PubMed Health⌕ Search

Biomedical subjects

D R Abernethy

Publications and source records attributed to D R Abernethy.

At least 19 recordsLinked to original sources
PubMed1995

Local angiotensin-converting enzyme inhibition blunts endothelin-1-induced increase in forearm vascular resistance.

OBJECTIVE: The physiologic role of endothelin-1 is not well established; however, it may have a role in modulation of peripheral vascular tone complimentary to angiotensin II. In vitro and animal studies suggested an interrelationship between angiotensin II and endothelin-1 vasoconstriction. We hypothesized that local vascular or systemic renin-angiotensin II systems must be intact for endothelin-1-mediated vasoconstriction in humans. METHODS: To test this hypothesis, responses to brachial artery infusion of endothelin-1 alone and endothelin-1 plus local low-dose infusion of enaliprilat were studied in seven healthy male and seven healthy female volunteers. RESULTS: In these subjects, baseline forearm vascular resistance (mean +/- SEM; 24 +/- 3.5 mm Hg.ml/dl forearm vol/min) increased with a 38.2 ng/min endothelin-1 infusion (61.8 +/- 6.8 mm Hg.ml/dl forearm vol/min; p < 0.01). Forearm vascular resistance decreased when 38.2 ng/min endothelin-1 was infused concomitantly with a local 5 micrograms/min infusion of enaliprilat (45.5 +/- 5.9 mm Hg.ml/dl forearm vol/min; p < 0.01 compared with endothelin-1 alone). CONCLUSIONS: These data indicate that an endothelin-1-induced increase in forearm vascular resistance is inhibited by local forearm angiotensin-converting enzyme inhibition.

Adult↗
PubMed1995

Adenosine deaminase isoenzymes of the opossum Didelphis virginiana: initial chromatographic and kinetic studies.

Extracts of liver and spleen were used to isolate opossum adenosine deaminase isoenzymes (ADA1 and ADA2) and to determine their activities with adenosine and 2'-deoxyadenosine as substrates. Km values (microM) for adenosine and 2'-deoxyadenosine, respectively, as substrates for partially purified opossum liver adenosine deaminase isoenzymes were ADA1: 57 +/- 7 vs. 26 +/- 4 and ADA2: 285 +/- 25 vs. 580 +/- 92. In crude spleen extract, ADA2 activity was stable at 56 degrees C during 40 min of incubation. ADA1 activity declined in a linear fashion under the above conditions with an apparent T1/2 of 80 min. Sephadex G-150 column chromatography of crude spleen extract showed the apparent molecular weight of the ADA activity not inhibited by (+/-)-EHNA (i.e. ADA2) to be 170 kDa; ADA activity fully inhibited by (+/-)-EHNA (i.e. ADA1) eluted in the fractions corresponding to a molecular weight of 35 kDa.

Adenosine Deaminase↗
PubMed1994

An overview of the pharmacokinetics and pharmacodynamics of amlodipine in elderly persons with systemic hypertension.

Pharmacokinetic and pharmacodynamic data were compared between elderly and young patients with hypertension who received single intravenous doses of amlodipine, a dihydropyridine calcium antagonist, followed by oral administration of amlodipine up to 10 mg once daily for 12 weeks. After intravenous administration, elderly patients had prolonged elimination half-life values (58 +/- 11 vs 42 +/- 8 hr; p < 0.05) caused by decreased clearance (19 +/- 5 vs 7 liters/hr; p < 0.05). Systolic and diastolic blood pressures were significantly decreased from baseline throughout the 3-month treatment period in both groups. After long-term oral administration, elderly and young patients had comparable decreases in mean blood pressure at a given drug plasma concentration. The antihypertensive effect of amlodipine is well correlated with plasma concentration and, at a given concentration, is similar in both elderly and young patients.

Administration, Oral↗
PubMed1994

Verapamil decreases lymphocyte protein kinase C activity in humans.

