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Biomedical subjects

W J George

Publications and source records attributed to W J George.

At least 19 recordsLinked to original sources
PubMed1978

A concept for the control of kidney production of erythropoietin involving prostaglandins and cyclic nucleotides.

Our hypothesis is that PGs released within the kidney play a role in the modulation of kidney production of Ep. PGs release probably at medullary and/or cortical sites following erythropoietic stimuli such as hypoxic hypoxia, anemic hypoxia, and ischemic hypoxia induced by renal artery constriction increase kidney production of Ep. PGs which are released probably activate a renal cortical adenylate cyclase thereby enhancing the production of intracellular cAMP. This initiates the cascade of events resulting in the production and/or secretion of Ep by the kidney. The endoperoxide analogs and PGE2 have been found to produce a dose-related and Ep-dependent increase in radioiron incorporation into newly formed red blood cells of exhypoxic polycythemic mice. Indomethacin, a potent PG cyclo-oxygenase inhibitior, attenuates Ep production and the appearance of PGE in the renal venous effluent of animals exposed to hypoxic hypoxia and renal artery constriction. Arachidonic acid (C20:4) and PGE2 infusion into the posthypoxic isolated perfused dog kidney produced a significant elevation in Ep titers in the perfusate. The increase in Ep production caused by arachidonate is blocked by indomethacin. It has been previously reported that PGs of the E series stimulate cAMP formation in several tissues. We have found that not only are renal cortical cAMP levels significantly elevated in rats following exposure to hypobaric hypoxia but that dibutyryl cAMP administration produces an increase in hematocrit and circulating red cell mass in normal mice. Our data thus far strongly support the hypothesis that the renal PGs and the cyclic nucleotides are intimately involved in the pharmacologic and/or pathophysiologic control of Ep production. Further work is necessary to determine whether the PGs and cyclic nucleotides are involved in the day-to-day control of Ep production by the mammalian kidney.

Animals↗
PubMed1978

Possible role of cyclic nucleotides in the mechanism of the protective effect of methylprednisolone on the hypoxic rat heart.

The isolated isovolumic rat heart was used as a model of cardiac hypoxia. Force of cardiac contraction and cardiac cyclic nucleotide levels (cyclic GMP and cyclic AMP) were monitored in hearts subjected to hypoxia for 5 min and allowed to recover by reoxygenation. Hearts were obtained from both control animals and animals pretreated with methylprednisolone at 18 hr and 1 hr prior to sacrifice. Myocardial levels of cyclic GMP which were significantly (p less than 0.05) elevated above control during all periods of hypoxia were found to be lower when hearts were pretreated with methylprednisolone prior to hypoxic exposure. Hearts of animals pretreated with methylprednisolone also demonstrated better recovery during reoxygenation than did control hearts. These studies suggest that methylprednisolone may be beneficial in the prevention of myocardial failure following hypoxia via a modulation in myocardial cyclid GMP content.

Animals↗
PubMed1976

Effects of derivatives of cyclic amp and cyclic gmp on contraction force of cat papillary muscles.

Right ventricular kitten papillary muscles were incubated with dibutyryl adenosine 3',5'-monophosphate (dbcAMP) at varying concentrations as low as 1 X 10(-4)M. A positive inotropic effect was observed with all concentrations of dbcAMP. Concomitant administration of 5 X 10(-4)M monobutyryl guanosine 3',5'-monophosphate (mbcGMP) and 1-2 X 10(-4)M dbcAMP prevented the inotropic response observed when dbcAMP was used alone. When higher doses of dbcAMP were used (5 X 10(-4) M, 10 X 10(-4) M), there was no significant difference in the inotropic response seen between control tissues and papillary muscles pretreated with mbcGMP.

Animals↗
PubMed1976

Changes in cyclic nucleotide levels and contractile force in the isolated hypoxic rat heart during perfusion with glucagon.

