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Biomedical subjects

H E Morgan

Publications and source records attributed to H E Morgan.

At least 37 records · Page 2Linked to original sources
PubMed1991

Control of growth in the neonatal pig heart.

The newborn heart is an excellent model in which to study cardiac growth because the neonatal period is a normal situation in which the left ventricle (LV) grows rapidly and the right ventricle grows slowly. Accelerated LV growth is in response to mechanical, neural, and endocrine changes at birth. Faster growth of the LV is accounted for by greater capacity for protein synthesis, as evidenced by greater RNA content. At 18 h of life, ribosomes are formed in preference to total heart protein, but at 48 h of life, faster rates of both ribosome formation and total protein synthesis are observed. In the LV of hearts from 2-day-old pigs, these rates are insensitive to the addition of glucagon, 1-methyl-3-isobutylxanthine, or a combination of norepinephrine and propranolol. These observations could result because of maximal growth stimulation already present in the LV of the newborn heart. To restrain LV growth in the neonatal period, we treated pigs with enalapril maleate, an angiotensin II-converting enzyme inhibitor. Enalapril blocked growth of the LV as well as the increase in RNA content. When hearts from enalapril-treated pigs were perfused in vitro, rates of protein synthesis and ribosome formation in the LV were lower. These studies suggest that angiotensin II is an important factor accounting for rapid growth of the neonatal heart in response to pressure overload at birth.

1-Methyl-3-isobutylxanthine↗
PubMed1990

Accelerated ribosome formation and growth in neonatal pig hearts.

Rapid growth (5 mg dry heart/h) of the left ventricular free wall (LVFW) in the newborn pig heart accompanied by lack of growth of the right ventricular free wall (RVFW) represents a unique natural model of cardiac enlargement that is free of pathophysiological influences. By 3 days of life, LVFW was 71% larger than at 4 h of age. Rates of protein synthesis were measured during perfusion of isolated pig hearts with bicarbonate buffer containing glucose, lactate, insulin, and plasma concentrations of amino acids of an aortic pressure of 60 mmHg. In hearts from pigs that were 18 h of age, rates of protein synthesis were the same in RVFW and LVFW, but in 2-day-old pigs the rate was 52% greater in LVFW than RVFW. During the first 3 days of life, RNA content (mg/g) increased 3.4-fold faster in LVFW than RVFW. When RNA content was expressed per total heart portion, the increase was 7.9-fold greater. Because approximately 85% of total RNA is rRNA, these values indicated much more rapid formation of ribosomes in the LVFW than RVFW. When ribosome formation was measured in vitro in hearts from 48-h-old pigs, rates of formation were 39% greater in LVFW than RVFW, and at 18 h of age, ribosome formation was 40% faster in LVFW than RVFW. These findings indicated that formation of new ribosome preceded accelerated synthesis of total heart proteins. These findings indicated that rapid growth of LVFW compared with no growth of RVFW was associated with a 67% faster rate of ribosome formation and a 32% greater rate of protein synthesis.

Aging↗
PubMed1990

Signal transduction in myocardial hypertrophy.

Transduction of stretch of the ventricular wall into accelerated growth and ultimately hypertrophy of cardiac muscle cells is a cyclic AMP (cAMP) dependent phenomenon. When stretch was induced in isolated perfused rat hearts by an increase in aortic pressure from 60 to 120 mmHg, protein synthesis was accelerated during the second hour of perfusion. Only a brief exposure to higher aortic pressure (2 min) was required to elicit this effect. Elevation of aortic pressure also increased cAMP content. Other interventions that increased cAMP content such as glucagon increased second hour rates of protein synthesis. Stretch of the ventricular wall had a more rapid effect on ribosome formation. During the first hour of perfusion, increased aortic pressure raised rates of 60S ribosomal subunit formation by 38% in the absence of added insulin and 35% in the presence of the hormone. Ribosome formation was also accelerated by addition of glucagon. The muscarinic cholinergic agonist, methacholine blocked the effects of elevated aortic pressure on protein synthesis, ribosome formation, and cAMP content. These studies indicate that stretch of the ventricular wall is transduced into greater cAMP content and that this intracellular messenger is one of the substances responsible for accelerated ribosome formation and protein synthesis.

