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Biomedical subjects

J G Dobson

Publications and source records attributed to J G Dobson.

At least 55 records · Page 3Linked to original sources
PubMed1987

The cardiac anti-adrenergic effect of adenosine.

Adenosine has an anti-adrenergic action in the heart and appears to serve as negative-feedback modulator of beta-adrenoceptor-mediated myocardial contractile and metabolic responses. This action of adenosine has been assessed in various heart preparations by the application of exogenous adenosine, the determination of tissue and coronary venous effluent levels of adenosine and the degradation of endogenous adenosine by adenosine deaminase. The evidence suggests that the anti-adrenergic function of adenosine has vital physiological and clinical implications in the normoxic, hypoxic and ischemic myocardium.

Adenosine↗
PubMed1986

Endogenous adenosine inhibits catecholamine contractile responses in normoxic hearts.

The importance of endogenous myocardial adenosine in attenuating catecholamine-elicited contractile responses was investigated in perfused oxygenated rat hearts. Perfusion of the isolated hearts with adenosine deaminase potentiated the isoproterenol-induced increases of three contractile variables (left ventricular pressure development and rates of both left ventricular pressure development and relaxation). The peak (maximal, within 30 s) and maintained (after 1 min) increases of the contractile variables caused by 10(-8) M isoproterenol were enhanced by 15-22 and 31-43%, respectively. Adenosine deaminase appeared in epicardial surface transudates of similarly perfused hearts, indicating that the enzyme had entered the myocardial interstitial space. Isoproterenol alone elevated the release of adenosine into coronary effluents of isoproterenol-stimulated hearts, and adenosine deaminase prevented the release of the nucleoside. The higher the level of adenosine in the effluent, the greater the reduction of the peak contractile variables. Phenylisopropyladenosine at 10(-8) M prevented the adenosine deaminase potentiation of 10(-9) M isoproterenol-induced contractile responses. The adenosine analogue at 10(-6) M blocked completely the isoproterenol-produced increases in the contractile variables. These results suggest that endogenous adenosine prevents full mechanical responsiveness to beta-adrenoceptor stimulation in the oxygenated myocardium. In addition, the findings support the notion that adenosine serves as an important negative feedback modulator in the oxygenated heart.

Adenosine↗
PubMed1985

Adenosine inhibition of catecholamine-stimulated cardiac membrane adenylate cyclase.

Adenosine inhibition of hormone-sensitive adenylate cyclase activity was investigated using isolated myocardial membranes prepared from rat hearts. When cyclase activity was determined in membranes, using [alpha-32P]ATP as substrate, 10(-5) M adenosine inhibited isoproterenol-stimulated adenylate cyclase activity by 25% but did not inhibit basal activity or fluoride (5 mM) activation of the enzyme. The adenosine reduction of isoproterenol-sensitive cyclase activity was dependent on GTP but was not prevented by 10(-3) M theophylline. Adenosine neither appeared to compete with ATP for the substrate converting site of the enzyme nor reduced 5'-guanylyl imidodiphosphate activation of the enzyme. Inasmuch as lower concentrations of adenosine had no influence on enzyme activity, endogenous adenosine may be present in the adenylate cyclase assay. To obviate the effects of endogenous adenosine, the adenylate cyclase assay was then modified to a 2'-deoxy system with [alpha-32P]dATP used as the substrate in the presence of adenosine deaminase. With this assay system, the 15% inhibition of isoproterenol-stimulated adenylate cyclase activity produced by the adenosine receptor agonists, 10(-8) M 2-chloroadenosine or phenylisopropyladenosine, was prevented by 10(-4) M 8-phenyltheophylline or isobutylmethylxanthine (IBMX), respectively. While under these assay conditions, 10(-7) M 2',5'-dideoxyadenosine, a P-site analogue, did not influence the hormone-sensitive cyclase activity. The 35% reduction of the hormone-sensitive enzyme produced by this analogue at 10(-5) M was not prevented by IBMX. These results suggest that nanomolar concentrations of adenosine analogues interact with a methylxanthine-sensitive adenosine receptor that mediates the attention of membrane hormone-sensitive adenylate cyclase activity.

