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PubMed1982

Effects of vasoactive intestinal polypeptide (VIP) and cyclic-AMP on the isolated sphincter pupillae muscles of the albino rabbit.

Iris sphincter muscle strips were dissected from the albino rabbit eye pretreated with 0.5% topical indomethacin and incubated in a Krebs-Ringer solution. Vasoactive intestinal polypeptide (VIP) was added to the incubation medium, and the effects on the tension of the sphincter pupillae muscles and the cyclic AMP (c-AMP) level in the muscles were correlated. The c-AMP level in the muscles was determined by a radioimmunoassay method. VIP induced a relaxation of the sphincter muscles and a positive correlation was found between the VIP effects and the c-AMP levels. The ED50 was calculated to be 3.72 X 10(-9)M. A significant increase in the c-AMP level occurred prior to the onset of muscle relaxation after VIP treatment (10(-7)M), and a peak level of c-AMP was reached when the relaxation was almost completed. The sphincter muscles were treated with a c-AMP phosphodiesterase inhibitor, 1-methyl-3-isobutylxanthine (MIX) (10(-5)M), 10 minutes prior to the experiment. This pretreatment enhanced the relaxation of the muscles induced by VIP.

1-Methyl-3-isobutylxanthine↗
PubMed1980

A multivariate factor analysis of the high plasma concentration of cyclic AMP in patients with chronic renal failure.

The concentration of cyclic AMP which is known as an intracellular mediator of hormone action increased in the plasma of patients with chronic renal failure (CRF). In the present study, the plasma concentration of cyclic AMP significantly correlated not only with serum, creatinine, and urea levels, but also with plasma PTH and glucagon in patients with CRF. Furthermore, plasma concentrations of PTH and glucagon correlated with the serum creatinine concentration to a significant extent. To discuss the cause of the increased cyclic AMP concentration in plasma of patients with CRF, multivariate analyses were carried out on the obtained clinical data from patients and normal subjects. In the factor analysis on the clinical data from 61 subjects, cyclic AMP, creatinine and BUN correlated with the first factor and PTH correlated with the second factor. The cumulative contribution ratio by the second factor was 76%. The results of the cluster analysis indicated that cyclic AMP, creatinine, and BUN formed a cluster and PTH glucagon made another cluster. These results suggest that the elevated plasma concentration of cyclic AMP in patients with CRF was mainly introduced not by overproduction but by the retention of cyclic AMP due to the decreased renal function.

Adult↗
PubMed1980

Studies on the possible role of cyclic AMP in limb morphogenesis and differentiation.

Recent studies indicate that one of the major functions of the apical ectodermal ridge (AER) of the embryonic chick limb bud is to maintain mesenchymal cells directly subjacent to it (i.e. cells extending 0.4-0.5 mm from the AER), in a labile, undifferentiated condition, and that when mesenchymal cells are freed from the AER's influence either artificially or as a result of normal polarized proximal to distal limb outgrowth, they are freed to commence cyto-differentiation. In a preliminary attempt to investigate at a molecular level the mechanism by which the AER events its 'negative' effect on the cytodifferentiation of subjacent mesenchymal cells, we have examined the effect of a variety of agents that elevate cyclic AMP levels on the morphogenesis and differentiation of the unspecialized subridge mesoderm in an organ culture system. In vitro in the presence of the AER, undifferentiated subridge mesoderm explants undergo remarkably normal morphogenesis characterized primarily by progressive polarized proximal to distal outgrowth and changes in the contour of the developing explant. In the presence of cyclic AMP derivatives, explants fail to undergo the polarized outgrowth and contour changes characteristic of control explants. In fact, in the presence of dibutyrl-cyclic AMP and theophylline, AER-directed morphogenesis essentially ceases during the first day of culture. The cessation of AER-directed morphogenesis in the presence of cyclic AMP derivatives is accompanied by the histochemically and biochemically detectable precocious chondrogenic differentiation of the subridge mesenchymal cells. In control explants, cartilage differentiation only occurs in those proximal cells of the explant which gradually become located greater than 0.4-0.5 mm from the AER. In contrast, in the presence of cyclic AMP derivatives, cartilage differentiation by cells within 0.4-0.5 mm of the AER is detectable from the first day of culture, and by the third day cartilage formation has occurred throughout the entire explant. Overall, these results indicate that elevating the cyclic AMP content of the subridge mesenchymal cells enables the cells to overcome negative influences on cytodifferentiation and the positive influences on morphogenesis being imposed upon them by the AER. On the basis of this observation and previous studies, a testable model on the role of cyclic AMP in limp morphogenesis and differentiation is proposed.

