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-Aminoimidazole4-carboxamide-l-f-D-ribofuranosyl (ZTP), the pyrimidines, cytidine 5'-triphosphate (CTP), uridine 5'-triphosphate (UTP) and thymidine 5'-triphosphate (TTP) and the purines, adenosine 5'-triphosphate (ATP; in the presence of an Al-purinoceptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) (1 Mm)), adenosine 5'-0-(3-thiotriphosphate) (ATPyS), 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>ATPyS > >ATP? ITP=GTP, and for the pyrimidine 5'-triphosphates UTP>TTP>CTP. Depolarizations evoked by ATPyS were followed by concentration-dependent hyperpolarizations at 100 and 1000 MM. 3 At concentrations of between 0.1 Mm and 1 mm, uridine 5'-diphosphate (UDP), uridine 5'-diphosphoglucose (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 pY) depolarizations. The relative order of potency of uridine analogues in depolarizing ganglia was UDP> UTP > UDPG > UDPGA > > uracil > UMP = pseudouridine 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 uM 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 Mm), a P2-purinoceptor antagonist, significantly depressed depolarizations evoked by a,fi-methylene-ATP (a,fi-MeATP; 100 Mm), ATPyS (100 Mm), CTP (1 mM), GTP (1 mM), ZTP (30 MM) and ATP (300 MM) in the presence of DPCPX (1 yM). Suramin reversed a small depolarization evoked by UMP (1 mM) into a small hyperpolarization. In contrast depolarizations evoked by UDP, UTP, UDPG (all at 100 Mm) and TTP (300 Mm) were unaltered or enhanced by suramin. 5 It is concluded that the rat SCG contains distinct nucleotide receptors including a P2-purinoceptor (activated by a,f,-MeATP, ATP, GTP, ITP and ZTP) and a pyrimidinoceptor (activated by UTP, UDP, UDPG, UDPGA and TTP). The pyrmidinoceptor on rat SCG neurones had specific structure activity requirements with the di-and triphosphates of uridine being the most effective depolarizing agonists examined.