Increase of plasma renin activity after subcutaneous application of compound 48/80 in the rat

Subcutaneous (s.c.) administration of compound 48/80 (3.0 mg/kg) to conscious rats produced a time-dependent long-lasting increase of plasma renin activity (PRA). A dose-related increase of the hematocrit was also observed after injection of compound 48/80. The onset of the hematocrit increase preceded that of PRA increase. Pretreatment with a dose of more than 20 mg/kg of histamine H1-receptor antagonists such as tripelennamine or diphenhydramine prior to the injection of compound 48/80 (3.0 mg/kg s.c.) attenuated or abolished the effects of compound 48/80 on PRA, hematocrit and plasma extravasation. Pretreatment with cimetidine (histamine H2-receptor antagonist, 40 mg/kg i.p.) had no effect on these plasma variables. The increase of PRA caused by s.c. administration of compound 48/80 was not affected by the pretreatment with propranolol (beta-adrenoceptor antagonist, 10 mg/kg i.p.), which completely inhibited the isoproterenol (0.5 mg/kg s.c.)-induced PRA increase. Administration of compound 48/80 did not induce a significant PRA increase in the nephrectomized rats although the increase of hematocrit following s.c. administration of compound 48/80 persisted despite the absence of kidneys. S.c. administration of compound 48/80 (3.0 mg/kg) led to a significant decrease of histamine content at the site of injection and to a significant increase in plasma histamine concentration without affecting arterial blood pressure. The present data suggest that s.c. administration of compound 48/80 stimulates the release of histamine from cutaneous mast cells, which cause an increase in vascular permeability to plasma protein via the stimulation of histamine H1-receptors, then leads to hypovolemia. The resulting hypovolemia may directly stimulate the juxtraglomerular cells of the kidney to release renin.