Red cell haemolysis induced by SK&F 95018--a combined vasodilator and beta-adrenoceptor antagonist.
SK&F 95018, a potential antihypertensive agent with the combined properties of vasodilation and beta-adrenoceptor antagonism, induced red urine when given intravenously to a dog. Further studies revealed that in the dog, SK&F 95018 treatment led to haemoglobinaemia, haemoglobinuria and a fall in the red blood cell count. The compound was therefore suspected of causing red cell haemolysis and this was confirmed using dog blood in an in vitro haemolysis test system. Oral administration of the compound to dogs gave no indication of haemolysis, but the animals lost large portions of their dose through vomiting and the lack of effect is therefore questionable. Rats, which have no vomit reflex, were treated orally and although no direct evidence of haemolysis was obtained (e.g. haemoglobinaemia), the presence of polychromasia suggested some loss of mature red blood cells had occurred. Rat blood was haemolysed in vitro by SK&F 95018. Human red cells were also used in the in vitro haemolysis test system and these, too, were lysed by the compound. The haemolysis was shown to be related to the structure of the compound itself rather than to its pharmacological effects and development of SK&F 95018 as an antihypertensive agent was abandoned. Electron microscopy indicated that SK&F 95018 induced alterations in the red cell membrane which led to shape change, characterized by discocyte to spherocyte transformation, and finally haemolysis. The mechanism of this effect remains under investigation.
Sutton
T J
TJ
Department of Pathology and Toxicology, Smith Kline and French Research Ltd., Welwyn, Hertfordshire, UK.
Luke
J S
JS
Jones
H B
HB
D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000097:blood / Q000494:pharmacology* / Q000652:urine; D004285:Dogs; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000648:ultrastructure; D004912:Erythrocytes / Q000187:drug effects* / Q000648:ultrastructure; D005260:Female; D006461:Hemolysis / Q000187:drug effects*; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D008297:Male; D008854:Microscopy, Electron; D011724:Pyridazines / Q000097:blood / Q000494:pharmacology* / Q000652:urine; D051381:Rats; D011919:Rats, Inbred Strains
D000959:Antihypertensive Agents; D011724:Pyridazines; C053166:SK&F 95018