Animals↗
PubMed1990

Catecholamines, glucagon, energy metabolism and protein degradation in rat heart.

Isoproterenol, epinephrine, phenylephrine and glucagon inhibited proteolysis in isolated perfused rat hearts. All of these agents had a positive inotropic effect, while isoproterenol and glucagon were shown to increase cyclic AMP content. The catecholamines, but not glucagon, partially depleted the adenine nucleotide pool, but the creatine-phosphate/creatine ratio was unchanged or increased. Isoproterenol markedly increased lactate production and caused release of lactate dehydrogenase. The effects of isoproterenol on these parameters, including proteolysis, were blocked by propranolol and verapamil. Isoproterenol also inhibited proteolysis when perfusate calcium was reduced from 2.5 to 0.5 mM; but, in this circumstance, isoproterenol did not deplete ATP. In hearts arrested with tetrodotoxin, neither isoproterenol nor glucagon inhibited proteolysis and neither of them depleted ATP. Both hormones still increased cyclic AMP content. These findings suggest that cyclic AMP may not be involved in the control of proteolysis, and that the effects of isoproterenol and glucagon are mediated via effects on contractility. The studies stress the importance of preventing adenine nucleotide depletion and controlling contractility in experiments on the mechanisms of inotropic agents on cardiac protein turnover.

Adenine Nucleotides↗
PubMed1989

Accelerated rates of ribosomal RNA synthesis during growth of contracting heart cells in culture.

Contractile activity of neonatal cardiac myocytes stimulated hypertrophic growth as compared with nonbeating cells that were depolarized with 50 mM KCl. Growth of contracting myocytes was associated with an increased rRNA content as measured by the total RNA/DNA ratio. The fractional rates of rRNA synthesis (K8) and rRNA degradation were determined in contracting and nonbeating myocytes to assess their relative contributions in increasing rRNA content during growth. The values for K8 were calculated from the specific radioactivity of 3'-[3H]UMP in 18 and 28 S rRNA after purification by hybridization to cloned rDNA. The cellular [3H]UTP pool served as the precursor for rRNA synthesis in myocytes that were labeled with 50 microM [3H]uridine. K8 values for 18 and 28 S rRNA in contracting myocytes were accelerated by 59 and 53%, respectively, after 3 days as compared with nonbeating myocytes. Calculations of the rate of cellular rRNA synthesis, which took into account the increased content of myocyte rRNA, revealed that synthesis of both 18 and 28 S rRNA was accelerated 2-fold after 2 days of contraction. The derived values for degradation of 18 and 28 S rRNA were increased marginally in contracting myocytes, but cellular rRNA degradation rates averaged 57% higher. The difference between cellular rates of rRNA synthesis and degradation in contracting myocytes accounted for the 30% increase in rRNA content. These data demonstrated that increased rRNA content in contracting myocytes resulted from acceleration of the fractional rate of rRNA synthesis.

Animals↗
PubMed1989

Elevated aortic pressure, calcium uptake, and protein synthesis in rat heart.

Elevation of aortic pressure from 60 to 120 mmHg increased the initial rate of 45Ca2+ uptake and the steady-state level that was achieved. The increase in uptake was as great after the first 10 min of pressure elevation as it was after aortic pressure had been at 120 mmHg for 1 h. When aortic pressure was returned to 60 mmHg for 30 min after 1 h at 120 mmHg, calcium uptake was restored to the control value. Elevation of perfusate Ca2+, from 0.5 mM to 2.9 and 5.0 mM increased oxygen consumption and decreased creatine phosphate/creatine ratios in hearts supplied glucose but had not effect on the rate of total protein synthesis. When hearts were supplied pyruvate to maintain high energy phosphates, an increase in perfusate Ca2+ from 0.5 to 2.9 mM did not accelerate total protein synthesis or ribosome formation. These studies provide no support for a role for extracellular Ca2+ availability in mediating the effects of elevated aortic pressure on total protein synthesis and ribosome formation.

Animals↗
PubMed1989

Effect of higher aortic pressure on ribosome formation and cAMP content in rat heart.

