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Biomedical subjects

M Tuck

Publications and source records attributed to M Tuck.

At least 37 records · Page 2Linked to original sources
PubMed1990

The differential efficacy of antihypertensive agents in the elderly.

A number of controlled trials have shown that antihypertensive therapy is beneficial to the elderly (greater than or equal to 60 years of age). Even so, there may be deleterious age-related effects associated with such therapy. Because of physiological and pathophysiological problems peculiar to the elderly (many of which remain to be defined precisely), both benefits and untoward effects of antihypertensive drugs differ, sometimes within classes of agents themselves. None of the traditional agents is ideal for the management of hypertension in the elderly. Differential efficacy and tolerability of various antihypertensive agents has often been claimed but none of these claims appears established beyond dispute. Increasing evidence, however, suggests that the serotonin antagonist ketanserin may be more effective and better tolerated in elderly hypertensives. If the elderly are to derive maximum benefit from antihypertensive therapy, the question of age-related differential effects of agents used needs to be addressed in carefully designed studies to determine the nature and magnitude of such effects, where they exist and what clinical implications they may have.

Aged↗
PubMed1989

Inhibitory action of norepinephrine on sodium transport in vascular smooth muscle cells in culture.

Cultured vascular smooth muscle cells from porcine aortas incubated in Na+ -free medium rapidly release their intracellular Na+ contents (Nai) (23 +/- 4% of baseline after 60 min incubation, mean +/- SEM of 18 experiments). Total Nai release was inhibited by 35-40% after addition of ouabain and by 60-70% after addition of ouabain + bumetanide. Norepinephrine inhibited ouabain and bumetanide-sensitives Na+ efflux with an IC50 of about 10(-9)-10(-8) M. Addition of the alpha-adrenergic agonist phenylephrine (10 microM) to the cells mimicked the inhibitory action of norepinephrine on Nai release. Conversely, the beta-adrenergic agonist isoproterenol was without effect on Nai release. Simultaneous addition of 10 microM norepinephrine and the alpha-adrenergic antagonist phentolamine prevented any effect of norepinephrine on the rate of Nai decline. In A-10 cultured vascular smooth muscle cells, the alpha-adrenergic agonist phenylephrine (10 microM) inhibited 40.0 +/- 8.1% of ouabain-sensitive Rb+ influx and 70.7 +/- 6.9% of bumetanide-sensitive Rb+ influx (mean +/- SEM of three experiments). 50% inhibition of bumetanide-sensitive Rb+ influx was obtained with about 5 x 10(-7) M of phenylephrine. Our results show that in vascular smooth muscle cells a [Na+, K+, Cl-]-cotransport system is able to catalyze outward Na+ movements (in Na+ -free media) of a similar order of magnitude to those of the Na+, K+ pump and that alpha-adrenergic stimulation markedly inhibits Na+ efflux (and Rb+ influx) through these two transport systems.

Animals↗
PubMed1989

Site-specificity of histone H1 methylation by two H1-specific protein-lysine N-methyltransferases from Euglena gracilis.

1. The histone H1 fractions from rat spleen and liver were used as substrates for two H1-specific protein-lysine N-methyltransferases, V-A and V-B (protein methylase III) from Euglena gracilis. 2. When the enzymatically [methyl-3H]labeled H1 fractions were resolved by two-dimensional gel electrophoresis, four subtypes were found to be methylated (H1b, H1c, H1d and H1e). Both enzymes methylated H1c and H1b to approximately the same extent; H1d and H1e were methylated preferentially by enzyme V-B and V-A, respectively. 3. Histone H1c, [methyl-3H]labeled by the methyltransferase V-A, which had been digested by arginine-specific protease (Arg C protease), showed a single radioactive peptide on HPLC, indicating methylation site specificity of the enzyme. 4. Arg C protease-digestion of [methyl-3H]labeled H1c labeled by methyltransferase V-B indicated that this enzyme methylated two sites on the histone molecule. 5. The histone H1c methylation sites of these two enzymes did not overlap, indicating the two enzymes have different site specificity. 6. In combination with the other results, this suggests that the two enzymes serve discrete purposes, possibly involving the presumed different actions of histone H1 subtypes.

Amino Acids↗
PubMed1989

Renin regulation in type II diabetes mellitus: influence of dietary sodium.