1-Methyl-3-isobutylxanthine↗
PubMed1985

Nicotine increases heart adenosine release, oxygen consumption, and contractility.

The effect of nicotine on adenosine release, oxygen consumption, and contractility was investigated in perfused rat hearts. Continuous infusion of nicotine into the perfusing physiological saline (PS) elicited a propranolol (10(-6) M) sensitive transient elevation of developed left ventricular pressure (LVP) and maximum rates of left ventricular pressure development and relaxation (+/- dP/dtmax) within 20 s, which subsequently declined to maintained elevated plateau levels by 1 min. The continuous infusions of nicotine to achieve PS concentrations of 5 X 10(-4), 1 X 10(-4), or 5 X 10(-5) M, respectively resulted in significant increases in the mean plateau levels of LVP (33.4, 10.1, or 6.3%), +dP/dtmax (26.3, 10.8, or 6.9%) and-dP/dtmax (35.0, 11.9, or 9.0%) at 1 min. The inclusion of propranolol (10(-6) M) with or without atropine (10(-6) M) did not alter these maintained plateau responses to nicotine. During the plateau phase of the contractile response oxygen consumption of the hearts was significantly elevated by 36, 19, or 11%, and mean levels for adenosine in the coronary effluent rose by 261, 76, or 74% in response to 5 X 10(-4), 1 X 10(-4), or 5 X 10(-5) M nicotine, respectively. Nicotine did not influence [14C]adenosine uptake by the hearts. These results suggest that nicotine is capable of 1) augmenting cardiac contractility and oxygen consumption independent of beta-adrenergic or muscarinic influence, and 2) elevating the appearance of adenosine in the coronary circulation presumably by enhancing myocardial production of the nucleoside.

Acetylcholine↗
PubMed1985

Effects of divalent cation ionophore A23187 on cardiac contractile parameters.

The divalent cation ionophore A23187, when added to guinea pig papillary muscle, produced contractile effects that were similar to those produced by isoproterenol or histamine, but the ionophore's effects did not appear to result from the release of endogenous transmitters or prostaglandin production. Optimally effective concentrations of A23187 (6 microM) and isoproterenol (1 microM) more than doubled the peak contractile force and the rates of force development and relaxation and caused a 25% decrease in the duration of the contraction. Both A23187 and isoproterenol decreased the resting tension by approximately 0.15 g and significantly diminished the magnitude of a potassium-induced contracture. The positive inotropic effect of A23187 was prevented by incubating the tissue in calcium-depleted medium and antagonized by D 600, a blocker of sarcolemmal calcium influx, and acetylcholine. The contractile effects of A23187 appear to be related, in part, to its ability to increase the movement of calcium across the sarcolemma electroneutrally, since no change of the action potential occurred. In addition, possible intracellular actions of this ionophore may produce contractile effects that resemble those produced by isoproterenol and that reflect an increased sequestration of calcium within the myocardial cell.

Acetylcholine↗
PubMed1985

Biochemical changes accompanying enhanced cardiac contractility by ionophore A23187.

We have reported that the divalent cation ionophore A23187, like the beta-adrenergic agonist isoproterenol, increased the force of contraction and rate of relaxation and shortened the duration of contraction of papillary muscles isolated from guinea pigs. A23187 produced a fall in resting tension and decreased the contracture tension of K +/- depolarized muscles, as did isoproterenol. In the present studies, isoproterenol produced a concentration-dependent, rapid, and sustained increase in the cyclic AMP (cAMP) content of papillary muscle. In contrast, A23187 had no detectable effect on cAMP levels, even in the presence of the phosphodiesterase inhibitor, papaverine. Neither drug, at concentrations maximal for contractile effects, altered cyclic GMP (cGMP). Isoproterenol increased the cAMP-dependent protein kinase activity ratio, whereas A23187 did not change the activity of this enzyme. However, both A23187 and isoproterenol produced a concentration-dependent increase in phosphorylase activity. Concentrations of A23187 or isoproterenol that enhanced contractility maximally increased the alkali-labile phosphate (by ca. 35%) but were without effect on the acid-labile, alkali-stable phosphate in the total acid precipitable protein. Contractile effects of isoproterenol, which reflect activated Ca2+ uptake, and the increase in phosphorylase activity produced by this agent are believed to be due to an increase in cAMP with subsequent activation of cAMP-dependent protein kinases and phosphorylation of proteins. A23187 may produce similar contractile effects without an increase in cAMP or cAMP-dependent protein kinase activity by activating other protein kinases and/or inhibiting phosphoprotein phosphatases, most likely by its effects on intracellular calcium.