Isolated rat hearts were perfused with hormonal concentrations of glucagon during a hypoxic perfusion to determine whether it would enhance recovery after reoxygenation. Rat hearts were divided into two groups: (1) those perfused with glucose-free Tyrode's solution and (2) those perfused with Tyrode's solution containing glucose. During 3 minutes of exposure to hypoxia both untreated hearts and hearts perfused with glucagon demonstrated a decrease in contractile force to 10-20% of control. When glucose was present in the perfusion medium, cardiac performance was better during both the periods of hypoxia and reoxygenation. During reoxygenation, recovery of contractile force was significantly better (P less than 0.05) in glucagon-perfused hearts than in untreated hearts; this improved recovery occurred regardless of whether glucose was included in the medium. The enhanced recovery of the glucagon-perfused hearts was associated with decreases in myocardial levels of guanosine, 3',5'-monophosphate (cyclic GMP) both during the periods of hypoxia and reoxygenation. At the end of the hypoxic period, cyclic GMP levels in the glucagon-perfused hearts were 20-64% of the levels in untreated hearts. Similarly, after 5 minutes of reoxygenation cyclic GMP levels in the glucagon-perfused hearts were 21% of the levels in the untreated hearts. The effect of glucagon on adenosine 3',5'-monophosphate (cyclic AMP) concentrations in untreated hearts and in hearts receiving glucagon was not significantly different either after 3 minutes of hypoxia or during reoxygenation. The rate of anaerobic glycolysis after 3 minutes of hypoxia was higher in untreated hearts than in glucagon-perfused hearts, as determined by the lactate content of coronary perfusates. These studies suggest that hormonal concentrations of glucagon exert a protective effect on the hypoxic rat heart which involves a modulation of cardiac cyclic GMP accumulation.

Animals↗
PubMed1976

Effects of glucagon on cardiac cyclic nucleotides in the hypoxic heart.

Isolated rat hearts were perfused with a subinotropic concentration of glucagon during an hypoxic perfusion to determine whether glucagon would enhance recovery upon reoxygenation. Rat hearts were divided into two groups: 1) those perfused with glucose-free Tyrode's solution and 2) those perfused with Tyrode's solution containing glucose. During 3 min of hypoxic exposure, untreated hearts and hearts perfused with glucagon both demonstrated a dramatic decrease in contractile force regardless of whether glucose was included in the medium. However, when glucose was present in the perfusion medium cardiac performance was better during both hypoxia and the period of reoxygenation. Furthermore, during reoxygenation, the recovery of contractile force was significantly greater in glucagon-perfused hearts than in controls. Cardiac levels of cyclic AMP and cyclic GMP were monitored at various periods of hypoxic exposure to test the existence of a correlation between the concentrations of these cyclic nucleotides and cardiac performance. During reoxygenation of untreated hearts, the hearts perfused with glucose-free medium attained 45-50 percent of the contractile force seen in glucagon-treated hearts. This enhanced recovery in the glucagon-treated hearts was associated with decreases in cyclic GMP levels at the end of the hypoxic period. At this time, the cyclic GMP levels in the glucagon-treated hearts were only 25-55 percent of the levels seen in untreated hearts that were also exposed to hypoxia. The effect of glucagon on cyclic AMP content in untreated hearts and in hearts receiving glucagon was not significantly different at 3 min of hypoxia. These studies suggest that subinotropic concentrations of glucagon exert a protective effect on the hypoxic rat heart that is not related to the direct inotropic properties of this hormone but which may involve a modulation in cardiac cyclic GMP availability.

Animals↗
PubMed1975

The role of renal adenosine 3',5'-monophosphate in the control of erythropoietin production.

A regulatory role for adenosine 3',5'-monophosphate (cyclic AMP) in the production of the renal hormone rythropoietin following erythropoietic stimulation with cobaltous chloride hexahydrate is proposed. Studies in rates reveal a temporal relationship between renal cyclic AMP levels and plasma titers of erythropoietin. In addition, cobalt increases the activity of an erythropoietin-generating enzyme (renal erythropoietic factor) with maximal enzyme activity occurring after the rise in cyclic AMP levels but before the increase in erythropoietin titers. This increase in renal cyclic AMP is localized to the renal cortex. Cobalt stimulates renal cortical adenylate cyclase but has no effect on renal cyclic nucleotide phosphodiesterase. The addition of cyclic AMP (3 time 10-6 M) and a partially purified cyclic AMP-dependent protein kinase from rat kidney to an inactive preparation of renal erythropoietic factor increases the ability of renal erythropoietic factor to generate erythropoietin. Data from the polycythemic mouse assay, a bioassay used to quantitate erythropoietic activity of test substances, indicate that dibutyryl cyclic AMP is erythropoietically active with respect to its ability to increase radioactive-labelled iron (59Fe) incorporation into heme of newly formed red blood cells. Theophylline, which by itself is erythropoietically inactive, potentiated the erythropoietic effect of cobalt in polycythemic mice. These results suggest that cyclic AMP plays a significant role in the renal production of erythropoietin following cobalt administration. It is postulated that cobalt stimulates renal cortical adenyoate cyclase, thus increasing renal cyclic AMP levels. Cyclic AMP then activates a protein kinase which subsequently stimulates renal erythropoietic factor to generate erythropoietin. A similar cyclic AMP mechanism may be operative after erythropoietic stimulation by exposure to hypoxia or prostaglandin treatment.