Numerous abnormalities in the renin-angiotensin system have been described in diabetes mellitus. Plasma renin activity (PRA) has been noted to be low, normal, and high in diabetic patients; these variable results may be explained by differences in patient selection and standardization of study conditions. We evaluated PRA and inactive renin responses in Type II normotensive (n = 7) and hypertensive (n = 12) diabetic patients specifically selected for no or minimal evidence (background retinopathy) for microvascular complications. Patients were studied in a metabolic ward after 7 days on a constant low sodium (20 meq/day) and 7 days on a high sodium (250 meq/day) diet. Nondiabetic control subjects (n = 7) were evaluated under similar conditions. On low sodium intake, mean PRA levels were significantly reduced in the hypertensive diabetic group, but were not different between the control and normotensive diabetic groups. Hypertensive diabetic patients on high sodium intake also had greater reductions in PRA responses compared with the other study groups. In general, diabetic subjects on high sodium intake excreted less sodium and had more cumulative sodium retention than control subjects. Levels of inactive renin were not significantly different between the normotensive and hypertensive diabetic patients and were comparable with the levels in control subjects. Inactive renin levels changed in a similar direction and magnitude as PRA in response to sodium intake and posture in the three study groups. Infusion of angiotensin II led to comparable reductions in PRA in both diabetic groups and in the control group, suggesting an intact short feedback loop control.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1988

Management of hypertension in the patient with diabetes mellitus. Focus on the use of angiotensin-converting enzyme inhibitors.

Hypertension in patients with diabetes mellitus increases the risk of both macrovascular and microvascular complications. Such microvascular complications as diabetic nephropathy and retinopathy are accelerated in the presence of arterial hypertension. Evidence suggests that the complications of diabetes mellitus begin early in the course of the disorder as manifested by microalbuminuria and increased vascular reactivity. These findings are accompanied by changes in the renin-angiotensin-aldosterone system including reductions in plasma renin activity. These changes could be secondary to volume expansion that may be a direct consequence of elevated blood glucose, suggesting that the metabolic disorder in diabetes contributes to the etiology of hypertension in these patients. Adequate treatment of hypertension is crucial to the prevention of complications; however, many antihypertensive agents have limited usefulness in diabetes mainly because of their unfavorable side effects. Diuretics lower blood pressure in hypertensive diabetics, but their metabolic effects are especially undesirable in this population. beta-Blockers alter glucose and lipid metabolism in diabetic patients and reduce regional blood flow. Central acting agents and alpha-blockers are often associated with orthostatic hypotension, sexual dysfunction, and central nervous system side effects. Angiotensin-converting enzyme inhibitors (ACEIs) such as captopril effectively lower blood pressure in diabetic patients and have few unwanted effects. They may improve metabolic control and have favorable effects on glucose metabolism. The ACEIs also produce improved regional hemodynamics which may lead to the improvement in or prevention of the progression of diabetic nephropathy.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1987

Enzymatic methylation of in vitro synthesized apocytochrome c enhances its transport into mitochondria.

The gene for iso-1-cytochrome c from Saccharomyces cerevisiae was recloned into a pSP65 vector containing an active bacteriophage SP promoter. The iso-1-cytochrome c gene was cloned as an 856-base pair XhoI-HindIII fragment. When the resulting plasmid was digested at the HindIII site 279 bases downstream from the termination codon of the gene and transcribed in vitro using SP6 RNA polymerase, full length transcripts were produced. The SP6 iso-1-cytochrome c mRNA was translated using a rabbit reticulocyte lysate system, and the protein products were analyzed on sodium dodecyl sulfate-polyacrylamide gels. One major band with a molecular weight of 12,000 was detected by autofluorography and coincided with the Coomassie staining band of apocytochrome c from S. cerevisiae. The product was also shown to be identical with that of standard yeast apocytochrome c on an isoelectrofocusing gel. The in vitro synthesized iso-1-apocytochrome c was enzymatically methylated by adding partially purified S-adenosyl-L-methionine:cytochrome c-lysine N-methyltransferase (protein methylase III, EC 2.1.1.59) from S. cerevisiae along with S-adenosyl-L-methionine to the in vitro translation mixtures. The methylation was shown to be inhibited by the addition of the methylase inhibitor S-adenosyl-L-homocysteine or the protein synthesis inhibitor puromycin. The principal type of methylated amino acid in the protein was found to be epsilon-N-trimethyllysine which accounted for 77% of the total. Finally, the methylation of in vitro synthesized iso-1-apocytochrome c was found to increase its import into mitochondria isolated from S. cerevisiae 2-4-fold over unmethylated protein, but not into rat liver mitochondria. This suggests that methylation facilitates the import of apocytochrome c into mitochondria by a specific receptor mechanism.

