Substance P inhibits activation of calcium‐dependent potassium conductances in guinea‐pig myenteric neurones.

1. Intracellular recordings were made from myenteric AH neurones of the guinea‐pig ileum in vitro. Some experiments were done with a single‐electrode voltage clamp to measure membrane currents. 2. Substance P (SP) applied by superfusion (10 nM‐300 nM), pressure ejection (100 nM‐10 microM, 760 mmHg, for 10‐20 ms) or ionophoresis (1 mM, 100 nA, for 0.2 s) caused a membrane depolarization and an inward current, associated with a decrease in potassium conductance. 3. The SP‐induced depolarization was abolished within 15 min by superfusion with calcium‐free/high‐magnesium (10 mM) solution or solutions containing cobalt, manganese or nickel at 1‐3 mM. The response persisted even after 40‐60 min of superfusion with calcium‐free/normal‐magnesium (1.2 mM) solution. In all these solutions, synaptic potentials were abolished within 5 min. 4. SP inhibited a slowly developing outward current and an outward tail current during and after a long depolarizing command pulse (2‐10 s), and an outward after‐current following single or multiple brief depolarizing command pulses (10‐50 ms). These outward currents were suppressed in calcium‐free/high‐magnesium solution. 5. SP depressed both a calcium‐dependent slow after‐hyperpolarization following the action potential and an outward after‐current preceded by a brief depolarizing command. Both the SP‐induced depolarization and the SP‐induced inward current were augmented when the peptide was pressure‐ejected during the recovery phase of the slow after‐hyperpolarization and during that of the slow outward after‐current, but both of them were inhibited or almost abolished when SP was applied immediately after spike initiation or a brief depolarizing command. 6. The SP‐induced response was depressed by barium (1‐2 mM). The SP response was not inhibited by tetraethylammonium at low concentrations (5‐10 mM), but was depressed at high concentration (20 mM). 7. Superfusion (1‐10 nM) or pressure application of a calcium ionophore, A23187, inhibited or even reversed the SP depolarization and the SP‐induced inward current. 8. These results indicate that SP inhibits activation of a calcium‐dependent potassium conductance which contributes to both the slow after‐hyperpolarization and the resting membrane potential. SP may affect the process by which calcium activates this potassium conductance.