Electrophysiological subtypes of inhibitory P1 purinoceptors on myenteric neurones of guinea‐pig small bowel

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Abstract
1 Conventional intracellular microelectrode techniques were used to subclassify P1 purinoceptors linked to reduction of cell input resistance, steady-state hyperpolarization of the membrane potential, or inhibition of fast e.p.s.ps, in neurones of microdissected myenteric plexus preparations from guinea-pig ileum. The potencies of P1 purinoceptor agonists were estimated in neurones that were current clamped to a fixed membrane potential. 2 In AH/Type 2 neurones, the A2 agonist, CGS 21680, the A1 agonist, CCPA or the mixed A1-A2 agonist, NECA, suppressed excitability by reducing input resistance (40–50% max.) and causing hyperpolarization (20–25 mV max.). CGS 21680 (0.1-1 μm) enhanced the after-hyperpolarizing potential. 3 From cumulative dose-response data, the potency order for reducing input resistance was CCPA (IC50 = 5.1 ± 2.2nM) > > > CGS 21680 (IC50 = 5.6 ± 2.5 μm). This effect was reversed by the A1 antagonist, CPT (EC50 = 65 ± 11 nm). 4 In contrast, the potency order for membrane hyperpolarization was CCPA (IC50 = 61 ± 23 nm) = CGS 21680 (IC50 = 290 ± 90 nm) ≥ NECA (IC50 = 450 ± 100 nm). Hyperpolarization elicited by CCPA was sensitive to the A1-A2 antagonist, DPSPX. 5 Agonists suppressed fast e.p.s.ps, but not DMPP responses, with an order of CCPA (IC50 = 8.1 ± 3.0 nm) > > > CGS 21680 (IC30 = 10 ± 2.9 μm). 6 In conclusion, the excitability of AH/Type 2 neurones is suppressed by activation of high affinity A1 receptors that may be linked to a cyclic AMP-dependent pathway, leading to increase in calcium-dependent potassium conductance and enhancement of the after-hyperpolarizing potential. Activation of lower affinity non A1 receptors linked to a cyclic AMP-independent pathway reduces excitability and leads mainly to a steady-state hyperpolarization. Adenosine also suppresses nicotinic cholinergic transmission by activating presynaptic high affinity A1 receptors.