Animals↗
PubMed1984

Role of extracellular and intracellular adenosine in the attenuation of catecholamine evoked responses in guinea pig heart.

Isolated guinea pig hearts were used to determine whether an extracellular (interstitial) or intracellular pool of myocardial adenosine is most important in attenuating the catecholamine-induced enhancement of cardiac contractile state and glycogenolysis. Isoproterenol (2 X 10(-8) M) stimulation of hypoxic (30% O2) perfused hearts produced a marked elevation in tissue and effluent perfusate adenosine levels that were greater than the increases observed with the isoproterenol stimulation of oxygenated hearts (95% O2). In the isoproterenol stimulated hypoxic hearts nitrobenzylthioinosine (NBMPR), a potent inhibitor of adenosine cellular transport, further increased tissue adenosine content and markedly decreased the perfusate level of the nucleoside. Assuming that perfusate levels of adenosine correlate directly with extracellular levels, NBMPR was used as a tool to increase the intracellular and decrease the extracellular content of the nucleoside. When compared to responses in oxygenated hearts, hypoxia reduced the isoproterenol-produced increase in myocardial cyclic AMP content, cyclic AMP-dependent protein kinase activity and contractility but enhanced the increase in glycogen phosphorylase alpha formation. NBMPR completely prevented the reduction of the isoproterenol-induced cyclic AMP and cyclic AMP-dependent protein kinase responses but only partially prevented the attenuation of the contractile response. The increase in phosphorylase alpha formation in the hypoxic isoproterenol stimulated hearts was not influenced by NBMPR. The results suggest that an increase in extracellular adenosine is more influential than an elevation of intracellular adenosine in attenuating beta-adrenoceptor-elicited increases in myocardial cyclic AMP content, cyclic AMP-dependent protein kinase activity and contractile state.

Adenosine↗
PubMed1984

Adenosine and calcium alter adrenergic-induced intact heart protein phosphorylation.

Adenosine reduces cardiac mechanical and metabolic manifestations of catecholamine stimulation possibly by attenuating catecholamine-enhanced adenylate cyclase activity and sarcolemmal Ca2+ flux. The effects of adenosine and Ca2+ on catecholamine-induced myocardial protein phosphorylation were investigated using isolated rat hearts perfused with a 32P-enriched medium. Isoproterenol (10(-7) M, 1 min) elicited a 107-379% increase in 32P incorporation into proteins having molecular weights of 155, 92, 30, 28, 22, and 20 kdaltons. The left ventricular pressures and maximum rates of ventricular pressure development and ventricular relaxation were significantly elevated. These effects of isoproterenol were inhibited by propranolol (10(-5) M). Adenosine (10(-5) M, 2 min) decreased the isoproterenol-elicited increases in 32P incorporation by 50-86% and decreased the contractile responses but had no effect in the absence of isoproterenol. Raising the perfusion Ca2+ concentration from 1 to 4 mM did not alter the 32P incorporations but increased contractile parameters. The increase in Ca2+ augmented the isoproterenol 32P responses but not the contractile responses to isoproterenol. These results are consistent with the proposal that catecholamines augment cardiac metabolism and contractility by enhancing myocardial protein phosphorylation. Adenosine and Ca2+ modulate these responses.

Adenosine↗
PubMed1983

Adenosine reduces catecholamine contractile responses in oxygenated and hypoxic atria.