To determine if clinically used doses of the calcium antagonist verapamil measurably alter intracellular transduction mechanisms associated with the phosphatidylinositol pathway, lymphocyte protein kinase C activity was determined in subjects in a drug-free state, after 1 week of verapamil treatment (120 mg three times daily) and after a second week of verapamil treatment (240 mg sustained-release preparation once daily). Nine healthy male volunteers were studied and in these subjects baseline protein kinase C activity (mean +/- SEM; 5.07 +/- 0.76 pmol/microgram protein/min) tended to decrease after 1 week (3.50 +/- 0.20 pmol/micrograms protein/min) and was significantly decreased after 2 weeks (3.14 +/- 0.27 pmol/micrograms protein/min; p < 0.05 from baseline) of verapamil treatment. These data indicate that verapamil, at usual clinical doses, decreases protein kinase C activity in a marker tissue, the circulating lymphocyte. If protein kinase C activity in this tissue is a surrogate for other verapamil target tissues, such as vascular smooth muscle and heart muscle, these findings may provide insight into the in vivo mechanism by which verapamil decreases protein synthesis, limits cell growth, and reverses cellular hypertrophy in these tissues.

Adult↗
PubMed1993

Angiotensin II regulates human vascular smooth muscle alpha-actin gene expression.

Angiotensin II (AII) has been shown to induce vascular smooth muscle cell (VSMC) hypertrophy and increased expression of vascular cytoskeletal proteins. We have studied basal and AII-induced expression of the chloramphenicol acetyl transferase (CAT) gene driven by three fragments of the human vascular smooth muscle (SM) alpha-actin promoter. We show basal CAT expression driven by the three fragments of the promoter when the constructs are transiently transfected into rat aortic VSMCs. AII in a concentration-dependent manner (1.0 nM to 10 microM) increased expression of the CAT gene driven by 896 bp fragment. When comparing the 896 bp fragment to fragments successively deleted at the 5' end (674 bp and 258 bp respectively), AII markedly stimulated CAT expression driven by the 896 bp fragment (257 +/- 31% over control, p < 0.01), stimulated CAT expression driven by 674 bp fragment to an apparently lesser degree (189 +/- 20% over control, p < 0.01), and tended to stimulate CAT expression driven by the 258 bp fragment, though not significantly greater than baseline (157 +/- 28% of control). These data suggest that AII exerts transcriptional regulation of human SM alpha-actin gene through activation of cis-acting element(s) in an upstream area localized between positions -258 and -896 of the SM alpha-actin promoter. Such findings help establish the role of AII in enhancement of expression of components of the contractile apparatus.

Actins↗
PubMed1993

Antipyrine kinetics in patients with primary biliary cirrhosis.

Fourteen antimitochrodrial antibody-positive patients (13 women, 1 man) with biopsy-proven primary biliary cirrhosis, aged 40 to 71 years (mean, 57 years) weighing 43 to 102 kg (mean, 63 kg), along with 14 age- and sex-matched healthy controls, received a single 1.0- to 1.2-g dose of intravenous antipyrine. Plasma antipyrine levels were determined during a 12- to 24-hour period. Patients' mean serum chemistry values were: albumin, 3.9 g/dL (range, 3.1-4.4) and total bilirubin, 1.9 mg/dL (range, 0.3-10.9). Seven of the fourteen patients had cirrhosis. Mean kinetic variables for antipyrine in controls and primary biliary cirrhosis patients were: Vd, .54 versus .49 L/kg; half-life, 12.0 versus 15.1 hours (P < .07); clearance, .55 versus .41 mL/min/kg (P < .04). Within the primary biliary cirrhosis group, there was no correlation between total bilirubin and clearance (r = .09), nor did clearance vary significantly among histologic categories. Clearance of antipyrine in primary biliary cirrhosis patients is reduced by an average of 25%, but the clinical prognosticators of serum bilirubin levels and histologic grade do not correlate with or predict the degree of clearance impairment.

Adult↗
PubMed1993

Effect of calcium antagonists on RNA synthesis of NIH 3T3 cells.

Calcium antagonists have been shown to induce a decrease in peripheral vascular resistance as well as a decrease in synthesis of vascular-wall matrix proteins. It has been shown previously that calcium antagonists decrease RNA synthesis of cultured, vascular, smooth-muscle cells. Here, these findings are extended to the investigation of whether calcium antagonists produce their vascular effects through their action on vascular, smooth-muscle cells only or whether they regulate fibroblast cells as well. It is demonstrated that in a concentration-dependent manner verapamil, diltiazem, and nifedipine each induced a decrease in RNA synthesis of quiescent and serum-stimulated NIH 3T3 cells, a fibroblast cell line shown to express voltage-dependent Ca2+ channels. Verapamil and nifedipine (10(-5)M) and diltiazem (10(-4)M) caused a marked decrease of basal and serum-induced increase in [3H]uridine uptake of NIH 3T3 cells. This is the first report to demonstrate that calcium antagonists have a direct effect on a fibroblast cell line leading to a decrease of RNA synthesis. Such findings suggest that calcium-antagonist vascular effects extend beyond vascular smooth muscle cells to connective tissues associated with extracellular-matrix protein production.