Apoproteins↗
PubMed1987

Mechanisms of hypertension in obesity.

We conclude that the following may explain the rise in blood pressure with obesity and the subsequent fall in blood pressure (Fig. 2): (1) An increase in calories, protein, or carbohydrate leads to an increase in plasma catecholamines, sympathetic nervous system activity, and insulin secretion. (2) These factors, in turn, lead to increased renal sodium retention and stimulation of the renin-aldosterone system which, in turn, leads to: (3) An increased cardiac output with an inability to appropriately adjust the peripheral resistance to maintain normotension with resultant hypertension. Conversely, the fall in blood pressure with weight reduction can be explained by (Fig. 3): (1) A decrease in calorie, carbohydrate, or protein intake which leads to: (2) A decrease in circulating plasma catecholamines, sympathetic nervous system activity, and insulin secretion which results in: (3) A natriuresis and decrease in the renin-aldosterone system, which causes a decrease in circulating blood volume and in cardiac output. This, in turn, lowers blood pressure towards normal. The unanswered question still remains: why do some obese patients become hypertensive and others remain normotensive? Perhaps there are weight-sensitive individuals and weight-resistant individuals just as there appear to be salt-sensitive and salt-resistant hypertensive patients. Perhaps the answer is genetic. These questions also remain to be answered.

Adrenal Glands↗
PubMed1986

Myelin basic protein-specific protein methylase I activity in shiverer mutant mouse brain.

Myelin basic protein (MBP)-specific protein-arginine N-methyltransferase (protein methylase I) activity in homozygous shiverer (shi/shi) mutant mouse brain is significantly higher than in the normal littermate brain at the onset of myelination. While the enzyme activity (expressed as pmol of S-adenosyl-L-[methyl-14C]methionine used/min/mg enzyme protein) increases coincidently during the period of myelination in the normal brain (15-18 days of age), it decreases significantly in the mutant brain during this period of time. These results are in contrast to those found with another dysmyelinating mutant, jimpy (jp/Y) mice, in which the enzyme activity in the mutant brains is similar to that in the normal animals but remains unchanged during the myelination process. There is no difference in the weight and protein concentration of the normal and shiverer mutant brains with corresponding ages, and the histone-specific protein methylase I activity is also unaffected in the shiverer brain.

Animals↗
PubMed1986

Dopaminergic binding and inhibitory effect in the bovine adrenal zona glomerulosa.

Dopaminergic mechanisms may be involved in the regulation of aldosterone secretion in humans and in the rat. Whether these effects are indirect or are exerted directly at the adrenal level has not yet been resolved. We now report the identification of dopaminergic binding sites in the bovine adrenal zone glomerulosa using [3H]spiperone, a butyrophenone with high affinity for D2 dopamine receptors. Specific [3H]spiperone binding (defined as binding displaceable by 10 microns (+)-butaclamol) reached equilibrium within 20 minutes at 22 degrees C, was reversible, and was heat labile (60 degrees C). Binding was of high affinity and saturable with a Kd of 1.8 +/- 0.2 nM and maximal specific binding of 38 +/- 8 fmol/mg (means +/- SEM; n = 18). [3H]Spiperone binding was unaffected by coincubation with angiotensin II, adrenocorticotropic hormone, or KCl. Binding characteristics, including a dissociation constant at the nanomolar range, greater potency of the D2-agonist LY 171555 relative to the D1-agonist SKF 38393 in inhibiting [3H]spiperone binding, and lack of stimulation of cyclic adenosine 3',5'-monophosphate by dopamine (10(-4) M), were consistent with a predominantly D2-receptor. In vitro studies with collagenase-dispersed adrenal zona glomerulosa cells showed that dopamine (10(-4) M) attenuated angiotensin II-stimulated aldosterone secretion. These observations are consistent with a direct inhibitory effect of dopamine on aldosterone secretion in the adrenal zona glomerulosa.

Adrenal Cortex↗
PubMed1985

Purification and characterization of enzymes from Euglena gracilis that methylate methionine and arginine residues of cytochrome c.