The properties of adenosine attenuation of catecholamine-elicited increases in peak contractile force, rate of force development, and rate of relaxation were studied in isolated rat atria. Adenosine, at a concentration that did not cause a direct depressant effect by itself, was capable of reducing by approximately 15% the increase in the contractile parameters elicited by isoproterenol. This reduction was not overcome by elevating the catecholamine concentration. The adenosine reduction was prevented by theophylline or the presence of adenosine deaminase. The reduction appears to be independent of the acetylcholine-mediated reduction of catecholamine responses. Adenosine reduced the positive inotropic responses elicited by norepinephrine and epinephrine but not phenylephrine. Adenosine deaminase in oxygenated atria potentiated the catecholamine-elicited contractile responses and reduced the progressive fall of the elevated contractile responses observed with continual catecholamine stimulation. In hypoxic atria adenosine deaminase potentiated the positive inotropic responses observed with catecholamine stimulation. The results suggest that an adenosine-specific mechanism is capable of attenuating the elevation in contractility elicited by beta-adrenergic stimulation. In addition, endogenous adenosine may be responsible, in part, for the reduction of catecholamine-mediated contractile responses in oxygenated and hypoxic myocardial tissue.

Acetylcholine↗
PubMed1983

Interaction between adenosine and inotropic interventions in guinea pig atria.

Isolated guinea pig atria stimulated to contract isometrically were used to determine whether adenosine at a concentration that does not cause a direct depressant effect on peak contractile force, rate of force development, and rate of relaxation was capable of influencing the elevation in these contractile parameters caused by an increase in preload, paired electrical stimulation, an increase in contraction frequency, and catecholamine stimulation in K+-depolarized and nondepolarized atrial muscle. Adenosine had no effect on the contractile parameters that were enhanced by an increase in preload or paired electrical stimulation. The nucleoside reduced the increases in the contractile parameters produced by isoproterenol stimulation, an increase in contraction frequency, and isoproterenol-induced contractions in depolarized atria. All adenosine reductions were inhibited by theophylline, an antagonist of adenosine actions. The adenosine reduction of the elevated contractile parameters caused by increasing contraction frequency was not prevented by atropine (a muscarinic antagonist) or propranolol (a beta-adrenergic blocking agent). These results suggest that adenosine at a concentration that does not produce direct negative inotropic responses is capable of attenuating the elevation in contractility elicited by catecholamine stimulation, an increase in contraction frequency, and catecholamine-induced contractions in depolarized atria. However, the reduction by adenosine of the contractile responses elicited by an increase in contraction frequency appears to be independent of catecholamines.

Adenosine↗
PubMed1983

Mechanism of adenosine inhibition of catecholamine-induced responses in heart.

The properties of adenosine inhibition of catecholamine-induced responses were investigated, using an isolated rat heart preparation. Perfusion of hearts with 0.1 microM isoproterenol increased myocardial cAMP content 2.8-fold, activation of cAMP-dependent protein kinase 4.4-fold, phosphorylase a formation 3.4-fold, left ventricular pressure 1.8-fold, rate of ventricular pressure development 2.1-fold, and rate of ventricular relaxation 2.2-fold within 1 minute. When perfused with the isoproterenol, 10 microM adenosine reduced the catecholamine-produced increase in cAMP, cAMP-dependent protein kinase, and phosphorylase by 30-40%, and the elevation in left ventricular pressure and rate of ventricular pressure development by 40-70% within 40 seconds. More than 2 minutes were required for the nucleoside to significantly reduce the isoproterenol-elicited increase in the rate of ventricular relaxation. Perfusion of adenosine alone at concentrations from 0.1 to 10 microM were without effect on the above parameters. Theophylline at 50 microM had no effect alone on the above parameters but blocked the inhibitory actions of adenosine on the isoproterenol-induced responses. In the presence of 15 mM Mg++ adenosine reduced by approximately 56% the 2-fold increase in myocardial membrane adenylate cyclase activity produced by 1 microM isoproterenol without affecting basal or fluoride-stimulated activity. Adenosine also reduced the isoproterenol-induced increase in enzyme activity assayed at 1-2 mM Mg++, a level that more closely approximates the intracellular activity of the ion. The results suggest that physiological concentrations of adenosine attenuate the catecholamine-induced increase in cAMP content, cAMP-dependent protein kinase activation, phosphorylase a formation, and contractile parameters in the working heart, via reducing the beta-adrenergic activation of adenylate cyclase.