3T3 Cells↗
PubMed1993

Stereoselective verapamil disposition and dynamics in aging during racemic verapamil administration.

Stereoselective verapamil disposition and dynamics were evaluated after racemic verapamil administration of single i.v. doses, simulated steady-state intravenous infusions, chronic (1 week) administration of oral immediate-release tablets (120 mg three times daily) and chronic (1 week) administration of oral sustained-release tablets (240 mg once daily) to 15 young (mean +/- S.E.M. age 22 +/- 1 year) and 15 older (69 +/- 1 year) healthy male volunteers. After single i.v. doses S-verapamil clearance (young, 102 +/- 6 vs. older, 77 +/- 6 l/hr; P < .01) and R-verapamil clearance (young, 61 +/- 3 vs. older, 45 +/- 3 l/hr; P < .01) were similarly decreased. Electrocardiographic P-R prolongation using S-verapamil concentrations and an Emax model (young Emax, 69 +/- 8 vs. older, 42 +/- 6 msec; P < .05: young EC50, 15 +/- 1 vs. older, 23 +/- 3 ng/ml; P < .05) was greater in the young. Simulated steady-state i.v. S-verapamil clearance (young, 76 +/- 3 vs. older, 49 +/- 2 l/hr; P < .01) and R-verapamil clearance (young, 47 +/- 2 vs. older, 28 +/- 1 l/hr; P < .01) were similarly less in older subjects and this was unrelated to infusion rate. Qualitatively similar findings were observed during chronic oral (immediate release) treatment and chronic oral (sustained release) treatment. Plasma protein binding of S-verapamil was less in both groups (young, 8.5 +/- 0.4 and older, 8.0 +/- 0.5% unbound) than that of R-verapamil (young, 5.4 +/- 0.2 and older, 5.1 +/- 0.3% unbound) and not different between groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Verapamil blocks basal and angiotensin II-induced RNA synthesis of rat aortic vascular smooth muscle cells.

We evaluated VER effect on RNA synthesis of quiescent and angiotensin II (AII)- stimulated cultured rat aortic vascular smooth muscle cells (VSMC). In a dose-dependent manner, VER decreased [3H]uridine uptake by quiescent VSMCs (ED50 7 x 10(-6)M), an effect that was shared by other calcium antagonists, but to a variable degree. VER caused a significant effect within 3 hours and attained a maximal effect at 7 hours. In addition VER caused a 22 +/- 2% decrease in [3H]uridine uptake by VSMCs stimulated with 10% fetal bovine serum, while it completely abolished [3H]uridine uptake by VSMCs induced by AII. We conclude that VER decreases basal and inhibits AII-induced increase in mRNA synthesis of VSMCs. These data may explain in part how VER causes a decrease in vascular resistance and alters the vasoconstrictor effect of AII.

Angiotensin II↗
PubMed1992

Endothelin-I-mediated vasoconstriction: specific blockade by verapamil.

The capacity of three vasodilators that act by distinct mechanisms to reverse endothelin-I-mediated vasoconstriction was studied in 11 healthy nonsmoking male subjects (mean age +/- SEM, 26 +/- 2 years; mean weight +/- SEM, 74 +/- 2 kg) by use of brachial artery infusion and forearm strain-gauge plethysmography. Isoproterenol (cyclic adenosine monophosphate-mediated vasodilation), sodium nitroprusside (cyclic guanosine monophosphate-mediated vasodilation), and verapamil (L-type calcium channel blocker) were compared for capacity to reverse endothelin-I-mediated increase in forearm vascular resistance (FVR). Endothelin-I infusion increased FVR 1.9-fold in the control state. Isoproterenol infusion decreased FVR with or without concurrent endothelin-I infusion; however, at comparable isoproterenol infusion rates, endothelin-I increased FVR similar to the control state (for 5 ng/min isoproterenol, endothelin-I increased FVR 1.85-fold; for 12.5 ng/min isoproterenol, endothelin-I increased FVR 2.03-fold). Similarly, sodium nitroprusside infusion decreased FVR with or without concurrent endothelin-I infusion; however, at comparable sodium nitroprusside infusion rates the endothelin-I increase in FVR was similar to control (for 0.48 micrograms/min sodium nitroprusside, endothelin-I increased FVR 1.89-fold; for 0.96 micrograms/min sodium nitroprusside, endothelin-I increased FVR 2.36-fold). In contrast, verapamil infusion decreased FVR with or without endothelin-I infusion. At a verapamil infusion rate of 19.1 microns/min, endothelin-I increase in FVR was comparable to control (for 19.1 microns/min verapamil, endothelin-I increased FVR 1.36-fold, less than the 1.0-fold increase in the control state; p < 0.05). Isoproterenol and sodium nitroprusside decreased FVR during concurrent endothelin-I infusion but did not reverse the endothelin-I effect. In contrast, verapamil reversed endothelin-I--induced vasoconstriction to control FVR, suggesting a specific antagonism of endothelin-I--mediated increase in FVR.