Animals↗
PubMed1980

Regulation of platelet arachidonic acid oxygenation by cyclic AMP.

Intracellular cyclic adenosine monophosate (AMP) levels regulate the generation of thromboxane by platelets by inhibiting the hydrolysis of arachidonic acid from membrane phospholipids. However, there is conflicting evidence regarding the role of cyclic AMP in the control of the subsequent oxygenation of arachidonic acid by cyclooxygenase. We studoed the regulation of cyclooxygenase activity by agents that elevate platelet cyclic AMP (dibutyryl cyclic AMP and prostaglandins), measuring arachidonate-induced aggregation, O2 consumption, and malonaldehyde formation. In platelet-rich cyclic AMP. This inhibitory effect of cyclic AMP was absent in gel-filtered platelets suspended in buffer containing 0.5% albumin, and was progressively restored as plasma was added in increasing concentrations. Increasing the albumin concentration in platelet buffer suspensions likewise increased the ability of cyclic AMP to block the arachidonate-induced O2 burst and MDA production. We conclude that (1) the presence of plasma proteins is important in investigating platelet plasma milieu or at least in the presence of physiologic albumin concentrations.

Arachidonic Acids↗
PubMed1980

Export of cyclic AMP by mammalian reticulocytes.

Suspensions of reticulocyte-enriched red cells produce and extrude cyclic AMP in proportion to their reticulocyte content. When reticulocytes are treated with the beta-adrenergic agonist isoproterenol, up to 3.5 pmoles of cyclic AMP/min/mg protein appear in the extracellular medium. Extruded cyclic AMP can occur against apparent concentration gradients and is inhibited by agents (iodoacetate, dinitrophenol) that deplete cellular ATP, as well as by probenecid and prostaglandin A1. Extrusion of cyclic AMP depends on the availability of intracellular cyclic AMP but is not obligatorily coupled to adenylate cyclase activity: extrusion continues following termination of a pulse of stimulation and exhibits a temperature dependence that differs from that for cyclic AMP production in response to isoproterenol. Erythropoietin affects neither production nor extrusion of cyclic AMP by reticulocytes. In whole blood, cyclic AMP extruded by reticulocytes may be a significant source of plasma cyclic nucleotide.

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗
PubMed1981

Properties of hepatic and pancreatic cyclic AMP phosphodiesterase in the cat.

Cyclic adenosine-3',5'-monophosphate phosphodiesterase has been characterized in homogenates of feline pancreas and liver. The cyclic AMP phosphodiesterase of feline liver showed a pH optimum at 7.8-7.9. In contrast, cyclic AMP phosphodiesterase activity of feline pancreas increased at up to pH 8.8 without attaining a peak. Hepatic cyclic AMP phosphodiesterase appeared to possess two different enzyme activities, a high and a low affinity form for cyclic AMP. The Michaelis constant for this enzyme was 0.567 and 85.6 microM, respectively. The maximal velocity of this enzyme was 0.135 and 2.84 nmol cyclic AMP hydrolyzed per mg of protein per min. The presence of multiforms of pancreatic cyclic AMP phosphodiesterase was neither demonstrated nor excluded. The kinetics constant for this enzyme for a one-enzyme model without cooperativity was 5.30 microM, and the maximal velocity was 4.97 nmol cyclic AMP hydrolyzed per mg of protein per min.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1981

Membrane milieu is regarded as the native environment of the cyclic AMP degrading enzyme cluster.

