Modulation of Cyclic Nucleotides in Isolated Rat Glomeruli

Abstract

Because glomerular functions are modulated by numerous humoral agents, probably acting through cyclic nucleotides, the effects of some polypeptide hormones and biogenic amines on cyclic AMP (cAMP) and cyclic 3′,5′-guanosine monophosphate (cGMP) were studied in glomeruli isolated from rat renal cortex. Glomeruli and cortical tubules were prepared by a combination of sieving and density-gradient centrifugation. Under basal conditions, the contents of cAMP and cGMP in glomeruli were significantly higher than in tubules and unfractionated renal cortical tissue. Histamine caused a striking increase in cAMP in glomeruli (+Δ% 675±87) and, to a lesser degree, increased cAMP in tubules (+Δ% 103±25) or in tissue slices. This stimulation was dose-dependent in the range of 1 μM-1 mM histamine. Metiamide (an H₂-antagonist), but not pyrilamine (an H₁-antagonist) blocked the effect of histamine on cAMP, which indicates that histamine causes its effect via interaction with H₂ receptors. Histamine caused less extensive increases in cGMP in both glomeruli and tubules. Carbamylcholine caused a marked increase in cGMP in glomeruli (+Δ 295±7) and a much lower increase in tubules (+Δ% 70±20); these effects were blocked by atropine. Parathyroid hormone (1 μg/ml) increased cAMP and, to a much lesser degree, also cGMP in glomeruli. In tubules, parathyroid hormone caused much more extensive increases in cAMP than in glomeruli; no changes, or rather a small decline in cGMP, was observed. Angiotensin-II (2 μM) markedly lowered cAMP in glomeruli (−Δ% −45±8) and in tubules (−Δ% 33±7) but had no effect on cGMP. Bradykinin (20 μM) did not consistently influence either cAMP or cGMP in glomeruli or tubules. Present results demonstrate that cAMP and cGMP metabolism in glomeruli are controlled independently by humoral agents known to alter glomerular functions in vivo. Our findings are consistent with the view that histamine and cholinergic agents generated and (or) released locally in glomeruli or in their vicinity may play important roles as mediators of immunopathological injury of glomeruli, and that these effects are mediated by cAMP and (or) cGMP through interaction with H₂ receptors and muscarinic receptors. Likewise, our results suggest that the effects of angiotensin-II and parathyroid hormone on glomerular dynamics may be mediated by cyclic nucleotides. Thus, we surmise that extrarenal as well as intrarenal humoral agents may play an important role in the pathology and physiology of glomeruli through mediation of either cAMP, cGMP, or both.