM) shifted to the left the frequency-response curve to nerve stimulation. This potentiating effect was prevented by 5-HT receptor antagonists (0.1 microM methysergide, 0.1 microM pizotifen and 0.1 microM morphine) and also by the beta-adrenoreceptor blocker propranolol (0.1 microM). The alpha 2-adrenoreceptor antagonist yohimbine (0.1 microM) had no effect on the 5-HT-induced potentiation. In the guinea-pig isolated atria the responses to cardioaccelerans nerve stimulation were diminished by 5-HT (0.1 to 1.0 microM). The shift to the right in the frequency-response curve induced by 5-HT (1.0 microM) was additive to the antagonism caused in the atria by propranolol (0.1 microM). The inhibitory effect of 5-HT on the pacemaker responses to nerve stimulation was prevented by the 5-HT receptor antagonists methysergide (1.0 microM) and pizotifen (1.0 microM) and also by the alpha-adrenoreceptor antagonist phentolamine (0.1 microM). The selective alpha 2-adrenoreceptor agonist clonidine (0.01 microM) reduced to the same extent as 5-HT (1.0 microM) the responses to the guinea-pig atria to nerve stimulation. The inhibitory effect of clonidine was prevented by the alpha-adrenoreceptor blocker phentolamine (0.1 microM) but not by the 5-HT receptor blocker pizotifen (1.0 microM). With the exception of propranolol, which in the atria shifted to the right the concentration-response curve to exogenous noradrenaline (NA), neither 5-HT nor the different antagonists employed modified the sensitivity to NA in the tissues studied. The present observations show that 5-HT can produce a dual effect on the sympathetic neurotransmission. It is proposed that a modification in the overflow of NA in response to nerve stimulation is caused by 5-HT and results from the interaction of 5-HT with specific receptors located on the sympathetic fibres. These presynaptic 5-HT receptors behave as excitatory (cat nictitating membrane) or inhibitory (guinea-pig atria) depending on the tissue studied.