The phenomenon of kinetic advantage of nucleoside formation from cyclic AMP, via the intermediate 5'AMP has been observed in the microsomal fraction after subcellular fractionation of beef adrenal cortex tissue. It was explained by the existence of a multienzyme sequence previously evidenced [H. Wombacher, 1982, Arch. Biochem. Biophys. 201, 8-19]. In the present study a similar enzyme cluster was prepared from the soluble fraction of the cell homogenate after two steps of gel-chromatography. An elusive channeling of cyclic AMP degradation could be disclosed. The time course reaction of cyclic AMP degradation to the nucleosides, adenosine and inosine, via 5'AMP as an intermediate compared with the time course reaction of 5'AMP hydrolysis to the nucleosides, adenosine and inosine, under otherwise identical conditions showed that the nucleoside formation from cyclic AMP was faster after the lag phase of the reaction sequence. This kinetic advantage effect, however, was much less pronounced than to be seen in the membrane-bound multienzyme sequence. For an analysis of the influence of the environmental conditions on the activity of both enzyme cluster forms they were treated by chaotropic agents, detergents and ultrasonic power. Common to all results was: the activity of the membrane-bound enzyme cluster is highly stable in comparison with the soluble form. On basis of these and previous findings a hypothesis is suggested explaining the similarities between the membrane-bound enzyme cluster and the soluble form. Thus, the soluble enzyme cluster form is considered a partially preserved form of the membrane-bound form arisen from the cell homogenization process and/or vice versa the soluble form might present a pro-form of the membrane-bound enzyme cluster, and the most stable and active assembly has to be yet first membrane-triggered.

Adenosine Monophosphate↗
PubMed1983

Evidence for the presence of cholesterol side chain cleavage cytochrome P-450 and adrenodoxin in fresh granulosa cells. Effects of follicle-stimulating hormone and cyclic AMP on cholesterol side chain cleavage cytochrome P-450 synthesis and activity.

The synthesis of cholesterol side chain cleavage cytochrome P-450 (cytochrome P-450scc) and adrenodoxin was studied both in freshly harvested bovine granulosa cells and in granulosa cells maintained in primary monolayer culture. In addition, the action of follicle-stimulating hormone (FSH) and cyclic AMP analogs to stimulate the synthesis of cytochrome P-450scc was investigated in cultured cells. Precursor forms of cytochrome P-450scc and adrenodoxin were immunoisolated from a cell-free translation system directed by RNA prepared from freshly obtained granulosa cells that were not luteinized. Furthermore, the presence of cytochrome P-450scc in lysates of granulosa cells freshly obtained from very small follicles (containing less than 0.1 ml of follicular fluid) and in mitochondria of freshly obtained granulosa cells was demonstrated by using an immunoblotting technique. Continuous treatment of cultured granulosa cells with FSH or with cyclic AMP analogs (dibutyryl cyclic AMP or 8-bromo cyclic AMP) for 72 h increased incorporation of [35S]methionine into immunoprecipitable cytochrome P-450scc. Moreover, FSH, dibutyryl cyclic AMP, and 8-bromo cyclic AMP stimulated pregnenolone production by cultured granulosa cells (2.3-, 4.0-, and 7.5-fold increase over control, respectively), indicative of an increase in cholesterol side chain cleavage activity. The results of this study demonstrate for the first time the presence of two components of the cholesterol side chain cleavage system in freshly obtained granulosa cells, and provide direct evidence for the trophic effect of FSH and its presumed mediator, cyclic AMP, on the synthesis of cytochrome P-450scc in granulosa cells.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1983

Compartments of cyclic AMP and protein kinase in mammalian cardiomyocytes.

