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Biomedical subjects

R A Fenton

Publications and source records attributed to R A Fenton.

48 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

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↗
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↗
PubMed1982

Effect of adenosine on calcium uptake by intact and cultured vascular smooth muscle.

The effect of adenosine (ADO), a potent vasodilator, on the cellular calcium uptake by vascular smooth muscle (VSM) was studied. In addition, similar experiments were conducted with other vasoactive agents to ensure the validity of results obtained with the cultured VSM cell model. Primary VSM monolayers from rat aorta were incubated for 30 min in 45Ca-enriched physiological salt solution (PSS) (37 degrees C) and washed with 20 mM Ca-EGTA (4 degrees C) to remove extracellular 45Ca. Calcium uptake with 4.6 mM K+ was 65.3 +/- 2.4 pmol Ca/10(5) cells. Verapamil (10(-6) M) or 4 degrees C incubation decreased this value 27 and 65%, respectively, whereas ADO (10(-7) M) and isoproterenol (10(-6) M) elevated calcium uptake 21 and 9%, respectively. Elevation of extracellular K+ (25 mM) increased calcium uptake to 87.8 +/- 5.0 pmol Ca/10(5) cells. ADO (10(-7) M), isoproterenol (10(-6) M), and 4 degrees C incubation significantly attenuated this K+-induced increase 25, 19, and 64%, respectively. The calcium uptake of nondepolarized cells was not changed by norepinephrine (10(-6) M) in the presence of either alpha- or beta-adrenergic blockade. Experiments were performed in a similar manner with porcine carotid artery strips in the presence of alpha- and beta-adrenergic blockade. Calcium uptake increased from 2.3 +/- 0.2 X 10(-7) to 3.0 +/- 0.1 X 10(-7) mol Ca/g wet wt after elevation of the medium K+ to 25 mM. This increase was inhibited by 10(-6) M ADO. ADO (10(-6) M) was found to have no effect on the 45Ca efflux from cultured VSM. It is concluded that ADO relaxes VSM by reducing the inward movement of calcium during stimulation. The significant ADO-induced elevation of cellular calcium under conditions when cultured cells were not partially depolarized suggests the existence of an enhanced calcium sequestration within these cells.

Adenosine↗
PubMed1981

Adenosine and the acid-base state of vascular smooth muscle.

Hog carotid artery media was incubated under conditions of normocapnia (95% O2-5% CO2) and hypercapnia (nominally 75% O2-25%CO2). The intracellular pH (pHi) was determined from the distribution of 14C-labeled 5,5-dimethyloxazoladine-2,4-dione, alpha- and beta-receptor antagonists were used to block the effects of endogenous catecholamines. With 5% CO2, adenosine had no effect on the pHi. High K+ (25mM) and dipyridamole (DPM) induced a cellular metabolic acidosis that was reversed by adenosine and not affected by 0.5 mM ca2+ or ouabain. Hypercapnia decreased the resting pHi from 7.30 to 6.79. Adenosine significantly attenuated this decrease. With high K+ or DPM, a similar degree of hypercapnia only depressed the pHi to 6.91 and 6.90, respectively. The alkalinizing effect of high K+ and DPM was not altered by 0.5 mM Ca2+, was partically reversed by ouabain, and was completely reversed by adenosine. These results suggest that, under normocapnic conditions, although adenosine relaxes the contraction associated with K+-depolarization, it does not do so by elevating cellular proton levels. However, adenosine may decrease a tissue's ability to attenuate a local respiratory acidosis characteristic of increased O2 demand, resulting in relaxation under hypercapnic conditions. In any case, this demonstrates an interaction, with respect to the acid-base state of the vascular smooth muscle cells, among adenosine, K+, and H+, all suggested components of the metabolic theory of blood flow autoregulation.

Acid-Base Equilibrium↗
PubMed1978

The effect of dibutyryl cyclic AMP and glucagon on the myocardial cell pH1.

DBcAMP or crystalline glucagon was utilized to elevate the intracellular cyclic AMP concentration in isolated rat hearts. Butyric acid, a metabolite of DBcAMP, was also investigated. Their effect on the intracellular pH (pHi) as determined by the distribution of [14C]DMO was investigated. Rat hearts, perfused with a recirculated modified Krebs-Henseleit solution maintained at 30 degrees C, were exposed to respiratory acidosis by bubbling the perfusate with 20% CO2. alpha- and beta-receptor antagonists were used to block the effects of endogenous catecholamines. Hypercapnia decreased the pHi from 7.09 to 6.82. A similar degree of hypercapnia decreased the pHi to only 6.95 in the presence of DBcAMP and to only 6.96 in the presence of glucagon. The effective buffer values (delta[HCO-3]i/deltapHi) were: control, 19; butyric acid, 16; DBcAMP, 139; glucagon, 148. These data suggest that cAMP mediates the effect of norepinephrine, which has been shown to diminish the change in pHi accompanying respiratory acidosis.

Acid-Base Equilibrium↗
PubMed1976

Effect of beta-adrenoreceptor blockade on rat cardiac and skeletal muscle pH.

The effect of catecholamines on the intracellular pH of rat cardiac and skeletal muscle during varying extracellular acid-base states was determined. Intracellualr pH (pHi) was calculated from the distribution of [14C]DMO. Acid-base disturbances were produced by placing the animals in an environmental chamber containing 10 or 20% CO2 or by administering HCL or NaHCO3. Two hours later the animals were anesthetized with sodium pentobarbital and blood and tissue samples obtained. In one series of animals, the effects of catecholamines were attenuated by administering the beta-adrenoreceptor antagonist MJ 1999 (Sotalol). In animals breathing 20% CO2, cardiac muscle pH was lower in beta-blocked than unblocked animals (6.69 vs. 6.78). During metabolic acidosis, cardiac muscle pH of beta-blocked animals was lower than that of unblocked animals (6.75 vs. 6.84). The same relationship was observed for skeletal muscle during metabolic acidosis-beta blockade pHi, 6.66; unblocked pHi, 6.77. The pHi of beta-blocked versus unblocked animals was not significantly different under normal acid-base conditions or metabolic alkalosis for cardiac or skeletal muscle. The effective buffer value of both tissue over the normal acidotic range was decreased by the beta-blocking agent. These results indicate that catecholamine release accompanying acidosis attenuates the change in pHI and increases the effective buffer value of cardiac and skeletal muscle.

Acid-Base Imbalance↗