2-Chloroadenosine↗
PubMed1980

Inhibition by adenosine of catecholamine-induced increase in rat atrial contractility.

Because adenosine has been shown to attenuate the catecholamine-induced increase in myocardial cAMP formation and glycogen phosphorylase activity (Circ. Res. 43: 785-792, 1978), the present study was undertaken to determine whether the nucleoside inhibits the catecholamine-elicited increase in cardiac contractile state. Isolated rat atria were bathed in oxygenated physiologic saline and stimulated to contract isometrically at 2/s. Isoproterenol (0.1 microM) increased peak contractile force (PCF) by 96% and the rate of force development (+dF/dt) by 107%. Adenosine (10 microM) alone had no effect on these contractile parameters. Isoproterenol in the presence of adenosine increased PCF and +dF/dt only 15 and 14%, respectively. Elevation of bathing medium Ca2+ or administration of dibutyryl cAMP (DBcAMP) increased PCF and +dF/dt, but these responses were not decreased by adenosine. Inosine, adenine, adenosine 5'-monophosphate, and guanosine inhibited the isoproterenol-induced responses 5-22%. The results indicate that adenosine markedly inhibits, whereas some related purines only mildly attenuate, the catecholamine-elicited, but not the Ca2+- or DBcAMP-elicited, increases in contractility. Thus, adenosine may antagonize catecholamine-elicited glycogenolysis and enhanced contractile state in the heart by exerting an effect at the level of, or proximal to, cAMP formation.

Acetylcholine↗
PubMed1978

Properties of epinephrine-induced activation of cardiac adenosine 3',5'-monophosphate-dependent protein kinase.

The effects of epinephrine on cyclic AMP content and protein kinase activity were examined in an in situ rat heart preparation. Bolus injection of epinephrine into the superior vena cava caused an increase in the activity ratio (-cyclic AMP/"cyclic AMP) of 12 000 X g supernatant protein kinase. The increase was significant within 5 s and maximal in 10 s. Epinephrine produced a dose-dependent increase in both protein kinase activity ratio and cyclic AMP content. The increases in both parameters exhibited a high degree of correlation. The increase in protein kinase activity ratio observed with low doses of epinephrine (less than or equal to 1 microgram/kg) resulted from an increase in independent protein kinase activity (-cyclic AMP) without a change in total protein kinase activity (+cyclic AMP). However, the increase in the activity ratio observed with higher doses of epinephrine (greater than 1 microgram/kg) was due mainly to a decrease in total protein kinase activity rather than a further increase in independent protein kinase activity. The loss of supernatant total protein kinase activity could be accounted for by an increase in activity associated with particulate fractions obtained from the homogenates. A similar redistribution of protein kinase could be demonstrated by the addition of cyclic AMP to homogenates prepared from hearts not stimulated with epinephrine. These results demonstrate that epinephrine over a wide dose range produces a parallel increase in the content of cyclic AMP and the activation of soluble protein kinase. The findings also suggest that protein kinase translocation to particulate material may depend on the degree of epinephrine-induced enzyme activation.

Animals↗
PubMed1978

Protein kinase regulation of cardiac phosphorylase activity and contractility.

The relationship between cAMP-dependent protein kinase activity and epinephrine-produced activation of phosphorylase and increase in contractility was investigated in the intact working rat heart. Epinephrine was administered as a bolus into the superior vena cava of open-chest preparations and the hearts were rapidly frozen. cAMP increased within 5 s and returned to control within 20-30 s. Protein kinase and phosphorylase kinase activity ratios increased transiently with the same time course as that for cAMP. The phosphorylase activity ratio and the rate of left ventricular pressure development increased maximally within 15 s and returned to control in 30-60 s. Continuous infusion of epinephrine caused a sustained elevation of the protein kinase. Free catalytic protein kinase activity increased proportionately with the dose of epinephrine. The beta-adrenergic blocking agent, practolol, had no effect on the basal levels of the five parameters studied, but did prevent the epinephrine-produced increases. The results suggest that the time course of cAMP-dependent protein kinase activation is appropriate if this enzyme is to play a role in the catecholamine-induced increase in both glycogenolysis and contractility in the in vivo heart.

Animals↗