Effects of parathyroid hormone on plasma and urinary adenosine 3′,5′-monophosphate in man

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 mumoles 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 AMP, PTH, in large doses, and calcium infusion produced up to 2-fold increases in the other known naturally occurring cyclic nucleotide, guanosine 3',5'-monophosphate (cyclic GMP).     

Kinetic parameters and renal clearances of plasma adenosine 3′,5′-monophosphate and guanosine 3′,5′-monophosphate in man

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 nmoles/min for cyclic GMP. Plasma clearance rates averaged 668 ml/min 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.     

Regulation of cyclic adenosine 3',5'-monophosphate levels in guinea-pig cerebral cortex by interaction of alpha adrenergic and adenosine receptor activity.

Direct assay of adenosine 3',5'-monophosphate (cyclic AMP) in guinea-pig cerebral cortex in vitro has shown that an alpha adrenergic receptor that was previously found to increase tissue content of cyclic AMP requires the co-presence of adenosine. This alpha adrenergic receptor complex was characterized with blocking agents and contrasted with other activities by examining the effect of other biogenic amines on cyclic AMP content in the presence of adenosine. Phentolamine (but not propranolol) reduced the potentiated response to norepinephrine (NE) (or epinephrine) plus adenosine to the level seen with adenosine alone. Theophylline, an adenosine antagonist, blocked the entire effect of NE plus adenosine. The failure of a high Mg++/Ca++ ratio to block the effect of NE plus adenosine argues against indirect mediation of the alpha receptor effect via the release of K+ or via an unknown neurohumoral agent. The complex variety of potentiative interactions between biogenic amines and adenosine is unique to brain. These interactions may be explained by the proposed existence of both independent and dependent receptors. The dependent receptors respond only to the co-presence of two or more neurohumoral agents. An alternative explanation would involve a compartmentally selective impairment of cyclic AMP degradation.     

Effects of glucagon on adenosine 3′,5′-monophosphate and guanosine 3′,5′-monophosphate in human plasma and urine

Glucagon, infused intravenously into fasting, well-hydrated, normal men in doses of 25-200 ng/kg per min, induced up to 30-fold increases in both plasma and urinary cyclic AMP. Cyclic GMP levels were unaffected by glucagon. Simultaneous cyclic AMP and inulin clearance studies demonstrated that the glucagon-induced increase in urinary cyclic AMP was entirely due to glomerular filtration of the elevated plasma levels of the nucleotide.The cyclic AMP response to glucagon was not mediated by parathyroid hormone or epinephrine, and trypsintreated glucagon was completely inactive.The perfused rat liver released cyclic AMP into the perfusate in response to glucagon, indicating that the liver is a possible source of the cyclic AMP entering the extracellular fluids in response to glucagon in vivo.     

Prevention of tissue factor generation in mononuclear cells by agents known to increase intracellular cyclic AMP.

Agents known to increase intracellular levels of cyclic 3', 5'-adenosine monophosphate (cyclic AMP) were examined for their effect on tissue factor generation by mononuclear cells cultured with E. coli endotoxin. Aminophylline, an inhibitor of phosphodiesterase, and epinephrine, a beta-adrenergic agent, showed an inhibitory effect, and these effects were reversible. Moreover, dibutyryl cyclic AMP also exhibited the effect. Dibutyryl cyclic GMP, however, did not enhance the tissue factor generation by mononuclear cells. On the basis of these observations, it was concluded that the phenomenon of tissue factor generation by mononuclear cells is a biological event, and that intracellular cyclic AMP has a possible role in modulating this phenomenon.     

Urinary excretion of cyclic guanosine 3'.5'-monophosphate in children with malignant tumours

The present study shows an increased urinary cyclic guanosine 3'.5'-monophosphate (cyclic GMP) excretion rate in children of all age groups bearing malignant tumours or lymphomas. The incidence of increased cyclic GMP excretion was highly significant (79%). Follow-up studies of up to three years have revealed that during periods of remission of malignant disease the urinary cyclic GMP excretion drops to near normal values, whereas recurrences are accompanied by a new increase of cyclic GMP excretion.     

