Structure‐activity relationship of a pyrimidine receptor in the rat isolated superior cervical ganglion

1 The effects of pyrimidines and purines on the d.c. potential of the rat isolated superior cervical ganglion (SCG) have been examined by a grease‐gap technique to determine the structure‐activity requirements of the receptor activated by pyrimidines, i.e. a pyrimidinoceptor. 2 5‐Ammoimidazole‐4‐carboxamide‐1‐β‐D‐ribofuranosyl (ZTP), the pyrimidines, cytidine 5′‐triphosphate (CTP), uridine 5′‐triphosphate (UTP) and thymidine 5′‐triphosphate (TIT) and the purines, adenosine 5′‐triphosphate (ATP; in the presence of an A1‐purinoceptor antagonist 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX) (1 μ)), adenosine 5′‐O‐(3‐thiotriphosphate) (ATPγS), guanosine 5′‐triphosphate (GTP), inosine 5′‐triphosphate (ITP) depolarized ganglia in a concentration‐dependent manner. The relative order of ZTP and purine 5′‐triphosphates in depolarizing ganglia was ZTP≥ATPγS > > ATP ≥ ITP=GTP, and for the pyrimidine 5′‐triphosphates UTP > TTP ≥ CTP. Depolarizations evoked by ATPγS were followed by concentration‐dependent hyperpolarizations at 100 and 1000 μm. 3 At concentrations of between 0.1 μm and 1 mm, uridine 5′‐diphosphate (UDP), uridine 5′‐diphospho‐glucose (UDPG) and uridine 5′‐diphosphoglucuronic acid (UDPGA) evoked significant and concentration‐dependent depolarizations, whereas uridine 5′‐monophosphate (UMP), uridine and uracil were inactive or produced small (< 45 μV) depolarizations. The relative order of potency of uridine analogues in depolarizing ganglia was UDP ≥ UTP > UDPG > UDPGA > > uracil≥ UMP=pseudour‐idine≥ uridine. At 3 and 10 mm, uridine produced concentration‐dependent hyperpolarizations. Nikkomycin Z, a nucleoside resembling UTP (viz. the triphosphate chain at the 5′‐position on the ribose moiety being replaced by a peptide), was inactive between 1 μm and 1 mm. Generally, a concentration of 10 mm was required before thymidine, 6‐azathymine, 6‐azauracil or 6‐azauridine depolarized ganglia. 4 Suramin (300 μm), a P2‐purinoceptor antagonist, significantly depressed depolarizations evoked by α,β‐methylene‐ATP (α,β‐MeATP; 100 μm), ATPγS (100 μm), CTP (1 μm), GTP (1 μm), ZTP (30 μm) and ATP (300 μm) in the presence of DPCPX (1 μm). Suramin reversed a small depolarization evoked by UMP (1 μm) into a small hyperpolarization. In contrast depolarizations evoked by UDP, UTP, UDPG (all at 100 μm) and TTP (300 μm) were unaltered or enhanced by suramin. 5 It is concluded that the rat SCG contains distinct nucleotide receptors including a P2‐purinoceptor (activated by α,β‐MeA