PubMed Health⌕ Search

Biomedical subjects

D R Rutledge

Publications and source records attributed to D R Rutledge.

At least 19 recordsLinked to original sources
PubMed1995

Polymorphisms within the atrial natriuretic peptide gene in essential hypertension.

OBJECTIVE: To investigate polymorphisms in the atrial natriuretic peptide gene of African Americans at intron two (Hpall) and exon three (Scal). RESULTS: The allele frequency of the Hpall mutation was 25% in the hypertensive group (n =60) compared with only 3.4% in normotensive individuals (n = 44, P < 0.0001). The genotype heterozygote for the present mutation was much more common among those with hypertension (50 versus 6.8%, P < 0.0001). The groups were no different for the Scal site alone, although the two mutations were present together more often in the hypertensive group. The Hpall mutation was associated with hypertension in this typically salt-sensitive population.

Adult↗
PubMed1995

Polymorphism of the angiotensin I converting enzyme gene in essential hypertensive patients.

Insertion/deletion (I/D) polymorphism of the angiotensin I converting enzyme (ACE) gene has been associated with ischemic heart disease and hypertension. The D allele reportedly correlates with myocardial infarction and it has been suggested that it may serve as the basis of population-based risk assessment. Similarly, determining whether there is an ACE allele pattern associated with hypertension could be useful in developing screening strategies. Previous reports have not shown consistent findings in Caucasian and Japanese population groups, some having a predominance of the I allele. Although African Americans have the highest prevalence of hypertension in the world, their ACE gene polymorphism frequencies have not been clearly defined. We studied the allele and genotype frequencies in this group, consisting of 133 essential hypertensive subjects, and compared their findings with those reported from normotensive African Americans and from other racial groups. The black patients had a different allele distribution than the other populations in that the D was more common than the I allele, occurring at a rate of 59.7%. The most common genotype was DD and it was present in 42.5% of the hypertensive subjects in contrast to the ID genotype which was the most commonly reported genotype in normotensive individuals. The genotype pattern (frequencies of II, ID, DD) was significantly different (p < 0.005, 2 df) from Japanese and Caucasian (Scotland and Australia) populations. There was no common allele or genotype distribution amongst these diverse hypertensive groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Analysis of two variants of the angiotensinogen gene in essential hypertensive African-Americans.

Two mutations (T174M and M235T) in the angiotensinogen gene have been reported to be associated with hypertension. This study examines the frequency of these mutations among African-American hypertensive patients (n = 109). The allele frequency of the T174M mutation was 4.6% and the frequency of the M235T mutation was 86.7%. The genotypic frequencies agreed with the conditioned Hardy-Weinberg predictions based on allele frequencies. The homozygote wild-type genotype at the T174 site was more frequent than the mutation and occurred at a rate of 91.7%. Conversely, the homozygote for the mutation at the M235 site was more frequent and occurred at a rate of 75.2%. Mutation frequencies for T174M and M235T in this African-American population differ from those previously reported from a white hypertensive population (P = .0058 and P = .0001, respectively). In summary, the representation of the angiotensinogen allele frequencies differ among hypertensive populations.

Adult↗
PubMed1994

Simultaneous determination of verapamil and celiprolol in human plasma.

A simple and reproducible method for the simultaneous determination of the beta 1-selective adrenergic blocker, celiprolol, and the calcium antagonist, verapamil, in human plasma is described. It involves a two-step liquid-liquid extraction and separation using a C18 column with ultraviolet detection at 237 nm. Deacetyldiltiazem is used as the internal standard. Within-day and between-day coefficients of variation are less than 10%. The lower limits of detection are 4, 2, and 4 ng/mL for celiprolol, deacetyldiltiazem, and verapamil, respectively. The assay has clinical applicability.

Celiprolol↗
PubMed1994

Race and hypertension. What is clinically relevant?

Hypertension, once considered rare in Africa, occurs frequently in most Black populations outside of the continent as well as within more urban areas of Africa. The frequency of hypertension in Black citizens of the US is among the highest in the world. Pathophysiological mechanisms suggest the frequency of salt-sensitive blood pressure is more common in Black patients. More Black than White patients initially present with volume expansion. However, in Black patients there appears to be no significant relationship between plasma renin activity, plasma volume and blood pressure. The syndrome of insulin resistance has also been reported in African Americans. Future studies should address this issue, both because it relates to identifying individuals at risk for development of high blood pressure and because it has implications for initial selection of antihypertensive therapy. Hypertensive kidney disease is prevalent in Black people. Lowering the blood pressure with diuretic-based therapies has not been shown to delay or prevent the loss of kidney function in patients with this condition, suggesting that this treatment approach may not be optimal. Lifestyle modifications remain the initial therapeutic regimen. Because diuretics and beta-blockers have been shown to reduce cardiovascular morbidity and mortality in controlled clinical trials, they are preferred therapies. The Hypertension Detection and Follow-up Program showed significant reductions in morbidity and mortality in Black patients using primarily diuretic-based therapies. However, controversy persists regarding use of diuretics since some investigators believe that greater reductions in overall cardiovascular risk may be achieved in Black patients using other agents. These agents may eventually be able to exert a beneficial cardiovascular effect in addition to and independent of their blood pressure-lowering effect. Long term data documenting reduced morbidity and mortality rates with other agents are needed for all populations, particularly in Black hypertensive patients.