Regulation of cyclic nucleotide levels and glycogen phosphorylase activity by acetylcholine and epinephrine in perfused rat hearts.

Acetylcholine (ACh) produced a time and dose-dependent increase in cyclic 3',5'-guanosine monophosphate (cyclic GMP) levels in perfused rat hearts without any significant (P greater than .05) change in cyclic 3',5'-adensoine monophosphate (cyclic AMP) level or glycogen phosphorylase activity. Epinephrine produced a dose-dependent increase in both cyclin AMP and phosphorylase activity but no significant (P greater than .05) change in cyclic GMP levels. When ACh (10(-6) M) was infused into hearts during the infusion of epinephrine (10(-6) M), a time-dependent increase in cyclic GMP and decrease in cyclic AMP occurred, both of which preceded a significant (P less than .05) decrease in glycogen phosphorylase activity. In epinephrine-stimulated hearts, ACh produced a dose-dependent increase in cyclic GMP levels. Similar concentrations produced a fall in cyclic AMP levels and phosphorylase activity. No condition tested resulted in a significant (P greater than .05) change in glycogen synthase activity. It is concluded that ACh can reduce cyclic AMP levels and phosphorylase activity only when they have been elevated above basal values. These changes are associated with an increase in cyclic GMP. The reduction in phosphorylase produced by ACh may be the result of either or both of the changes in cyclic nucleotide levels.     

Effect of cholera enterotoxin on pacemaker rate and cyclic adenosine 3':5'-monophosphate in isolated rabbit sinoatrial node.

The positive chronotropic effect of cholera enterotoxin on isolated rabbit sinoatrial (S-A) node was investigated. This toxin produced a time and dose-related increase in pacemaker rate and cyclic adenosine 3':5'-monophosphate (cyclic AMP) levels and shifted to the left the dose-response curves of norepinephrine on the pacemaker rate and cyclic AMP content in the S-A node. Thus, the sensitivity of the S-A node to norepinephrine was increased by the toxin. These effects of the toxin were not blocked by propranolol. There was a linear relation between the increases in pacemaker rate and cyclic AMP content after application of both the toxin and norepinephrine. However, the slope of the regression line relating pacemaker rate to cyclic AMP level differed with these two agents. These results suggest that cholera enterotoxin increases pacemaker rate with activation of the adenylate cyclase system in the S-A node, but the mechanism differs from that of norepinephrine.     

Effects of Dibutyryl Cyclic Adenosine 3′,5′-Monophosphate and Parathyroid Extract on Calcium and Phosphorus Metabolism in Hypoparathyroidism and Pseudohypoparathyroidism

It has been proposed previously that the metabolic defect in pseudohypoparathyroidism which accounts for parathyroid hormone unresponsiveness is an absence or abnormal form of the adenyl cyclase system in kidney and presumably in bone. To determine whether there is an associated defect in the response mechanism to cyclic adenosine 3',5'-monophosphate (cyclic AMP), the effects of parathyroid extract (PTE), and dibutyryl cyclic AMP were compared in patients with either surgical hypoparathyroidism or pseudohypoparathyroidism. PTE and dibutyryl cyclic AMP both increased serum and urinary calcium, lowered the serum phosphorus, and increased urinary phosphorus in patients with hypoparathyroidism. PTE also increased urinary cyclic AMP in these patients. PTE increased serum and urinary calcium and urinary phosphorus but did not alter serum phosphorus or urinary cyclic AMP in the patients with pseudohypoparathyroidism. Dibutyryl cyclic AMP increased the serum and urinary calcium, lowered the serum phosphorus, and increased urinary phosphorus in all the patients with pseudohypoparathyroidism. The results indicate that (a) dibutyryl cyclic AMP can reproduce the effects of parathyroid hormone on calcium and phosphorus metabolism in man, (b) the response mechanism to cyclic AMP appears to be intact in pseudohypoparathyroidism, and (c) PTE apparently produces some of its characteristic effects on calcium and phosphorus metabolism in pseudohypoparathyroidism in the absence of an increase in urinary cyclic AMP.     

