Renal hemodynamic and natriuretic effects of manganese and interactions with atrial natriuretic peptide

Manganese (Mn²⁺) is a cofactor for guanylate cyclase (GC), which is involved in the generation of guanosine 3′,5′-cyclic monophosphate (cGMP), a second messenger for atrial natriuretic peptide (ANP) action. Mn²⁺ is also, however, a nonselective calcium-channel blocker. We examined the effects of infusion of MnCl₂ into normal rats and its interaction in vivo and in vitro with GC and ANP. MnCl₂ significantly increased glomerular filtration rate (GFR) and effective renal plasma flow rate (RPF). These effects were caused by selective afferent arteriolar vasodilatation, which allowed the glomerular capillary plasma flow rate and hydraulic pressure to rise, thus elevating single-nephron GFR. Urinary Na⁺ excretion (U_NaV̇) also increased with MnCl₂. The natriuresis was, unlike ANP, not mediated by GC activation and cGMP production, as MnCl₂ had no effect on either urinary cGMP excretion or cGMP accumulation in intact inner medullary collecting duct cell (IMCD) suspensions, nor did it affect Na⁺-dependent oxygen consumption in these cells. When superimposed on an infusion of ANP, MnCl₂ resulted in significant increases in U_NaV̇, GFR, and RPF. These effects were associated with small but significant increments in urinary cGMP excretion. However, MnCl₂ did not affect in vitro cGMP production in intact IMCDs or glomeruli in response to ANP stimulation. It is uncertain therefore whether the in vivo augmentation of the natriuretic effect of ANP by MnCl₂ is related to GC activation and cGMP production.