Search PubMed⌕ Search

Biomedical subjects

C M Harvey

Publications and source records attributed to C M Harvey.

8 recordsLinked to original sources
PubMed1991

Cation and harmaline interactions with Na(+)-independent dibasic amino acid transport system y+ in human erythrocytes and in erythrocytes from a primitive vertebrate the pacific hagfish (Eptatretus stouti).

Transport systems y+, asc and ASC exhibit dual interactions with dibasic and neutral amino acids. For conventional Na(+)-dependent neutral amino acid system ASC, side chain amino and guanido groups bind to the Na+ site on the transporter. The topographically equivalent recognition site on related system asc binds harmaline (a Na(+)-site inhibitor) with the same affinity as asc (apparent Ki range 1-4 mM), but exhibits no detectable affinity for Ha. Although also classified as Na(+)-independent, dibasic amino acid transport system y+ accepts neutral amino acids when Na+ or another acceptable cation is also present. This latter observation implies that the y+ translocation site binds Na+ and suggests possible functional and structural similarities with ASC/asc. In the present series of experiments with human erythrocytes, system y(+)-mediated lysine uptake (5 microM, 20 degrees C) was found to be 3-fold higher in isotonic sucrose medium than in normal 150 mM NaCl medium. This difference was not a secondary consequence of changes in membrane potential, but resulted from Na+ functioning as a competitive inhibitor of transport. Apparent Km and Vmax values for lysine transport at 20 degrees C were 15.2 microM and 183 mumol/l cells per h, respectively, in sucrose medium and 59.4 microM and 228 mumol/l cells per h in Na+ medium. Similar results were obtained with y+ in erythrocytes of a primitive vertebrate, the Pacific hagfish (Eptatretus stouti), indicating that Na(+)-inhibition is a general property of this class of amino acid transporter. At a permeant concentration of 5 microM, the IC50 value for Na(+)-inhibition of lysine uptake by human erythrocytes was 27 mM. Other inorganic and organic cations, including K+ and guanidinium+, also inhibited transport. In parallel with its actions on ASC/asc harmaline competitively inhibited lysine uptake by human cells in sucrose medium. As predicted from mutually competitive binding to the y+ translocation site, the presence of 150 mM Na+ increased the harmaline inhibition constant (Ki) from 0.23 mM in sucrose medium to 0.75 mM in NaCl medium. We interpret these observations as further evidence that y+, asc and ASC represent a family of closely related transporters with a common evolutionary origin.

Animals↗
PubMed1991

Heart failure augments the cardiovascular and renal effects of neutral endopeptidase inhibition in rats.

We compared the cardiovascular and renal actions of the neutral endopeptidase (NEP) inhibitor, SQ 28,603, in normal rats and in rats with healed myocardial infarcts. The infarcted rats were studied in the conscious state 8 weeks after ligation of the left main coronary artery and 4 h after placement of cardiovascular and renal catheters. Infarct size was 39 +/- 1.2% of left ventricle circumference; right ventricle and lung weight to body weight ratios were twice those of normal rats. These postmortem values were shown to be associated with elevated left ventricular end diastolic pressure and high plasma atrial natriuretic peptide (ANP) concentration in separate groups of rats. SQ 28,603 at 100 mumol/kg intravenously (i.v.) caused urine volume and sodium excretion to increase by 79 +/- 11 microliters/min and 8.2 +/- 1.4 microEq/min, respectively, 20 min after injection in infarcted rats; these changes were significantly greater than those in normal rats (12 +/- 5 microliters/min and 1.6 microEq/min, respectively). Thoracic venous pressure decreased by 1.9 +/- 0.4 mm Hg 80 min after SQ 28,603 in infarcted rats and by only 0.1 +/- 0.1 mm Hg in normal rats (p less than 0.05 vs. infarcted rats). SQ 28,603 had no effects on mean arterial pressure (MAP), cardiac output (CO), or glomerular filtration rate (GFR). The observation that NEP inhibition has more pronounced effects in animals with high ambient ANP level than in those with normal ANP is consistent with previous studies in a variety of animal models and supports the concept that NEP inhibition potentiates endogenous ANP.