Adult↗
PubMed1992

Pharmacokinetics and pharmacodynamics of amlodipine.

Amlodipine is a low-clearance, dihydropyridine calcium antagonist. The slow rate of elimination (elimination half-life of 40-60 h) confers several pharmacokinetic characteristics that are not seen with other calcium-antagonist drugs. It has high oral bioavailability (60-80%) and accumulates to a steady-state with once-daily administration over a period of 1-1 1/2 weeks. Fluctuation of plasma drug concentration between doses is between 20 and 25% when once-daily dosing is used. Onset of effect is gradual after oral administration which is due, in part, to an intermediate rate of drug absorption (peak plasma drug concentration occurs 6-8 h after dosing) and perhaps also to the physicochemical characteristics of the drug-cell membrane-receptor interaction. The pharmacodynamic profile of the drug in hypertensive patients is consistent with the disposition of the drug. After single doses, blood pressure decreases gradually over 4-8 h and may slowly return to baseline over 24-72 h. No change in heart rate is noted after the dose as the onset is gradual and physiological reflexes are not activated. During chronic, oral, once-daily dosing blood pressure is decreased from pretreatment baseline with little fluctuation over the 24-hour dose interval. Discontinuation of amlodipine treatment results in a slow return of blood pressure to baseline over 7-10 days, with no evidence of a 'rebound' effect. Amlodipine is a low-clearance, dihydropyridine calcium antagonist which is effective for the treatment of hypertension and angina pectoris with once-daily dosing.

Amlodipine↗
PubMed1992

Calcium antagonists block angiotensin II-mediated vasoconstriction in humans: comparison with their effect on phenylephrine-induced vasoconstriction.

Calcium antagonists are known to decrease peripheral vascular resistance in vivo in humans. The mechanism of this vascular relaxation has not been clearly elucidated. Vascular tone is maintained by several endogenous neurohumoral systems including sympathetic nervous system activity and angiotensin II. We compared and contrasted the capacity of calcium antagonist drugs to prevent angiotensin II and phenylephrine-induced alpha-1 adrenergic vasoconstriction using brachial artery infusion and measurement of forearm blood flow by strain gauge plethysmography. In a dose-dependent manner, calcium antagonists blocked angiotensin II-induced vasoconstriction. The rank order of this blockade was nifedipine greater than verapamil greater than diltiazem. Nifedipine and verapamil, but not diltiazem blocked alpha-1 adrenergic (phenylephrine-induced) vasoconstriction. At 7.64 and 19.1 micrograms/min infusion rates for nifedipine and verapamil, respectively, they abolished the angiotensin II effect; however, the phenylephrine effect was incompletely blocked. Calcium antagonist-induced vascular relaxation in vivo in humans is in part explained by their capacity to block angiotensin II-mediated vasoconstriction. In addition, two calcium antagonists (nifedipine and verapamil) may inhibit alpha-1 adrenergic vasoconstriction.

Adult↗
PubMed1991

Structure-activity relationship of ligands of human plasma adenosine deaminase2.

Diethylaminoethyl-cellulose chromatography was used to separate the two isoenzymes of adenosine deaminase (EC3.5.4.4), adenosine deaminase1 (ADA1) and adenosine deaminase2 (ADA2), in human plasma. One hundred and fifteen purine base, nucleoside, and nucleotide analogs were tested as inhibitors of this partially purified preparation of ADA2. Coformycin and 2'-deoxycoformycin were by far the most potent inhibitors of this isoenzyme (apparent Ki values 20 and 19 nM, respectively). ADA2 was also inhibited by nebularine (apparent Ki 1.5 mM) but was resistant to the potent ADA1 inhibitor (+)-erythro-9(2-S-hydroxy-3-R-nonyl)adenine. alpha-D-Adenosine also inhibited ADA2, as did several halogenated purine and adenine base analogs. Structural requirements for the binding of purine analogs to ADA2 are presented which provide a general basis for the design of specific inhibitors of ADA2. Such inhibitors may be useful in studies designed to provide an understanding of the physiological role of ADA2 both in the normal state and in diseases such as human immunodeficiency virus-1 infection where levels in plasma are increased markedly.

