Effects of substance P on neurones of the inferior mesenteric ganglia of the guinea-pig.

1. The membrane effects of substance P on neurones of isolated inferior mesenteric ganglia and the underlying ionic mechanisms were investigated by means of intracellular recording techniques.2. When applied to the neurones by superfusion, substance P (0.5 mum) caused a membrane depolarization; in a few neurones, the depolarization was preceded by a small hyperpolarization. Substance P effects were not altered in a low Ca(2+)/high Mg(2+) solution or in a solution containing d-tubocurarine and atropine.3. When the membrane potential was clamped manually at the resting level between -50 and -60 mV, substance P caused, in about an equal number of neurones, a slight to moderate decrease and also increase of membrane resistance; a brief increase occurred prior to the decrease of membrane resistance.4. In neurones with high resting membrane potential (> -70 mV), substance P elicited a large depolarization accompanied by a marked increase in membrane resistance; the latter was probably due to anomalous rectification.5. Conditioning hyperpolarization of the membrane close to the level of E(K) increased and decreased substance P-induced depolarization in eleven and two neurones, respectively.6. Substitution of external Na(+) with an equimolar amount of either sucrose or Tris buffer markedly attenuated the depolarizing effect of substance P.7. The substance P-induced depolarization was diminished in a high K(+) (10 mm) solution, and it could be augmented when membrane was hyperpolarized to E(K). On the other hand, the effect of substance P was not appreciably affected in a low Cl(-) solution.8. It is concluded that substance P depolarizes the sympathetic neurones by increasing and decreasing membrane permeability to Na(+) and K(+), respectively, and that the concomitant membrane resistance change depends on interaction of G(Na) activation and G(K) inactivation.9. The possibility that substance P is the transmitter mediating the non-cholinergic slow excitatory potential elicited by repetitive preganglionic stimulation in the neurones of the inferior mesenteric ganglia is suggested.