Alanine↗
PubMed1989

Increased lysine transport capacity in erythrocytes from patients with chronic renal failure.

1. The initial rate of L-lysine influx into erythrocytes from 13 patients with chronic renal failure has been measured using 14C-labelled lysine. Ten patients were on maintenance haemodialysis and three had never been dialysed. The results are compared with data obtained from 12 normal individuals. 2. The rate of lysine influx into washed cells from buffered saline containing 0.02-0.5 mmol of L-lysine/l has been calculated. The results can be fitted with a model in which influx has a single saturable component obeying Michaelis-Menten kinetics, and a linear non-saturable component. 3. In uraemic erythrocytes the saturable component had a mean Vmax. of 0.762 mmol h-1 litre-1 of cells (n = 13, SEM 0.072) and a mean Km of 68.2 mumol/l (SEM 5.7). These values in normal erythrocytes were 0.566 mmol h-1 litre-1 of cells (n = 12, SEM 0.033) and 70.5 mumol/l (SEM 4.1), respectively. The mean apparent diffusion constant (KD) for the linear component of influx was 0.224 h-1 (SEM 0.039) in uraemic cells and 0.178 h-1 (SEM 0.028) in normals. 4. The 35% increase in mean Vmax seen in uraemic erythrocytes was statistically significant (P = 0.02). A similar increase in Vmax. in uraemic cells compared with controls was seen in erythrocytes which were studied in zero-trans conditions after depletion of intracellular amino acids. The mean values of Km and KD were not significantly different in uraemia. The origins of this increased membrane transport capacity for lysine in uraemia are discussed.

Adult↗
PubMed1989

Differentiation of angiotensin-converting enzyme (ACE) inhibitors by their selective inhibition of ACE in physiologically important target organs.

Seven ACE inhibitors were studied for possible differences in distribution to aorta, brain, heart, lung, and kidney after administration of single oral doses to spontaneously hypertensive rats (SHR). Doses, normalized for differences in inhibitory potency and molecular weight, were expected to deliver equivalent levels of ACE-inhibitory activity to the circulation, and this was confirmed by preliminary dose-response studies. The relative potencies of the active moieties of the seven drugs and the normalized oral doses used were: SQ 29,852 (1.0), 100 mg/kg; captopril (3.5), 30 mg/kg; enalapril (12), 20 mg/kg; fosinopril (13), 25 mg/kg; zofenopril (20), 10 mg/kg; lisinopril (24), 10 mg/kg; and ramipril (51), 5 mg/kg. In these ex vivo studies, ACE activities were determined fluorometrically in SHR sera and in uncentrifuged homogenates of the solid tissues at various times after oral dosing with the ACE inhibitors. As expected, the normalized oral doses of the seven inhibitors had equivalent effects on serum ACE. In lung, where ACE has a vascular endothelial localization, and in aorta, where ACE inhibition correlates with antihypertensive action, ramipril, lisinopril, and zofenopril were distinguished by the magnitude and duration (three to four days) of their effects. In the brain, where ACE may affect central regulation of blood pressure and participate in the degradation of certain neuropeptides, ramipril and enalapril had no effect; captopril and zofenopril had modest, short-lasting effects, and fosinopril, lisinopril, and SQ 29,852 had delayed but long-lasting inhibitory actions. In the kidney, where ACE inhibition may have positive or negative effects on renal function, ramipril and fosinopril could be distinguished by their weak actions, perhaps associated with biliary routes of excretion. In the heart, where ACE inhibitors may prevent ischemic damage to the myocardium, single oral doses of captopril, fosinopril, and particularly zofenopril produced striking and long-lasting inhibition, whereas equivalent doses of ramipril and enalapril produced barely detectable inhibition.