Adenine Nucleotides↗
PubMed1975

Renal cyclic AMP accumulation and adenulate cyclase stimulation by erythropoietic agents.

The regional distribution of cyclic AMP in the kidney was determined following erythropoietic stimulation with hypoxia and cobalt. Following these stimuli, increases in renal cyclic AMP concentrations were restricted to the cortex. The basis for this localization in the case of cobalt treatment was found to reside in the stimulation of renal cortical adenylate cyclase activity in vitro by concentrations of cobalt similar to those found in vivo. The level of cobalt in the cortex after cobalt treatment was found to approach 500 mumol/kg of tissue, whereas no detectable levels of cobalt were found in the renal medulla. Additionally, other agents such as parathyroid hormone and lactic acid, that are known to lack stimulatory effects on medullary adenylate cyclase, were found to stimulate the cortical enzyme. This stimulation of renal cortical adenylate cyclase correlates with enhanced erythropoiesis as demonstrated by increased radiolabeled iron incorporation into erythrocytes. These results support previous reports which suggest that renal cortical cyclic AMP mediates erythropoietin production in response to erythropoietically active agents.

Adenylyl Cyclases↗
PubMed1975

Increase in hematocrit, hemoglobin and red cell mass in normal mice after treatment with cyclic AMP (38543).

Chronic treatment of normal mice with either dibutyryl cyclic AMP or erythropoietin produced elevations in the hematocrit, hemoglobin concentration and red cell mass when compared to these same hematological parameters in untreated mice. Dibutyryl cyclic AMP increased red cell mass by 46% while ESF treatment resulted in a 56% increase in red cell mass. These studies confirm earlier reports of the effects of cyclic AMP in increasing radioactive iron incorporation into red cells and further indicate that this change is associated with an absolute increase renal cyclic AMP concentrations probably stimulate erythropoiesis as a consequence of increased kidney production of erythropoietin.

Animals↗
PubMed1975

Influence of prostaglandins E1 and F2alpha on pulmonary vascular resistance, isolated lobar vessels and cyclic nucleotide levels.

The effects of prostaglandins E1 (PGE1) and F2alpha) on the pulmonary vascular bed were studied in the intact dog under conditions of controlled pulmonary blood flow. PGF2alpha increased lobar arterial and venous pressure when injected or infused into the lobar, artery. The pressor response was dose-related and doses as low as 0.03 and 0.1 mug, which established concentrations of 0.1 to 0.3 ng/ml in lobar arterial blood, increased pulmonary vascular resistance. PGF2alpha also increased airway resistance in the left lower lobe. However, the effects of this substance on the vascular bed were not related to its effects on bronchomotor tone since similar pressor responses were observed in normal and nonrespiring lobes, PGE1 decreased pressure in the lobar artery and vein when infused into the lobar artery and the effects of PGE1 and PGF2alpha on the pulmonary vascular bed were similar when the lung was perfused with dextran or with blood. PGF2alpha increased isometric tension in isolated helical segments of lobar vein 3 to 5 mm in diameter but was without effect on arterial segments of the same diameter. The increase in isometric tension in the venous segments with PGF2alpha was associated with a significant increase in intracellular levels of guanosine 3',5'-monophosphate (cGMP) but no change in adenosine 3',5'-monophosphate (cAMP) levels. PGE1 decreased isometric tension in both arterial and venous segments and the decrease in tension was accompanied by a significant elevation in smooth muscle cAMP levels and a small but significant reduction in vein cGMP. Results of the present study indicate that PGF2alpha increases pulmonary resistance by constricting lobar veins and to a lesser extent vessels upstream in the precapillary bed whereas PGE1 dilates lobar veins and upstream vessels. These results suggest that PGE1-induced vasodilation may be mediated by an increase in cAMP levels while PGF2alpha-induced venoconstriction may be related to increased smooth muscle levels of cGMP.

Airway Resistance↗
PubMed1975

Protective effect of methylprednisolone on the heart during ischemic arrest.