We have studied the compartmentation of cyclic AMP action in purified ventricular cardiomyocytes prepared by collagenase perfusion of adult rabbit hearts. Incubation of purified adult myocytes with 1 microM isoproterenol causes rapid accumulation of intracellular cyclic AMP in both soluble (2.3 leads to 7.7 pmol/ mg of protein) and particulate (3.0 leads to 9.2) fractions of cell homogenates (3000 X g for 5 min), increases in the total activity and activity ratio of soluble cyclic AMP-dependent protein kinase (0.21 leads to 0.66), a decrease in protein kinase activity remaining in the particulate fraction (47 leads to 30%), and an increase in the activity ratio of glycogen phosphorylase (0.15 leads to 0.47). Incubation of myocytes with 10 microM prostaglandin E1 (PGE1) leads to a comparable increase in soluble cyclic AMP (2.3 leads to 5.8 pmol/mg of protein) and activation of soluble cyclic AMP-dependent protein kinase (0.21 leads to 0.39) but does not result in any change in cAMP or protein kinase in the particulate fraction and fails to cause an activation of glycogen phosphorylase. PGE1 does not inhibit the effects of isoproterenol; when myocytes are incubated with both isoproterenol and PGE1, the accumulation of cyclic AMP, activation of cAMP-dependent protein kinase and phosphorylase b leads to a conversion are equal to that achieved with isoproterenol alone. Perturbation of cellular calcium using the ionophore A23187, verapamil, or high or low extracellular calcium did not alter the ability of isoproterenol to cause activation of particulate cAMP-dependent protein kinase or influence the inability of PGE1 to do so. Activation of adenylate cyclase by forskolin (30 microM) caused immediate activation of both soluble and particulate cAMP-dependent protein kinase leading to rapid activation of phosphorylase. We conclude that the hormonally specific compartmentation of cyclic AMP and cAMP-dependent protein kinase that occurs in intact heart (Hayes, J. S., Brunton, L. L., Brown, J. H., Reese, J. B., and Mayer, S. E. (1979) Proc. Natl. Acad. Sci. U.S.A. 76, 1570-1574) is not explained on the basis of cellular heterogeneity but has a subcellular basis within the cardiomyocyte.

Alprostadil↗
PubMed1983

[Effect of calmodulin and 3':5'-AMP-dependent protein kinases on calcium transport by sarcoplasmic reticulum of normal rabbit myocardium and in toxico-allergic myocarditis].

It was demonstrated that under normal conditions calmodulin and exogenous 3':5'-AMP-dependent protein kinase considerably active Ca2+ transport by sarcoplasmic reticulum of rabbit myocardium; a combined action of these compounds produces an additive effect. The protein-inhibitor of 3':5'-AMP-dependent protein kinase and trifluoroperazine eliminate the activating effect of 3':5'-AMP-dependent protein kinase; in addition, trifluoroperazine decreases significantly the basal level of Ca2+ uptake. The 3':5'-AMP-dependent activation of Ca2+ transport becomes apparent after Ca2+-calmodulin-dependent phosphorylation of FSR membrane proteins. In toxico-allergic myocarditis calmodulin and 3':5'-AMP-dependent protein kinase do not activate the low level of Ca2+ uptake. No differences were observed between the action of calmodulin and 3':5'-AMP-dependent protein kinase isolated from normal and pathological rabbit heart. A conclusion is drawn that the decrease of Ca2+ transport is due to the impairment of Ca2+-calmodulin and 3':5'-AMP-dependent phosphorylation in sarcoplasmic reticulum membranes.

Animals↗
PubMed1983

Effects of vasoactive intestinal polypeptide (VIP) and cyclic AMP on isolated dilator pupillae muscle of albino rabbit eye.