Administration, Oral↗
PubMed1989

Comparisons in vitro, ex vivo, and in vivo of the actions of seven structurally diverse inhibitors of angiotensin converting enzyme (ACE).

1. Seven drugs (captopril, zofenopril, enalapril, ramipril, lisinopril, fosinopril, and SQ 29,852) were compared in vitro in homogenates of aorta, brain, heart, lung, and kidney and in sera of spontaneously hypertensive rats (SHR) both with respect to potencies of their active moieties as inhibitors of angiotensin-converting enzyme (ACE), and, where applicable, rates of hydrolysis of their prodrug ester functions. 2. In ex vivo dose-response and time-course studies, the inhibitory effects of the seven drugs on tissue ACEs and their relative distributions to SHR tissues were compared following oral administration. 3. The relative potencies of the inhibitory moieties of the drugs (in parentheses) and the normalized 'equiactive' oral doses employed for time-course studies were: SQ 29,852 (1.0), 100 mg kg-1; captopril (3.5), 30 mg kg-1; enalapril (12), 20 mg kg-1; fosinopril (13), 25 mg kg-1; zofenopril (20), 10 mg kg-1; lisinopril (24), 10 mg kg-1; and ramipril (51), 5 mg kg-1. 4. Following oral administration of the drugs to SHR, the degree and duration of ACE inhibition in aorta and lung correlated with the antihypertensive actions, with ramipril, lisinopril, and zofenopril producing effects of the greatest magnitude and duration. 5. Ramipril and enalapril did not inhibit brain ACE ex vivo; captopril and zofenopril had modest but short-lasting effects; and fosinopril, lisinopril, and SQ 29,852 had long-lasting inhibitory actions, which, with the latter two, were delayed in onset. 6. All of the drugs produced significant inhibition of kidney ACE, with ramipril and fosinopril having somewhat weaker effects, perhaps due to biliary routes of excretion. 7. Captopril, fosinopril, and particularly zofenopril inhibited cardiac ACE ex vivo with degrees and durations that were marked compared with those of the other drugs; preliminary studies with isolated hearts suggest a possible relationship between inhibition of cardiac ACE and preservation of cardiac function subsequent to ischaemia.

Administration, Oral↗
PubMed1988

Biology of a novel class of potent long-acting angiotensin converting enzyme inhibitors: the acyl lysinamido phosphonates.

The acyl lysinamido phosphonates represent a novel class of angiotensin I converting enzyme (ACE) inhibitors. Representatives of this class produce 50% inhibition of purified rabbit lung ACE at concentrations less than 8 nmol/l. After intravenous and oral administration to normotensive rats the phosphonates inhibited an angiotensin I pressor response by 50% at doses less than or equal to enalapril (oral studies) or its free acid, MK-422 (intravenous studies); however, the duration of effect was much longer after the phosphonates. In conscious cynomolgus monkeys, representatives of the phosphonate class showed greater inhibition of an angiotensin I pressor response and for a much longer period of time than enalapril, fosinopril and lisinopril. Similarly, in sodium-depleted monkeys the blood pressure lowering effects of enalapril, lisinopril and fosinopril were of short duration compared with those of the phosphonates. It is concluded that the acyl lysinamido phosphonates represent a potent and long-acting class of ACE inhibitors in vitro and in vivo.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1988

Developing comprehensive smoking control programs in schools.

During the school years, students encounter peer influences and role models who encourage smoking initiation. To counteract these influences, schools can provide comprehensive programs that include smoking prevention and cessation education and a supportive nonsmoking environment. In the past several years, programs and information have become available to help schools establish curricula to address smoking and to create nonsmoking environments. In addition, state and local governments have acted to legally restrict smoking in schools or to require smoking content in curricula. Efforts can be categorized into three avenues of intervention: student education, school and school system policy, and governmental regulation. Resources are suggested for each category to assist in developing a comprehensive intervention to foster nonsmoking by children and adolescents in the school setting.

Adolescent↗