A B S T R A C T The effects of parathyroid hormone (PTH) on plasma and urinary adenosine 3',5'-monophosphate (cyclic AMP) levels were studied in normal subjects. Under basal conditions normal adults have plasma concentrations of cyclic AMP ranging from 10 to 25 nmoles/liter and excrete from 1.5 to 5 imoles of cyclic AMP per g of urinary creatinine. About one-half to two-thirds of the cyclic AMP excreted in the urine is derived from the plasma by glomerular filtration, and the remainder is produced by the kidney. Renal production of cyclic AMP is partly under the control of PTH. It can be suppressed by infusions of calcium and stimulated by infusions of the calcium chelating agent, EDTA. Infusions of PTH in doses up to 10 mU/kg per min were associated with dose-related increases both in urinary cyclic AMP and phosphate. Infusions of PTH in doses ranging from 20 to 80 mU/kg per min did not lead to any further increase in phosphaturia but did lead to further marked increases in urinary cyclic AMP. A modest increase in plasma cyclic AMP was noted when PTH was infused at 40 mU/kg per min. Anephric patients failed to show appreciable increases in plasma cyclic AMP in response to large doses of PTH but did show expected increases in response to glucagon. Surgical removal of parathyroid adenomas from nine patients with primary hyperparathyroidism was invariably followed by a decrease in urinary cyclic This work was presented in part at the 61st Annual

A B S T R A C T Kinetic parameters and the renal clearances of plasma adenosine 3',5'-monophosphate (cyclic AMP) and guanosine 3',5'-monophosphate (cyclic GMP) were evaluated in normal subjects using tritium-labeled cyclic nucleotides. Each tracer was administered both by single, rapid intravenous injection and by constant intravenous infusion, and the specific activities of the cyclic nucleotides in plasma and urine were determined.Both cyclic AMP and cyclic GMP were cleared from plasma by glomerular filtration. The kidney was found to add a variable quantity of endogenous cyclic AMP to the tubular urine, amounting to an average of approximately one-third of the total level of cyclic AMP excreted. Plasma was the source of virtually all of the cyclic GMP excreted.Plasma levels of the cyclic nucleotides appeared to be in dynamic steady state. The apparent volumes of distribution of both nucleotides exceeded extracellular fluid volume, averaging 27 and 38% of body weight for cyclic AMP and cyclic GMP, respectively. Plasma production rates ranged from 9 to 17 nmoles/min for cyclic AMP and from 7 to 13 nnmoles/min for cyclic GMP. Plasma clearance rates averaged 668 mln/in for cyclic AMP and 855 ml/min for cyclic GMP. Approximately 85% of the elimination of the cyclic nucleotides from the circulation was due to extrarenal clearance.These studies were presented in part at the Annual Meeting of the Southern Society for Clinical Investigation, New Orleans, La., January, 1970. Clin. Res. 18: 73. (Abstr.) INTRODUCTION Adenosine 3',5'-monophosphate (cyclic AMP) and guanosine 3',5'-monophosphate (cyclic GMP) were identified in urine several years ago (1-3), but definitive studies concerning the sources of the excreted cyclic nucleotides have not been reported. Cyclic AMP has been found in dog plasma (1), and we have identified both cyclic nucleotides in human plasma, raising the possibility that renal plasma clearance could account for at least a portion of the cyclic nucleotides excreted into the urine. Two hormones known to stimulate renal adenyl cyclase systems (4) have been reported to increase cyclic AMP excretion (5, 6) suggesting the kidney as a source of urinary cyclic AMP. Similarly, the kidney has been suggested as a source of urinary cyclic GMP (7). In the absence of definitive clearance studies, it has not been possible to know whether the cyclic nucleotides in urine are derived solely from the kidney, solely from plasma, or both from plasma and from the kidney.The present studies were designed to evaluate the renal clearances as well as other kinetic parameters of the extracellular cyclic nucleotides. Tracer doses of tritiumlabeled cyclic nucleotides were administered to human subjects by rapid intravenous injection and by constant intravenous infusion. Specific radioactivity determinations of the cyclic nucleotides in plasma and urine provided information regarding the sources of cyclic AMP and cyclic GMP excreted into the urine. The effects of certain hormones on plasma and urinary cyclic nucleotides are repo...