Two forms of cytochrome c-specific methyltransferases from Euglena gracilis were purified approximately 100- and 50-fold, respectively, using DEAE-cellulose and gel-filtration chromatography. The methylation product of enzyme I was identified as S-methylmethionine and that of enzyme II as NG-monomethylarginine. Both enzymes were located in the cytosol and exhibit maximum activity at pH 7.0. Among the various proteins tested as substrates, the enzymes were highly specific toward cytochrome c. Various types of histones, in particular, were not modified by either enzyme. The molecular weights of enzyme I and II were 28,000 and 36,000, respectively. Various S-adenosyl-L-homocysteine analogs were tested for their inhibitory activity toward the enzymes. Only the D- and L-isomers of S-adenosylhomocysteine and sinefungin were significantly inhibitory. The Ki values for S-adenosyl-L-homocysteine were 8.13 X 10(-6) and 1.17 X 10(-5) M for enzyme I and II, respectively. Two-dimensional peptide mapping revealed the methylation site of enzyme I to be the methionine residue at position 65 while that of enzyme II to be the arginine residue at position 38. The methylation of either methionine or arginine residues by enzyme I and II, respectively, lowers the isoelectric point (pI) of cytochrome c: 9.23, 9.33, and 10.06 for S-methylmethionine-, NG-monomethylarginine-modified, and unmodified cytochrome c, respectively.

Chymotrypsin↗
PubMed1985

Defective renal prostaglandin synthesis in hypertensive patients with morbid obesity.

Renal prostaglandin synthesis in 36 obese hypertensive patients was estimated from measurements of 24-hour urinary prostaglandin E2 (PGE2) excretion rates. PGE2 was measured by radioimmunoassay using Dray antiserum prior to and 1 week after starting a fast supplemented by 320 cal derived from 30 g of carbohydrate, 45 g protein, and 2 g essential fatty acids. Sodium intake was 120 mEq daily or less. Comparisons were made to a control population of age-matched, nonobese, normotensive, healthy volunteers on a normal diet. Mean weight fell from 260 +/- 8 to 247 +/- 8lb, p less than 0.001. Urinary PGE2 in the obese patients prior to the fast was 104 +/- 27 ng/day, significantly lower than the 404 +/- 124 ng/day found in the control population, p less than 0.005. After the 1st week of the fast urinary PGE2 rose to 213 +/- 55, p less than 0,02. This value was not different from that in the control group. Blood pressure fell (p less than 0.001) in these patients from 143/94 +/- 3/2 to 134/87 +/- 3/2 mm Hg after the 1st week of the fast. Deficient renal prostaglandin synthesis in obese hypertensive patients was corrected by fasting. Such changes in the prostaglandin system may mediate or occur in response to changes in the sodium-volume balance of these patients. These changes in renal prostaglandin synthesis may partly contribute to the blood pressure reduction of these patients.

Blood Pressure↗
PubMed1985

Observations on the "cascade" of Na-K-ATPase inhibitory and digoxin-like immunoreactive material in human urine: possible relevance to essential hypertension.

Previous investigations have demonstrated an increased amount of a sodium pump inhibitor (N.H.) in plasma from humans with essential hypertension and from animals with various forms of experimental hypertension. The present study has employed Sephadex column and C18 reverse phase separation of urines from patients with essential hypertension and normal controls to distinguish "high", "intermediate" and "low" molecular weight forms of N.H., measured through properties of Na-K-ATPase inhibition and digoxin-like immunoreactivity. The major difference between hypertensive and normotensive urines was a highly significant increase in the "intermediate" molecular weight form of N.H., as measured by Na-K-ATPase inhibition. In contrast, digoxin-like immunoreactivity was significantly decreased in urine from hypertensive patients. The results are compatible with an hypothesis that the defect in some forms of essential hypertension may be partial inhibition of enzymatic conversion of intermediate to final form of N.H., with the increased sodium pump inhibition primarily related to the precursor.

Chromatography, Gel↗
PubMed1984

Studies on myelin basic protein-specific protein methylase I in various dysmyelinating mutant mice.

Jimpy mice are dysmyelinating mutants characterized by producing near normal levels of myelin basic protein (MBP) in the brain but failing to incorporate these proteins into the myelin sheath. In this study, the activity of MBP-specific protein-arginine N-methyltransferase (protein methylase I) was studied in the brains of normal and jimpy mice of different ages. The enzyme activity varied little with age in normal mice but in 18 and 21 days-old homozygous jimpy mice the activity was reduced by 50% and 75% respectively from the level of their normal littermates. Interestingly, however, heterozygous jimpy mice who are phenotypically normal and quaking mice (a similar dysmyelinating mutant) showed unaltered enzyme levels.