Enhanced exocytotic release of norepinephrine consequent to nerve stimulation by low concentrations of cyclic nucleotides in the presence of phenoxy-benzamine

Stimulation at 5 Hz of postganglionic nerves to the isolated guinea-pig heart which had been labeled with [3H]norepinephrine (NE) resulted in a proportional release of NE, total 3H, [3H]NE, and dopamine beta-hydroxylase. Phenoxybenzamine (3 micrometer) caused a significant increase in the release of all these indices of neurotransmitter release throughout a series of four consecutive stimulations. Stimulation in the presence of dibutyryl cyclic adenosine 3':5'-monophosphate (dibutyryl cyclic AMP) (1 X 10(-9) M) and 8-bromo cyclic guanosine 3':5'-monophosphate (8-bromo cyclic GMP) (1 X 10(-8) M) failed to alter any of the measured indices of release when compared with control. However, when perfused in combination with phenoxybenzamine, both cyclic nucleotide analogs significantly increased total 3H, [3H]NE, NE and dopamine beta-hydroxylase outflow with stimulation, as compared with phenoxybenzamine alone. Lower concentrations of both agents (1 X 10(-10) M dibutyryl cyclic AMP and 1 X 10(-9) M 8-bromo cyclic GMP) were less effective in augmenting release. The increased release of NE with nerve stimulation in the presence of phenoxybenzamine alone and with both phenoxybenzamine and the cyclic nucleotide analogs was associated with a significant increase in intraventricular pressure. In contrast, only the combination of 1 X 10(-9) M dibutyryl cyclic AMP plus phenoxybenzamine resulted in an increase in heart rate. The results suggest that phenoxybenzamine and the cyclic nucleotides, probably operating by two distinct mechanisms to enhance neurally mediated release, can act in concert to enhance neurotransmitter release when subeffective concentrations of cyclic nucleotides are used in conjunction with an effective concentration of phenoxybenzamine.     

Effects of acute and chronic ethanol administration and withdrawal on adenosine 3':5'-monophosphate and guanosine 3':5'-monophosphate levels in the rat brain.

The effect of ethanol on cyclic nucleotide levels was investigated in male Sprague-Dawley rats. The rats were sacrificed by microwave irradiation, the brains were divided into four areas, and cyclic nucleotides were measured by radioimmunoassays. Administration of a single dose of ethanol per os produced a dose-dependent decrease of adenosine 3':5'-monophosphate (cyclic AMP) in cerebral cortex, cerebellum, pons and medulla oblongata while guanosine 3':5'-monophosphate (cyclic GMP) was decreased in all brain areas. Dependence on ethanol was induced by three daily administrations of ethanol p.o. for 7 days. The last dose of ethanol did not produce any decrease of cyclic AMP levels while the decrease of cyclic GMP levels was still present. During ethanol withdrawal cyclic AMP levels increased in cerebral cortex, pons and medulla oblongata and did not change in cerebellum. Changes of cyclic AMP in subcortex were more complex. Cyclic GMP levels increased during ethanol withdrawal in cerebellum, pons and medulla oblongata and did not change in cerebral cortex and subcortex. These results indicate that changes of cyclic nucleotides might participate in the mechanism of ethanol dependence and withdrawal.     

Influence of a phosphodiesterase inhibitor on the chronotropic effects of glucagon and norepinephrine in fetal mouse hearts

Fetal mouse hearts develop tachycardia in response both to norepinephrine and to glucagon, but although adenylate cyclase is stimulated and adenosine 3':5'-monophosphate (cyclic AMP) elevated by norepinephrine, no measurable changes are produced by glucagon. To test further the possible independence of glucagon chronotropy from the cyclic AMP system, the effects of a phosphodiesterase inhibitor were evaluated. The dose-response curve to norepinephrine was shifted to the left by the phosphodiesterase inhibitor 4-(3,4-dimethoxybenzyl)-2-imidazolidinone (Ro7-2956), but the dose-response curve to glucagon was unaltered. Thus, 10(-6) M norepinephrine produced an increase of 40 +/- 5 beats/min in hearts pretreated with Ro7-2956, as compared to an increase of 22 +/- 3 in control hearts (P less than .01). In contrast, 10(-6) M glucagon produced a rate increase of 25 +/- 4 beats/min in treated hearts vs. 26 +/- 4 beats/min in controls. These data are compatible with the hypothesis that adenylate cyclase and cyclic AMP are involved in the chronotropic response of the fetal mouse heart to norepinephrine but not to glucagon.     