Although corticosteroids have been shown to stabilize lysosomal membranes and prevent release of hydrolytic enzymes, the mechanism of membrane stabilization remains obscure. The few reports regarding the use of steroids in myocardial ischemia have been conflicting. This study was undertaken to determine if a pharmacologic dose of the glucocorticoid methylprednisolone would protect the heart during ischemic cardiac arrest. A randomized double-blind study was performed in 25 dogs. Biochemical and hemodynamic parameters were assessed during and after cardiopulmonary bypass and after 30 minutes of ischemic cardiac arrest. Animals were divided into two groups. Group I served as controls and consisted of dogs injected intravenously with the vehicle of methylprednisolone 18 hours and 1 hour prior to experiment. Group II comprised dogs injected with methylprednisolone, 30 mg. per kilogram, IV, at the same time periods. Blood pH, gases, and electrolytes were measured; aortic, left atrial, and left ventricular pressures were monitored; the first derivative of the left ventricular pressure (dp/dt max.) was also determined. Arterial and coronary sinus blood samples were assayed for lactate levels and activity of the lysosomal enzyme, beta-glucuronidase. Left ventricular muscle was assayed for the nucleotides cyclic adenosine 3',5' monophosphate (AMP) and cyclic guanosine 3',5' monophosphate (GMP). Following restoration of coronary flow, mean aortic and left ventricular systolic pressures and left ventricular contractility as determined by dp/dt max. and dp/dt max./IP were depressed in both groups as expected but were significantly higher in Group II than in Group I (p less than 0.05). An increase in levels of both cyclic nucleotides occurred in each group during ischemia, but this increase in cyclic GMP was significantly greater in Group I (p less than 0.05). beta-glucuronidase activity and myocardial potassium loss as determined in coronary sinus blood were both significantly greater in Group I than in Group II (p less than 0.05). Results of this study demonstrate that pretreatment with a pharmacologic dose of methylprednisolone significantly enhances cardiac recovery after ischemia. Lysosomal membrane stability and modulation of cyclic GMP levels may be critical determinants in the mechanism of cardiac ischemia.

Animals↗
PubMed1975

Opposing regulatory influences of cyclic guanosine monophosphate and cyclic adenosine monophosphate in the control of cardiac muscle contraction.

The effects of acetylcholine chloride (ACh) and isoproterenol (Iso) on myocardial levels of guanosine 3', 5'-monophosphate (cyclic GMP) and adenosine 3', 5'-monophosphate (cyclic AMP) and on force of contraction were studied in elelctrically driven isolated rabbit atria. Incubation of atria with Tyrode's solution containing ACh (5 x 10(-7) M) produced significant decreases in contractile force that were associated with significant elevations in atrial cyclic GMP levels. Atrial levels of cyclic AMP were significantly lowered at 15 sec after the addition of ACh but were only slightly lowered at earlier time intervals. The effects of acetylcholine on force of contraction and on cyclic nucleotide levels were prevented with atropine (1 x 10(-7) M). The addition of Iso (1 x 10(-7)-M) to isolated atria produced significant increases in contractile force that were associated with significant elevations in effects of Iso on force of contraction and on cyclic nucleotide levels were prevented with practolol (1 x 10(-5) M). The increases in atrial cyclic GMP and cyclic AMP levels following addition of ACh and Iso, respectively, precede the changes in contractile force. These data support our hypothesis that cyclic AMP and cyclic GMP exert oppositional effects on cardiac contrctility.

Acetylcholine↗
PubMed1975

Oppositional effects of acetylcholine and isoproterenol on isometric tension and cyclic nucleotide concentrations in rabbit atria.

The effects of acetylcholine chloride and isoproterenol on myocardiial cyclic GMP, cyclic AMP and on isometric tension were studied in isolated electrically driven rabbit atria. Acetylcholine (0.5 muM) produced a significant decrease in isometric force that was associated with a significant elevation in atrial cyclic GMP. Cyclic AMP was significantly lowered at 15 seconds after the addition of acetylcholine, but was only slightly decreased at earlier time periods. Both the negative inotropic action and increase in cyclic GMP after addition of acetylcholine were blocked by atropine. Isoproterenol (0.1 muM) produced a significant increase in isometric tension that was associated with a significant elevation in atrial cyclic AMP levels, whereas cyclic GMP levels were not changed. These effects were blocked by practolol. The increases in atrial cyclic GMP and cyclic AMP following addition of acetylcholine and isoproterenol, respectively, preceded the changes in isometric tension in response to these agents. These data support the hypothesis that changes in intracellular levels of cyclic AMP and cyclic GMP may mediate the positive and negative inotropic effects of adrenergic and cholinergic agents.

Acetylcholine↗