Modulation of Cyclic Nucleotides in Isolated Rat Glomeruli

Abstract

A B S T R A C T 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 (+A% 675±87) and, to a lesser degree, increased cAMP in tubules (+A% 103+25) or in tissue slices. This stimulation was dose-dependent in the range of 1 ,uM-1 mM histamine. Metiamide (an H2-antagonist), but not pyrilamine (an H,-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 (+A 295±7) and a much lower increase in tubules (+A% 70+20); these effects were blocked by 1334atropine. Parathyroid hormone (1 ug/ml) increased cAMP and, to a much lesser degree, also cGMP in glomeruli. In tubules, parathyroid hormone caused nmuch more extensive increases in cAMP than in glomeruli; no changes, or rather a small decline in cGMP, was observed. Angiotensin-I1 (2 uM) markedly lowered cAMP in glomeruli (-A% -45±8) and in tubules (-A% 33±7) but had no effect on cGMP. Bradykinin (20 ,M) did not consistently influience 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 mediatecl 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. INTRODUCTIONIt has become increasingly evident in recent years that many extrarenal and intrarenal humoral agents mraymodulate diverse aspects of glomerular function (1). For example, the administration of agents such as para- thyroid hormone (PTH)' (2), angiotensin (3, 4), bradykinin, acetylcholine (5,6), and others (1) causes changes in glomerular microcirculation, hydraulic permeability, or in the ultrafiltration properties of glomerular membrane. Perhaps more importantly,...

Subpressor infusions of angiotensin II alter glomerular binding, prostaglandin E2, and cyclic AMP production.

“…It suggests that prostaglandins contribute to maintenance of GSA through stimulation of cAMP production. 29 Observations in the present study about the ability of ANG II to enhance binding and contractile responses of the isolated glomerulus differ from those of Bellucci and Wilkes." They demonstrated a decrement in glomerular ANG II receptor density following infusion of ANG II and reported no change in binding affinity.…”

“…28 ANG II has been demonstrated to decrease glomerular cAMP production, albeit at pharmacological concentrations. 29 Initial studies were designed to evaluate the effect of ANG II infusion in vivo on ANG II-induced changes in glomerular cAMP production. Knowing the effects of vasoactive agents, one could predict that decrements in mesangial or glomerular cAMP would enhance contraction, with the opposite change favoring relaxation.…”

“…28 We confirmed the observation that pharmacological concentrations of ANG II are required to decrease cAMP production by glomeruli from normal rats. 29 However, subpressor infusions of ANG II that have no acute effect on glomerular function 6 greatly enhanced the sensitivity of ANG II-induced decrements in cAMP production after a 36-hour infusion in vivo. The ANG II concentration at the ED,,, was 15 nM, and the maximum response was 44% inhibition below basal levels.…”

The role of histamine receptors in the release of renin

“…It is possible that at higher infusion rates histamine and dimaprit would have stimulated renal renin release in the filtering kidney but at higher infusion rates there are changes in systemic vascular resistance which would have made accurate evaluation of the direct effect of histamine more difficult. Histamine H2-receptor stimulation has been shown to be coupled to adenylate cyclase in many systems including the rat renal glomeruli and the mammalian brain (Torres, et al, 1978;Nahorski, Rogers & Smith, 1974 (Data & Whorton, 1982). These facts are consistent with our findings that stimulation of the H2-receptors can result in renin release when the inhibitory influence of the macula densa is excluded.…”

“…A more direct demonstration of the presence of histidine decarboxylase has been reported in the glomeruli of the rat kidney (Heald & Hollis, 1976). Recently Torres, Northrup, Edwards, Shah & Dousa (1978) have demonstrated that histamine activates adenylate cyclase in the rat glomeruli, an effect blocked by H2-receptor antagonists. In addition, the actual presence of H2-receptors has been demonstrated in rat glomeruli by the use of [3H]-cimetidine as a ligand (Chansel, Oudinet, Nivez & Ardaillou, 1982).…”