The iris dilator muscle strips were dissected from the albino rabbit eye pretreated with 0.5% topical indomethacin and were incubated in a Krebs-Ringer solution. After pretreatment with 3 X 10(-5)M of L-phenylephrine, vasoactive intestinal polypeptide (VIP) was added to the incubation medium at final concentrations ranging from 1 X 10(-10) to 3 X 10(-7)M. The VIP effects on the tension of the dilator muscles and the cyclic AMP (c-AMP) levels in the muscles determined by a radioimmunoassay method were correlated. VIP induced a dose-dependent relaxation of the dilator muscles in the VIP concentration range between 3 X 10(-10) and 3 X 10(-8)M: the ED50 obtained from 21 muscle strips averaged 6.08 +/- 1.34 (mean +/- SEM) X 10(-9)M. The c-AMP level in the dilator muscles increased in a dose-dependent manner in the VIP concentration range from 1 X 10(-9) to 1 X 10(-7)M: the ED50 was computed to be 5.12 X 10(-9)M. The dose-response relationships both for the muscle tension and for the c-AMP level were similar. The time-courses in c-AMP change and muscle relaxation were compared. The c-AMP level increased significantly prior to the onset of muscle relaxation after VIP treatment (10(-7)M), and the level reached a maximum when the muscle relaxation was almost completed. It was concluded that the dilator muscle relaxation by VIP is mediated by an increase in the intracellular c-AMP.

Animals↗
PubMed1984

Islet cyclic AMP levels are not lowered during alpha 2-adrenergic inhibition of insulin release.

Epinephrine-induced changes in insulin release and cyclic AMP levels were measured simultaneously in isolated rat islets. Forskolin was used to enhance islet cyclic AMP levels. Forskolin (30 microM) stimulated adenylate cyclase activity 10-fold in islet homogenates and raised cyclic AMP levels 5-fold in intact islets (both at low and high glucose). Insulin release was enhanced by forskolin only at high glucose. Epinephrine (0.1 microM) inhibited glucose- and forskolin-induced insulin release to basal rates. At the same time epinephrine potentiated forskolin-elevated cyclic AMP levels. In contrast epinephrine attenuated forskolin-stimulated adenylate cyclase activity in islet homogenates. At low glucose, both alpha 2- and beta-adrenergic blockade counteracted the epinephrine potentiation, each by 50%. At high glucose the effect was mainly beta-adrenergic in nature. The actions of epinephrine in the presence of a beta-blocker were mimicked by the alpha 2-agonist clonidine. Despite the variations in cyclic AMP levels stimulated insulin release was always inhibited by activation of alpha 2-receptors. Finally, insulin release stimulated by exogenous cyclic AMP was abolished by epinephrine. These results suggest that epinephrine inhibits insulin release at a step distal to the generation of cyclic AMP.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1983

Platelet AMP deaminase. Regulation by Mg-ATP2- and inorganic phosphate and inhibition by the transition state analog coformycin.

Kinetic studies with platelet AMP deaminase, at pH 7.0 and 100 mM NaC1, gave cooperative initial velocity curves with AMP as substrate, with Mg-ATP2- as an activator, and with Pi as an inhibitor. In the absence of Mg-ATP2-, the s0.5 for AMP was 4.5 mM with a Hill coefficient approaching 2.0. In the presence of saturating Mg-ATP2-, the s0.5 for AMP was reduced to 0.18 mM, the maximum velocity was increased by about 35%, and the Hill coefficient was 1.0. The half-activation constant for Mg-ATP2- varied from 0.7 to 0.07 mM as the concentration of AMP was varied from 0.1 to 5.0 mM and the Hill coefficient for Mg-ATP activation changed from 2.0 to 1.0 over the same range. Phosphate inhibition was competitive with AMP and with Mg-ATP2- (Ki = 2.0 mM) and reversed the activation by Mg-ATP2-. Coformycin inhibited the Mg-ATP-activated enzyme with a Ki less than 0.25 microM. Coformycin inhibition was slow, with a second order rate constant of 6.0 X 10(4) M-1 min-1, suggesting that the compound acts as a transition state analog according to Frieden, C., Kurz, L. C., and Gilbert, H. R. (1980) Biochemistry 19, 5303-5309. The kinetic properties of the enzyme indicate that substantial regulation can occur through changes in AMP concentration acting synergistically to enhance Mg-ATP2- binding and displace Pi from a single type of regulatory site.