Adenosine Deaminase↗
PubMed1991

Plasma adenosine deaminase2 is a marker for human immunodeficiency virus-1 seroconversion.

Plasma adenosine deaminase2 (ADA2) has recently been proposed to be a marker for human immunodeficiency virus-1 (HIV) infection. We measured ADA2 levels in plasma from two groups of white homosexual males at 6-month intervals for a total of 2.5 years. One group consisted of 6 subjects who seroconverted for HIV, and the other consisted of 8 HIV seropositive patients who progressed from asymptomatic (CDC Groups II/III) to symptomatic (CDC Group IV) disease. Seroconversion was associated with a significant increase in plasma ADA2 which persisted throughout follow-up of 1.5 years. However, disease progression in HIV seropositive patients was not associated with any significant change in plasma ADA2. In conclusion, ADA2 may represent a unique marker for HIV seroconversion which does not change with later progression to symptomatic disease.

Adenosine Deaminase↗
PubMed1991

Plasma adenosine deaminase2: a marker for human immunodeficiency virus infection.

Plasma concentrations of the two isoenzymes of adenosine deaminase (ADA, E.C. 3.5.4.4), adenosine deaminase1 (ADA1) and adenosine deaminase2 (ADA2), were measured in a cohort of ambulatory patients infected with the human immunodeficiency virus (HIV) and controls. A sensitive isoenzyme-specific radioisotopic assay system was developed for these studies. Among 22 HIV-infected patients, plasma ADA2 was significantly elevated as compared with 16 control subjects (p less than 0.01) and 6 uninfected subjects having a risk factor for HIV infection (p less than 0.01). Plasma ADA2 was not associated with the stage of disease as defined by clinical status (p greater than 0.05) or helper (CD4) lymphocyte count (p greater than 0.05). Available evidence suggests that elevated plasma ADA2 could be a useful surrogate marker for HIV infection that occurs early in the disease process.

Adenosine Deaminase↗
PubMed1991

Selective inhibition of warfarin metabolism by diltiazem in humans.

Healthy men were administered i.v. racemic warfarin, S-warfarin or R-warfarin on two occasions, once in the drug-free state and once during concomitant administration of oral diltiazem 120 mg three times daily. Blood samples for determination of plasma warfarin and diltiazem concentrations, the prothrombin time and complete urine collections were obtained for determination of urinary excretion of dehydrowarfarin, 4'-hydroxywarfarin, 6-hydroxywarfarin, 7-hydroxywarfarin, 8-hydroxywarfarin and unchanged parent drug for 216 h after each dose. Concurrent diltiazem administration decreased total racemic warfarin clearance (+/- S.D.) [3.60 +/- 0.99 (control) versus 3.19 +/- 0.86 (diltiazem) ml/min; P less than .05]. Disposition of the more potent anticoagulant S-warfarin was not altered by diltiazem treatment. In contrast total clearance of R-warfarin was decreased [3.47 +/- 1.10 (control) versus 2.77 +/- 0.92 ml/min; P less than .05]. No change in the area under the prothrombin time versus time after warfarin administration curve was associated with diltiazem treatment for any warfarin trial. Inhibition of R-warfarin by diltiazem was regioselective for metabolites as determined by fractional clearance of urinary metabolites. R-6-hydroxywarfarin clearance (+/- S.E.) [29.5 +/- 7.2 (control) versus 15.7 +/- 2.8 ml/h; P less than 0.05] and R-8-hydroxywarfarin clearance [21.1 +/- 3.6 (control) versus 11.2 +/- 2.0 ml/h; P less than .05] were selectively decreased with no significant change in the urinary clearance of R-dehydro, R-4-hydroxy and R-7-hydroxywarfarin. Urinary clearance of unchanged R-warfarin was also decreased during diltiazem administration. Diltiazem inhibits warfarin disposition in humans in a stereospecific and regiospecific manner.

Adult↗