A comparison of the relative activities of a number of GABAB antagonists in the isolated vas deferens of the rat.

1. A series of GABAB receptor antagonists were tested against (+/-)-baclofen for activity on the presynaptic GABAB receptor in the rat vas deferens. 2. All the antagonists tested caused a rightward shift in the concentration-response curve to (+/-)-baclofen. 3. pA2 values calculated from full Schild analysis were as follows: phaclofen, pA2 = 4.3; delta-amino valeric acid, pA2 = 4.4; 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP 35348), pA2 = 5.0; 3-amino-propyl(n-hexyl)phosphinic acid (3-APHPA), pA2 = 4.5. 4. These results show that none of the above compounds possess potent antagonist activity at the GABAB receptor (i.e. pA2 > 6) in this peripheral tissue. In addition, the more recently available phosphinic acid antagonists, appear to offer no great advance over the GABAB antagonists previously available.

Toxic effects of the histamine H(2) receptor antagonist metiamide on bone-marrow haemopoietic and stromal progenitor cells in vitro.

The histamine H(2)-receptor antagonist, metiamide has been shown to cause agranulocytosis in vivo. In vitro colony forming assays for bone-marrow stromal fibroblast progenitors (CFU-F) and granulocyte/macrophage progenitor cells (CFU-GM) were performed, using murine bone marrow, to assess the relative sensitivity of committed haemopoietic cells, and the marrow stromal microenvironment to metiamide toxicity. CFU-F were more susceptible than CFU-GM to inhibition by metiamide, with 50% inhibition of colony formation (ID(50)) at 17 and 180 mug/ml in the CFU-F and CFU-GM assays, respectively. Inhibition of CFU-GM required the continuous presence of the drug, while CFU-F were inhibited similarly by either short-term (20-hr) or prolonged (10-day) incubation with metiamide (ID(50) 27 and 17 mug/ml, respectively). It is suggested that bone-marrow stromal cell damage may be an important contributory factor in the haemopoietic toxicity of metiamide.