AMP Deaminase↗
PubMed1983

Coformycin inhibition of platelet AMP deaminase has no effect on thrombin-induced platelet secretion nor on glycolysis or glycogenolysis.

Thrombin-stimulated platelet secretion is accompanied by a 30% reduction in the steady state level of cytosolic ATP, a breakdown that proceeds through ADP, AMP, IMP, and inosine to hypoxanthine. The ATP to hypoxanthine conversion could be blocked at the stage of AMP deamination by incubation of platelet-rich plasma for 6 h with 200 microM coformycin, a transition-state analog inhibitor of AMP deaminase. Abolition of AMP deaminase activity had no effect on thrombin-induced secretion from the dense granules, alpha-granules, or acid hydrolases measured in gel-filtered platelets. Coformycin treatment had no effect on thrombin-stimulated lactate production, even when oxidative phosphorylation was blocked by antimycin A, nor on the rate of thrombin-stimulated glycogenolysis. In addition, although it was clear that the adenylate energy charge was maintained by activation of AMP deaminase following thrombin treatment, the adenylate energy charge was also maintained in coformycin-treated platelets, albeit after a short lag, by stimulated ATP production and equilibration through the adenylate kinase reaction. Hydrogen peroxide brings about similar adenylate degradation which could also be inhibited by coformycin. The results indicate that AMP deamination and secretion, although temporally related, are not coupled. The role of AMP deaminase appears to be to maintain the adenylate energy charge in the absence of stimulation of ATP production or to buffer the adenylate charge before ATP production is stimulated.

AMP Deaminase↗
PubMedDate not supplied

[Functional importance of catecholamine metabolism in the regulation of AMP-aminohydrolase activity in mitochondria of the heart and other organs].

The paper deals with main pathways for conversion of catecholamines and their effect on the activity of AMP-aminohydrolase in mitochondria of the heart, liver, brain, kidneys and blood serum. Dopamine-beta hydroxylase is stated to participate in manifestation of dopamine effect on the heart AMP-aminohydrolase, the same may be said with respect to monoaminooxidase in realization of the norepinephrine action on the brain AMP-aminohydrolase. Adrenoxyl (stabilized adrenochrome) duplicates the catecholamine effect with respect to AMP-aminohydrolase in certain organs. A three-hour electric stimulation of the aorta arc is accompanied by activation of AMP-aminohydrolase in the heart and blood serum, which is, probably, associated with changes in the balance and metabolism of tissue catecholamines. Data of the AMP-aminohydrolase activity determination may be applied for testing the myocardium damage. AMP-aminohydrolase is discussed for its role in realization of the adrenochrome effect on the myocardium adenylate cyclase.

AMP Deaminase↗
PubMed1995

Cyclic AMP and glycerol concentrations in freeze-clamped human omental and subcutaneous adipose tissues.

OBJECTIVE: To compare intracellular concentrations of cyclic AMP, GTP, ATP, AMP and glycerol in omental and abdominal subcutaneous adipose tissues. DESIGN: Samples of omental and/or abdominal subcutaneous adipose tissues of 14 women undergoing elective surgery were freeze-clamped, deproteinized with perchloric acid and neutralized. All subjects were obese since it was not possible to freeze-clamp lean individuals. MEASUREMENTS: The concentrations of ATP and GTP were determined by ion-paired high performance liquid chromatography and AMP and glycerol enzymatically. Cyclic AMP was determined by radioimmunoassay. Intracellular nucleotide concentrations were calculated from tissue weights, water contents and relative amounts of sodium and potassium. RESULTS: The intracellular concentration of cyclic AMP in omental adipose tissue (31 mumol/l) was twice as high as that in subcutaneous fat while those of ATP, GTP and AMP were similar at the two sites. Glycerol concentrations were higher in subcutaneous (472 mumol/l) than in omental (325 mumol/l) adipose tissue. CONCLUSION: The results suggest higher relative stimulation of lipolysis by cyclic AMP in omental adipose tissue than in the subcutaneous region in situ. However, probably because of differences in blood flow and possibly in the lipolytic machinery, this is not reflected as a higher glycerol concentration.