Effect of chlorpropamide on renal response to parathyroid hormone in normal subjects and in patients with hypoparathyroidism and pseudohypoparathyroidism.

Chlorpropamide inhibited by 35 to 65% the increase in the urinary excretion of adenosine 3',5'-monophosphate (cyclic AMP) following a large dose (250 U) of parathyroid hormone (PTH) in normal subjects and patients with hypoparathyroidism and pseudohypoparathyroidism. By contrast, in normal subjects, the response of urinary cyclic AMP excretion to smaller amounts of PTH (15 and 30 U) was not decreased by chlorpropamide. Chlorpropamide did not decrease the phosphaturic response to any dose of PTH. The probable explanation for the discrepant effects of chlorpropamide on urinary cyclic AMP and phosphate excretions is that phosphaturia results from a minimal elevation of cyclic AMP and that chlorpropamide does not decrease cyclic AMP production to such a low level. Chlorpropamide decreased the accumulation of renal cyclic AMP in response to PTH in the parathyroidectomized rat, suggesting that this may be the mechanism of action for this drug in decreasing the urinary excretion of cyclic AMP in response to PTH in man. Tolazamide, another sulfonylurea, did not inhibit the elevation of urinary cyclic AMP excretion after PTH. Therefore, the sulfonylurea part of the molecule is probably not involved in the inhibition produced by chlorpropamide.     

The Effects of the Immunologic Release of Histamine upon Human Lung Cyclic Nucleotide Levels and Prostaglandin Generation

The effect of the antigen-induced, immunoglobulin (Ig)E-dependent release of mediators from human lung tissue was analyzed for coincident changes in the tissue levels of cyclic nucleotides. Simultaneously with the appearance of mediators, lung cyclic guanosine 3',5'-monophosphate (GMP) increased from 0.9+/-0.2 to 12.63+/-4.5 pmol/mg protein and cyclic AMP increased threefold from the initial levels of 5.1+/-1.4 pmol/mg protein. The release of histamine and prostaglandin (PG)F(2alpha), as well as the associated increases in cyclic nucleotides, peaked within 10 min of anaphylaxis. Antagonists of histamine's H-1 receptor prevented anaphylaxis-associated increases in cyclic GMP, whereas H-2 antagonists prevented the cyclic AMP response. Neither of these antagonists influenced the pattern or quantity of histamine or slow-reacting substance of anaphylaxis release. Prevention of PGF(2alpha) synthesis with acetylsalicylic acid failed to influence histamine or slow-reacting substance of anaphylaxis release or the concomitant increases in cyclic nucleotides. Histamine, added exogenously, produced a prompt increase in the cyclic AMP and cyclic GMP levels of human lung. As was seen after anaphylaxis, H-1 anatagonists prevented the cyclic GMP response to histamine, whereas H-2 antagonists prevented the cyclic AMP response.H-1 antagonists prevented 50% of the PGF(2alpha) synthesis accompanying anaphylaxis; H-2 antagonists had no effect. Exogenous histamine induced PGF(2alpha) synthesis; this synthesis was prevented by H-1 but not H-2 antagonists, and was reproduced by 2-methylhistamine (H-1 agonist) but not by dimaprit (H-2 agonist). Arachidonic acid generation of PGF(2alpha) was not influenced by antihistamines. Therefore, histamine interactions with human lung result in the synthesis of both PGF(2alpha) and cyclic GMP in response to H-1 stimulation, and of cyclic AMP through H-2 stimulation.     

Histamine receptors in adipose tissue: involvement of cyclic adenosine monophosphate and the H2-receptor in the lipolytic response to histamine in isolated canine fat cells.