Age Factors↗
PubMed1984

Enhanced response of plasma aldosterone to metoclopramide in essential hypertension.

Aldosterone responses to posture and the dopamine antagonist, metoclopramide, were studied in seven normotensive controls and 12 patients with essential hypertension. Both groups had similar basal supine plasma renin activity and aldosterone levels. Aldosterone levels of the hypertensive patients were greater than those of the controls 10 min after assuming an upright posture but indistinguishable at 120 min. Metoclopramide induced a peak fourfold increase above basal aldosterone levels in the hypertensive group as compared to a peak twofold increase observed in the normotensive controls. Mean 120-min integrated aldosterone response area for the hypertensives (237 +/- 44 10(-10) mol min/l) was greater (P less than 0.05) than that for normotensive subjects (106 +/- 32 10(-10) mol min/l). Simultaneous cortisol, plasma renin activity, and serum potassium levels were unaffected by metoclopramide. It is concluded that dopaminergic modulation of aldosterone secretion may be altered in essential hypertension.

Adult↗
PubMed1983

Plasma corticosteroids in hyperreninemic hypoaldosteronism: evidence for diffuse impairment of the zona glomerulosa.

A subgroup of critically ill patients with selective hypoaldosteronism despite hyperreninemia has recently been defined. The mechanism underlying the subnormal response of aldosterone secretion is poorly understood. As cortisol secretion remains intact and the condition usually follows hypotensive episodes, ischemic or functional impairment restricted to the adrenal glomerulosa may be involved. To evaluate the possibility that a specific biosynthetic pathway deficiency exists in hyperreninemic hypoaldosteronism (HH), basal and ACTH-stimulated levels of aldosterone and its immediate precursors 18-hydroxycorticosterone (18-OHB) and corticosterone (B) were determined in eight HH patients, six critically ill subjects with normal aldosterone responsiveness, and nine healthy subjects. Baseline aldosterone (8.2 +/- 3.2 vs. 44.7 +/- 23.6 ng/dl) and 18-OHB (44.7 +/- 13.6 vs. 547.6 +/- 300.4 ng/dl) were lower in HH patients than in Intensive Care Unit controls (both P less than 0.01) despite similarly increased renin concentration and activity. ACTH-stimulated aldosterone and 18-OHB were significantly lower in HH patients, although the percent increase was similar to Intensive Care Unit controls. Plasma B was also lower in HH patients, though not significantly. After ACTH, B was markedly lower than both ICU controls (1764 +/- 576 vs. 6299 +/- 1266 ng/dl, P less than 0.01) and healthy controls (3261 +/- 248 ng/dl, P less than 0.01). All groups had appropriate cortisol responses demonstrating normal zona fasciculata function. Since 18-OHB arises predominantly from the zona glomerulosa, whereas B also derives in part from the zona fasciculata, the data suggest generalized impairment of the adrenal zona glomerulosa probably affecting both early and late pathway corticosteroid biosynthesis.

18-Hydroxycorticosterone↗
PubMed1982

Effects of bromocriptine on renin, aldosterone, and prolactin responses to posture and metoclopramide in idiopathic edema: possible therapeutic approach.

This study examines the effect of bromocriptine therapy (2.5 mg three times daily for 4-5 days) on orthostatic increases in weight, PRA, plasma aldosterone, and PRL in patients with idiopathic edema and in normal female controls. Additionally, PRA, aldosterone, and PRL responses to the dopamine antagonist metoclopramide were examined in both groups before and after bromocriptine. Edema patients demonstrated greater orthostatic weight gain and greater aldosterone and PRL responses to upright posture and isometric handgrip exercise. However, after bromocriptine treatment, these orthostatic responses were similar to those noted in normal controls. After metoclopramide administration, edema patients displayed normal PRA and aldosterone responses, but had exaggerated PRL responses. After bromocriptine, the PRL, but not the PRA or aldosterone, response to metoclopramide was greatly reduced. The PRL responses to metoclopramide were similar in edema patients and controls after bromocriptine treatment. These data suggest that there is decreased dopaminergic inhibition of aldosterone and PRL in response to upright posture in the idiopathic edema syndrome. Diminished orthostatic urinary excretion of sodium appears to be related to decreased dopaminergic tone in this syndrome. These abnormalities are largely corrected by tolerable doses of the dopamine agonist bromocriptine.

Adult↗