European Journal of Pharmacology, 58 (1979) 407--418 407 © Elsevier/North-Holland Biomedical Press THE RENAL EFFECTS OF CLONIDINE IN UNANESTHETIZED RATS * JI~ROME BIOLLAZ **, FRAN~OISE ROCH-RAMEL, ERNST J. KIRCHERTZ ***, JEFFREY ATKINSON and LISE PETERS-HAEFELI **** Institut de Pharmacologie de l'Universitd de Lausanne, Lausanne, Switzerland Received 13 March 1979, revised MS received 11 June 1979, accepted 11 July 1979 J. BIOLLAZ, F. ROCH-RAMEL, E.J. KIRCHERTZ, J. ATKINSON and L. PETERS-HAEFELI, The renal effects of clonidine in unanesthetized rats, European J. Pharmacol. 58 (1979) 407--418. Clonidine s.c. (0.01-0.3 mg/kg), in unanesthetized rats, caused an initial rise (+ 20 mm Hg), followed by a continuous fall of BP and a dose-dependent natriuresis and diuresis for up to 2 h. Glomerular filtration rate (GFR) (CIn) increased during the first 20 min, while effective renal plasma flow (ERPF) (CpAH) remained normal. Subsequently, between 20 and 60 min after injection, ERPF (CpAH) decreased considerably while GFR had reverted to its normal value. In saline-infused rats clonidine diuresis was accompanied by an "inappropriate" positive free water clearance. Pentobarbital anesthesia suppressed the initial BP peak and the diuresis. Phenoxy- benzamine (1 mg/kg i.v.) was antinatriuretic in saline diuresis; the effect of phenoxybenzamine + clonidine on diuresis and salt excretion represented the sum of the effects of both drugs, but phenoxybenzamine enhanced the clonidine-induced increase of GFR. Neither haloperidol (1 mg/kg i.v.) nor bulbocapnine (3 mg/kg i.v.) inter- fered with the renal effects of clonidine. Clonidine s.c. caused hyperglycemia and glucosuria which did not account for the natriuresis. Clonidine thus appears to increase the GFR and "filtration fraction" (FF) by a phenoxybenzamine-insensitive rise of glomerular ultrafiltration, to depress ERPF by a-adrenergic afferent vaso- constriction, to induce natriuresis by a tubular action not blocked by phenoxybenzamine and to exert an anti- vasopressin effect, either by depressing pituitary vasopressin secretion or the renal response to vasopressin. Inappropriate water diuresis Dopaminergic receptors a-Adrenergic receptors Phenoxybenzamine Bulbocapnine Haloperidol 1. Introduction Clonidine is an a-adrenergic agent with short-lasting peripheral effects (Boissier et al., 1968; Rand and Wilson, 1968). After an initial rise of blood pressure (BP) which occurs only in unanesthetized animals (Hoefke and Ko- binger, 1966) clonidine induces a fall in BP by stimulating cerebral a-receptors (Boissier * Supported by the Swiss National Science Founda- tion, Grant No. 3.028-0.76. ** 'Present address : D~partement de m~decine, CHUV, CH-1011 Lausanne, Switzerland. *** Present address: Nephrologische Abteilung der Medizinischen Klinik der Universit~t, D-3400 GSt- tingen, F.R.G. **** To whom correspondence should be sent. et al., 1968; Rand and Wilson, 1968; Van Zwieten, 1973; reviews: Peters and Haefeli, 1970; Peters and Peters-Haefeli, 1974), situated in the caudal part of the brain stem (Bousquet and Guertzenstein, 1963). The stimulation of these receptors depresses central sympathetic activity and sympathetic outflow into the periphery (Boissier et al., 1968; Van Zwieten, 1973) and enhances central vagal activity inducing bradycardia (Kobinger and WaUand, 1971 ; Scriabine et al., 1970). Clonidine also exerts a less important peripheral a-receptor blocking action (Boissier et al., 1968) and, possibly, induces a minor depression of peripheral sympathetic nerve conduction (Scriabine et al., 1970; Armstrong and Boura, 1973}. The renal effects of