The effects of histamine on lipolysis and associated changes in adenosine 3',5'-monophosphate (cyclic AMP) levels were examined in the isolated canine fat cell. Histamine, like norepinephrine, caused a dose-dependent increase in free fatty acid (FFA) and glycerol levels. The lipolytic response to histamine was preceded by a rise in the levels of cyclic AMP and was greatly potentiated by the addition of theophylline. In isolated canine fat cells, histamine (2 muM) caused a 7-fold increase in FFA levels. This effect was inhibited more than 50% in the presence of insulin (0.4 mmu/ml) or prostaglandin E1 (2.8 muM). In similar experiments, cyclic AMP Levels were increased 11-fold by histamine (2 muM) in the presence of 1 mM theophylline. Burimamide (0.1 mM), a histamine H2-receptor antagonist, reduced the effect of histamine (2 muM) on FFA levels as well as the effect on cyclic AMP levels greater than 95% but did not inhibit the lipolytic response to norepinephrine (2 muM). Propranolol (0.01 mM), a beta adrenergic antagonist, reduced the lipolytic response to norepinephrine by 97% but did not inhibit the effects of histamine on FFA or cyclic AMP levels. Tripelennamine and 1,5-diphenyl-3-dimethylaminopyrrolidine, histamine H1-receptor antagonists, inhibited neither the lipolytic response to histamine nor the effect on cyclic AMP levels. It was concluded that histamine induces lipolysis in canine fat cells by a mechanism involving cyclic AMP and the histamine H2-receptor.     

Vascular and metabolic effects of circulating epinephrine and norepinephrine. Concentration-effect study in dogs.

Vascular and metabolic effects of circulating epinephrine and norepinephrine have been studied in relation to the plasma concentration of these amines in dogs. Intravenous infusion of epinephrine or norepinephrine (0.1, 0.5, and 2.5 nmol x kg-1 x min-1) raised the plasma concentration of the infused amine by 2.5 , 13, and 63 nM from resting levels of 2.4 and 3.6 nM, respectively. Blood flow to isolated adipose tissue; skeletal muscle preparations; and plasma levels of glycerol, glucose, and cyclic AMP were measured. Epinephrine and norepinephrine displayed a distinct selectivity with regard to both vascular and metabolic effects. Epinephrine caused significant vasoconstriction in adipose tissue already at a plasma concentration of 5 nM, whereas no significant effect was seen on skeletal muscle vascular resistance. Norepinephrine, on the other hand, caused significant vasoconstriction in skeletal muscle at 5 nM but had no vasoconstrictor effect in adipose tissue. Epinephrine was more potent than norepinephrine in increasing plasma cyclic AMP and glucose, whereas the converse was true for plasma glycerol. Epinephrine had significant effects on plasma cyclic AMP at 5 nM and on plasma glucose and glycerol at 15 nM. Norepinephrine, on the other hand, had significant effects on plasma glycerol at 5 nM, plasma cyclic AMP at 15 nM and plasma glucose only at 65 nM. It is suggested that these response patterns are related to a preferential action of epinephrine on beta 2-adrenoceptors and a preferential action of norepinephrine on beta 1-adrenoceptors. Our results support the view that both epinephrine and norepinephrine may act as circulating hormones, because vascular and metabolic effects of both amines were seen at plasma concentrations encountered during various kinds of stress in animals and man.     

Plasma renin activity and plasma concentrations of norepinephrine and cyclic nucleotides in heart failure after prazosin

A single oral dose of 1.0 to 2.0 mg prazosin was given to 14 patients with congestive heart failure to assess its effect. Prazosin increased cardiac index (+27.5%) and decreased pulmonary arterial diastolic pressure (-29.1%), systemic vascular resistance (-27.7%), mean blood pressure (-11.8%), and double products (-12.9%). Plasma renin activity (?.8%) and plasma concentrations of norepinephrine (+67.5%) and cyclic adenosine monophosphate (AMP) (+10.6%) rose. There was a negative correlation between plasma cyclic AMP concentration and the increase of plasma cyclic AMP concentration after prazosin (Y = -0.53X + 18.7). There were no changes in heart rate and plasma cyclic guanosine monophosphate concentration. The effects were maximum at 3 hr and lasted 5 hr. The results indicate that oral prazosin has a beneficial hemodynamic effect in patients with congestive heart failure, and that the pathologic effects of prazosin, "alpha-blocker." induces a rise in plasma renin activity as well as in plasma concentrations of norepinephrine and cyclic AMP.     