Elevation of aortic perfusion pressure from 60 to 120 mmHg in beating and arrested rat hearts raised cAMP content and increased rates of ribosome formation but had no effect on total protein synthesis during 1 h of perfusion. The activity of adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase increased as perfusion pressure was elevated in arrested hearts. A regulatory link between increased cAMP content and accelerated ribosome formation was hypothesized to exist. When hearts were arrested with tetrodotoxin and exposed to 0.2 mM methacholine, a muscarinic-cholinergic agonist that blocked pressure-induced increases in cAMP content, elevation of aortic pressure to 120 mmHg failed to increase the rate of ribosome formation. When aortic pressure was maintained at 60 mmHg, exposure of beating hearts to glucagon increased cAMP content and mimicked the effect of elevated aortic pressure to accelerate rates of ribosome formation. These studies support the hypothesis that increased aortic pressure preferentially accelerates rates of ribosome formation by a cAMP-dependent mechanism.

Animals↗
PubMed1989

Mechanisms of differential growth of heart ventricles in newborn pigs.

The left ventricular free wall (LVFW) grew approximately three times faster than the right ventricular free wall (RVFW) during the first 10 days of life in neonatal pigs. Faster growth was associated with proportional increases in total RNA and messenger RNA. These findings indicated that greater capacity for protein synthesis was a major factor in accelerated growth. Despite faster growth, heart content of ribosomal subunits was higher in piglets than in 60-day-old pigs or adult rats, suggesting a relatively slower rate of peptide chain initiation than elongation. When hearts from 5-day-old pigs were perfused in vitro, protein synthesis was more rapid in the LVFW than in the RVFW. In the absence of added insulin, the higher rate was due to both greater efficiency and greater capacity for protein synthesis. In the presence of the hormone, greater capacity was responsible for the increased rate of protein synthesis in the LVFW as compared with the RVFW.

Animals↗
PubMed1989

Contraction modulates the capacity for protein synthesis during growth of neonatal heart cells in culture.

Neonatal ventricular myocytes that were incubated in a well-defined serum-free medium containing 50 mM KCl did not contract and maintained stable cell size, as assessed by the protein/DNA ratio. The present study utilized KCl-arrested cells to examine the effect of constant rates of synchronous contraction in normal [K+]o (4 mM) as a physiological stimulus for myocyte growth. Cell growth increased following the onset of contraction when measured over 3 days. The rate of protein synthesis was accelerated in parallel by contraction, but the rate of protein degradation remained similar to rates in noncontracting cells. The capacity for protein synthesis was estimated by total RNA content and was increased in contracting as compared with KCl-arrested cells. This increase was accompanied by faster rates of RNA synthesis as determined from the incorporation of [3H]uridine into RNA and the specific activity of the cellular UTP pool. The rate of RNA degradation was accelerated during contraction but the difference between the rates of RNA synthesis and degradation resulted in net RNA accumulation of 49% after 3 days. These data demonstrated that 1) contractile activity stimulated myocyte growth through an increased capacity for protein synthesis and 2) the increased capacity for protein synthesis involved acceleration of the rate of RNA synthesis. Since enhancement of protein synthetic capacity is a common feature of myocyte hypertrophy in vivo and in vitro, this model can be used to examine the regulation of ribosome synthesis during hypertrophic growth.

Animals↗
PubMed1989

Increased cyclic AMP content accelerates protein synthesis in rat heart.

