ELECTROPHYSIOLOGICAL SUBTYPES OF INHIBITORY P-1 PURINOCEPTORS ON MYENTERIC NEURONS OF GUINEA-PIG SMALL-BOWEL

1 Conventional intracellular microelectrode techniques were used to subclassify P-1 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 P-1 purinoceptor agonists were estimated in neurones that were current clamped to a fixed membrane potential. 2 In AH/Type 2 neurones, the A(2) agonist, CGS 21680, the A(1) agonist, CCPA or the mixed A(1)-A(2) agonist, NECA, suppressed excitability by reducing input resistance (40-50% max.) and causing hyperpolarization (20-25 mV max.). CGS 21680 (0.1-1 mu M) enhanced the after-hyperpolarizing potential. 3 From cumulative dose-response data, the potency order for reducing input resistance was CCPA (IC50 = 5.1 +/- 2.2 nM) >>> CGS 21680 (IC50 = 5.6 +/- 2.5 mu M). This effect was reversed by the A(1) antagonist, CPT (EC(50) = 65 +/- 11 nM). 4 In contrast, the potency order for membrane hyperpolarization was CCPA (IC50 = 61 +/- 23 nM) = CGS 21680 (IC50 = 290 +/- 90 nM) greater than or equal to NECA (IC50 = 450 +/- 100 nM). Hyperpolarization elicited by CCPA was sensitive to the A(1)-A(2) 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 (IC50 = 10 +/- 2.9 mu M). 6 In conclusion, the excitability of AH/Type 2 neurones is suppressed by activation of high affinity A(1) 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 A(1) 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 A(1) receptors.