Stimulation of adenosine 3',5'-monophosphate formation in rat cerebral cortical slices by methoxamine: interaction with an alpha adrenergic receptor.

Methoxamine elicits a rapid accumulation of adenosine 3',5'-monophosphate (cyclic AMP) in rat cerebral cortical slices with maximal effects at 100 muM. The accumulations of cyclic AMP elicited by this amine are completely blocked by the alpha adrenergic antagonists, phenoxybenzamine and dihydroergokryptine, partially blocked by the alpha antagonist, phentolamine, and unaffected by the beta blocking agent, propranolol, or by the local anesthetic, tetracaine. The magnitude of the accumulations of cyclic AMP elicited by methoxamine in cerebral cortical slices of four rat strains (F-344, ACI, BUF, and Sprague-Dawley) exhibit a strong negative correlation with spontaneous motor activity and a positive correlation with the magnitude of norepinephrine-elicited accumulations of cyclic AMP. The stimulatory interaction of methoxamine with alpha adrenergically regulated cyclic AMP-generating systems differs from the interaction of norepinephrine with alpha receptors as evidenced by the following observations: 1) the stimulatory effects of methoxamine and norepinephrine are nearly additive; 2) the stimulatory effects of methoxamine and adenosine are nearly additive, whereas the effects of norepinephrine and adenosine are much more than additive. Methoxamine, however, does not increase further the magnitude of accumulation of cyclic AMP elicited by a combination of norepinephrine and adenosine. The results are consonant with the interaction of methoxamine with alpha adrenergic receptors which are normally activated by norepinephrine only to a marginal extent. However, in the presence of adenosine, these receptors are now sensitive to activation by norepinephrine.     

Evidence for Delayed Development of the Glucagon Receptor of Adenylate Cyclase in the Fetal and Neonatal Rat Heart

The effects, in vivo, of epinephrine, glucagon, and dibutyryl cyclic adenosine 3',5'-monophosphate (cyclic AMP) on the glycogen content of rat heart and liver and, in vitro, upon adenylate cyclase activity in homogenates of rat heart and liver were determined during the latter third of gestation and the neonatal period. Hepatic glycogen was depleted by epinephrine, glucagon, and dibutyryl cyclic adenosine 3',5'-monophosphate, but myocardial glycogen was depleted only by epinephrine and dibutyryl cyclic AMP in the neonates. Hepatic adenylate cyclase activity was augmented by both epinephrine (10(-5) M) and glucagon (10(-5) M), and myocardial cyclase was increased only by epinephrine in tissue obtained from 16, 18, and 20 day fetal rats. Myocardial adenylate cyclase responsiveness to glucagon was present in tissue obtained from rats 4 wk of age and older. It is concluded that in contrast to hepatic adenylate cyclase, myocardial adenylate cyclase in the rat is not responsive to glucagon during gestation and that responsiveness to glucagon and the associated ability of glucagon to deplete myocardial glycogen do not develop until well after birth.     

The effect of tolbutamide on contractility and cyclic adenosine 3':5'-monophosphate concentration in the intact beating rat heart.

The effect of tolbutamide on contractility and the concentration of cyclic adenosine 3':5'-monophosphate (cyclic AMP) in ventricular muscle was examined in the intact beating rat heart. The hearts were perfused in a nonrecirculated (Langendorff) fashion. Bolus injections of tolbutamide caused an increase in cardiac contractility. This increase in contractility was markedly inhibited when bovine albumin (3 g/100 ml) was present in the perfusing fluid. The increase in contractility caused by tolbutamide was not preceded by or associated with any change in the concentration of cyclic AMP in the ventricular muscle. Further studies utilizing a simultaneous injection of norepinephrine and tolbutamide demonstrated no significant effect of this combination on the concentration of cardiac cylcic AMP produced by an injection of norepinephrine alone. Our findings suggest that in the intact beating rat heart the positive inotropic effect of tolbutamide is not mediated via an increase in the concentration of cardiac cyclic AMP and that tolbutamide does not significantly potentiate the effect of catecholamines on cardiac cyclic AMP concentration.