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A B S T R A C T Studies were performed in healthy volunteers to determine the effects of catecholamines and adrenergic-blocking agents on plasma and urinary levels of adenosine 3',5'-monophosphate (cyclic AMP) and guanosine 3',5'-monophosphate (cyclic GMP).Plasma cyclic AMP rose in response to infusions of the P-adrenergic agent, isoproterenol, or in response to infusions of either epinephrine or norepinephrine alone or -in combination with the a-adrenergic-blocking agent, phentolamine. Although urinary cyclic AMP also rose, the percentage increase was less than that observed in the plasma. These treatments caused no increase in plasma cyclic GMP.Plasma cyclic GMP rose in response to infusions of a-adrenergic agents, viz., epinephrine or norepinephrine infused together with the ,8-blocking agent, propranolol.These treatments caused no increase in plasmna cyclic AMP.These observations are consistent with the current concept that the actions of fl-adrenergic agents are mediated by increases in cyclic AMP formation in target tissues. Such a mediating role has not been established for cyclic GMP, but the data suggest the possibility that cyclic GMP metabolism is responsive either to a-adrenergic stimulation or to parasympathetic stimulation which occurs as a reflexive consequence of the pressor effect of a-adrenergic agents.

Guanosine 3': 5'-cyclic monosphosphate (cyclic GMP) levels in the ductus deferens of the rat were increased 2-to 3-fold by acetylcholine (10-1000 MM) or by 125 mM KCI, while adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels were not changed. After incubation for 30 min in the absence of Ca++, cyclic GMP control levels were decreased by 85% and were not affected by acetylcholine or KCI. The readdition of Ca++ (1.8 mM) for 3 min to Ca++-deprived tissue partially restored basal cyclic GMP levels and the effects of acetylcholine and KCI. The addition of Sr++ (3.6 mM) or of Ba++ (1.8 or 10 mM) also caused an increase in basal cyclic GMP in Ca++.deprived tissue. Cyclic AMP levels were not significantly changed under any of these conditions. The addition of the phosphodiesterase inhibitor, 1-methyl-3-isobutylxanthine (0.1 mM), to ductus deferentes increased the amount of cyclic AMP about 50% and that of cyclic GMP about 2-fold. The latter effect also depended on the presence of Ca++. I-Methyl-3-isobutylxanthine (0.1 mM) increased cyclic GMP and cyclic AMP levels in slices of rat submaxillary glands. Methacholine increased cyclic GMP if added in the presence of methyl isobutylxanthine. Cyclic GMP control levels and the effect of methyl isobutylxanthine were unchanged by Ca + + omission, but the effect of methacholine was abolished.These findings indicate that calcium ions are important for the control of cyclic GMP levels in these tissues.The role of adenosine 3': 5'-cyclic monophosphate (cyclic AMP) as an intracellular mediator in the action of various hormones has been well established (1). Hormones that increase cyclic AMP levels in intact cells can generally be shown to cause an increase in adenylate cyclase activity when added to broken cell preparations (1). While the physiological role of guanosine 3': 5'-cyclic monophosphate (cyclic GMP) is still unclear, the concentration of this nucleotide is increased by cholinergic and other agents in many mammalian tissues (2).The enzyme catalyzing the formation of cyclic GMP from GTP, guanylate cyclase, has been found in both particulate and high-speed supernatant fractions in many tissues (3). Neither of the forms of guanylate cyclase has consistently been affected in cell-free systems by agents that cause an increase in cyclic GMP levels in intact cells. Therefore, we have considered the possibility that the increase in intracellular cyclic GMP concentration in response to acetylcholine Abbreviation: SC-2964, 1-methyl-3-isobutylxanthine. * Present address: Department of Pharmacology, University of Heidelberg, Heidelberg, Germany.t To whom reprint requests should be sent. and other agents might be secondary to altered ion concentrations at the location of guanylate cyclase. The results presented in this paper show that calcium ions are involved in the regulation of cyclic GMP levels by cholinergic and other agents and that Ca++ may also be involved in the regulation of cyclic GMP formation under basal conditions. MATERIALS AND METHODSMaterials and methods u...