Adenosine Monophosphate↗
PubMed1996

P2 purinoceptor-mediated inhibition of cyclic AMP accumulation in NG108-15 cells.

In neuroblastoma X glioma hybrid NG108-15 cells, P2 purinoceptor agonists inhibited forskolin-stimulated cyclic AMP accumulation with distinct selectivities and their activities could be partially reversed by P2 purinoceptor antagonists. The rank order of potency in inhibition of cyclic AMP accumulation was UTP > 2 methylthio-ATP (MeSATP) > benzoylbenzoic ATP (BzATP) = alpha, beta-methylene ATP (AMPCPP) > beta, gamma-methylene ATP (AMPPCP) > ATP > ADP > adenosine 5'-thiotriphosphate (ATP gamma S). Neither adenosine nor AMP caused any inhibitory effect on cyclic AMP accumulation. Pertussis toxin treatment of cells attenuated the inhibitory effect of UTP, MeSATP and ATP on cyclic AMP accumulation whereas it had no effect on the BzATP-induced response. In addition, P2-purinoceptor-mediated inhibition of cyclic AMP accumulation was insensitive to cytosolic Ca2+ concentration. The breakdown of cyclic AMP was enhanced by MeSATP but not by the addition of ATP, UTP and BzATP. Our results suggest that a pertussis toxin-sensitive Gi signalling pathway is directly coupled to the occupancy of P2u and P2y receptors in NG108-15 cells.

Adenosine Triphosphate↗
PubMed1997

The effect of reduced myocardial cyclic AMP content on the response to milrinone in the isolated guinea pig heart.

BACKGROUND: Cardiac beta receptor down-regulation is associated with a reduction of tissue cyclic adenosine monophosphate (AMP) content. Milrinone exerts its effects by inhibiting the metabolism of existing cyclic AMP. The purpose of this study was to evaluate the effect of reduced myocardial cyclic AMP content on the pharmacologic action of milrinone. METHODS: A reduction of myocardial cyclic AMP content was produced by creating catecholamine depletion in the hearts of adult guinea pigs with intraperitoneal reserpine. Control animals received the reserpine vehicle. Isolated heart perfusion was maintained with modified Krebs buffer, and hearts were paced at 270 beats/min. A latex balloon and transducer-tipped catheter were inserted into the left ventricle. Isovolemic work was maintained at a constant balloon volume. Hearts from control and reserpine treated animals were perfused for 20 minutes with buffer containing either no milrinone, 1.7 x 10(-6), or 1.0 x 10(-4) mol/L milrinone (n = 12 for each dose). Maximal positive and negative dP/dt were assessed. The hearts were then frozen and cyclic AMP was measured. RESULTS: Cyclic AMP content was significantly lower in the reserpine-treated hearts at each milrinone concentration (0.33 +/- 0.01 vs 0.46 +/- 0.01; 0.33 +/- 0.01 vs 0.53 +/- 0.01; 0.30 +/- 0.01 vs 0.61 +/- 0.02 pmol/mg wet weight, p < 0.05). Milrinone significantly increased positive and negative dP/dtmax (p < 0.05), but no difference was observed between control and reserpine-treated hearts. CONCLUSIONS: Endogenous catecholamine depletion reduces myocardial cyclic AMP content but does not attenuate the response to milrinone in the isolated heart.

Animals↗