Elevation of cyclic AMP (cAMP) content in perfused rat hearts by exposure to glucagon, forskolin, and 1-methyl-3-isobutylxanthine (IBMX) increased rates of protein synthesis during the second hour of perfusion with buffer that contained glucose in the absence of added insulin. When tetrodotoxin was added to arrest contractile activity, glucagon, forskolin, and IBMX still elevated cAMP content and rates of protein synthesis. Perfusion of beating rat hearts at elevated aortic pressure (120 mm Hg vs. 60 mm Hg) also accelerated rates of protein synthesis and raised cAMP content and cAMP-dependent protein kinase activity during the second hour of perfusion. Insulin accelerated rates of protein synthesis in beating hearts during the first and second hour of perfusion but did not increase cAMP content. Elevation of aortic pressure in insulin-treated hearts raised cAMP content but had no further effect on rates of protein synthesis. Perfusion of arrested hearts for as little as 2 minutes at 120 mm Hg resulted in a rapid and sustained increase in cAMP content, cAMP-dependent protein kinase activity, and rate of protein synthesis after 60-120 minutes of additional perfusion at 60 mm Hg. Exposure of arrested hearts to 0.2 mM methacholine, a muscarinic-cholinergic agonist, for 5 minutes before elevation of perfusion pressure blocked the pressure-induced increases in cAMP content, cAMP-dependent protein kinase activity, and rates of protein synthesis. When hearts were removed from pertussis toxin-treated animals, methacholine did not block the effects of forskolin on these same three parameters. These studies indicated that elevation of tissue cAMP by hormone binding, direct activation of adenylate cyclase, or inhibition of phosphodiesterase resulted in acceleration of protein synthesis. Furthermore, the effects of increased aortic pressure to accelerate synthesis appeared to involve a cAMP-dependent mechanism that was independent of changes in contractile activity but could be blocked with a muscarinic-cholinergic agonist. Acceleration of protein synthesis by insulin was not associated with an elevation of cAMP.

1-Methyl-3-isobutylxanthine↗
PubMed1987

Biochemical mechanisms of cardiac hypertrophy.

Rapid cardiac growth in adult rats and neonatal pigs involves more efficient use of existing components of the protein synthesis pathway and synthesis of new ribosomes and mRNA to increase the capacity for protein synthesis. Greater efficiency of synthesis can be induced by mechanical perturbations that stretch the ventricular wall, including increased cardiac work and increased ventricular pressure development in beating hearts, and increased aortic and intraventricular pressure in arrested-drained hearts. The biochemical signal linking stretch to more efficient protein synthesis has not been identified. Preferential synthesis of new ribosomes occurs in the first two hours of exposure of Langendorff preparations to high aortic pressure or within four hours after injection of thyroid hormone into normal rats. The rate of protein degradation is either accelerated or unchanged in hypertrophing hearts but is inhibited by induction of cardiac work or high aortic pressure in Langendorff preparations. Overall, increased capacity for, and efficiency of, protein synthesis are the major factors accounting for cardiac growth.

Aging↗
PubMed1987

Faster ribosome synthesis induced by elevated aortic pressure in rat heart.

An increase in aortic pressure from 60 to 120 mmHg accelerated ribosomal protein synthesis in rat hearts during 1 or 2 h of labeling with 0.4 mM [3H]phenylalanine. When hearts were perfused with buffer that contained 20 mM glucose and normal plasma concentrations of 19 other amino acids without added insulin, ribosomal protein synthesis relative to the rate of total protein synthesis increased from approximately 0.22 to 0.36 and 0.30 as aortic pressure was raised from 60 to 120 mmHg during 1 or 2 h of labeling, respectively. With the addition of insulin, the relative rate of ribosomal protein synthesis averaged 0.33 at an aortic pressure of 60 mmHg and increased to 0.42 when aortic pressure was raised to 120 mmHg. These results indicate that elevation of aortic pressure has a preferential effect on synthesis of new ribosomes. This response appears to be an early and physiologically significant event in cardiac hypertrophy.

Animals↗
PubMed1987

Aortic perfusion pressure, protein synthesis, and protein degradation.

An increase in aortic pressure from 60 to 120 mm Hg accelerated protein synthesis and inhibited protein degradation in isolated rat hearts perfused as Langendorff preparations. This elevation of aortic pressure raised intraventricular pressure development, coronary flow, and oxygen consumption. The effect of aortic pressure on protein turnover was dissociated from intraventricular pressure development, contractile activity, and oxygen consumption by use of beating-drained and arrested-drained preparations. Results of other experiments argued against coronary flow as a determinant of rates of protein synthesis and degradation. These results indicated that effects of elevated aortic pressure on protein turnover were caused by stretch of the ventricular wall via its engorgement with blood, the so-called erectile properties of the heart or "garden-hose effect." These effects on protein turnover may be of importance in initiating hypertrophy of the heart secondary to pressure or volume overload.

Animals↗