Africa↗
PubMed1994

Frequencies of the angiotensinogen gene and angiotensin I converting enzyme (ACE) gene polymorphisms in African Americans.

The purpose of the present study was to characterize three polymorphisms within the renin-angiotensin-aldosterone system in an African American population. A new mispairing primer polymerase chain reaction (PCR) was developed to identify two polymorphisms (T174M, M235T) in the angiotensinogen gene. A previously described PCR method was used to identify an insertion (I)/deletion (D) polymorphism in the angiotensin I converting enzyme (ACE) gene. Forty healthy, unrelated African Americans participated. The T174M mutation occurs less frequently (5.0%) than the M235T mutation (87.5%). The ACE D polymorphism occurs at a higher rate (70%) than the I. The data reveals that the two angiotensinogen mutation allele frequencies occur at similar rates regardless of the ACE gene allele. There appears to be no association between the mutations, indicating the loci are not linked.

Alleles↗
PubMed1993

High-performance liquid chromatographic determination of diltiazem and two of its metabolites in plasma using a short alkyl chain silanol deactivated column.

A simple and reproducible method for the determination of diltiazem and its two major metabolites, demethyl- and deacetyldiltiazem, is presented using a new column containing a short alkyl chain silanol deactivated support. This method involves the extraction of alkalinized plasma with a hexane-isopropanol mixture (95:5, v/v) followed by back-extraction into 5 mM sulfuric acid. Reversed-phase liquid chromatography is used with ultraviolet detection at 237 nm over a concentration range of 20-400 ng/ml for the compounds. Imipramine is used as the internal standard. Within-day and between-day coefficients of variation are less than 10%. The lower limits of detection are 4, 2 and 4 ng/ml for diltiazem, deacetyl- and demethyldiltiazem, respectively. Samples can be stored for up to thirty days with no significant degradation. The assay has clinical applicability.

Chromatography, High Pressure Liquid↗
PubMed1993

Preventing and treating hypertension: can we do better?

Although controversy exists, the most recent reports from the NHBPEP provide new and beneficial facts and recommendations relative to hypertension. During the past 20 years, important advances have been made in this field, but there are still opportunities for improvement.

Algorithms↗
PubMed1991

Interspecies differences in the effect of pH on gallopamil protein binding to albumin and alpha 1-acid glycoprotein.

There is little information about the factors which influence drug protein binding between species. We have therefore investigated the role of pH on the binding of gallopamil, a calcium channel antagonist known to exhibit pH-sensitive binding, among four species, human, baboon, bovine, and canine. We used pure protein solutions of alpha 1 acid glycoprotein (AAG) (60 mg.l-1), albumin (45 gm.l-1), and their combination and three values of pH, 7.0, 7.4, and 8.0. Gallopamil protein binding was determined over a concentration range of 2.0 x 10(-7) mol.l-1 to 2.1 x 10(-3) mol.l-1 using equilibrium dialysis. Gallopamil binding in all solutions was best described using a two binding site model in the combination solution and a one binding site model in the pure solutions. pH did not affect the number of identical binding sites. However, the influence of pH on gallopamil binding was species specific. Increasing the pH from 7.0 to 8.0 influenced binding affinity differently between species. There were directionally similar changes in unbound fraction at a gallopamil concentration of 2 x 10(-7) mol.l-1 as pH increased, although there were species differences in the degree of change. In protein solutions containing both AAG and albumin a reduction in pH from 7.4 to 7.0 resulted in species-specific increases in the unbound fraction. Increasing the pH from 7.4 to 8.0 again resulted in species-specific reductions in the unbound fraction of gallopamil. Similar changes were seen when pure AAG or albumin solutions were used, indicating species variance in both gallopamil protein binding and the effect of pH on binding.

Acid-Base Equilibrium↗
PubMed1991

Racial differences in drug response: isoproterenol effects before and after propranolol.

The aim of this study was to determine in young, healthy men the relative contribution of pharmacodynamic factors inherent between two groups known to respond differently to hypertensive therapy. Black (n = 10) and white (n = 10) men received an isoproterenol sensitivity test before and after propranolol (0.1 mg/kg, then 50 micrograms/min). There were greater increases (twofold) in systolic BP following the 1.0- and 1.5-microgram isoproterenol dose (P less than 0.05) in the black group. During propranolol there were no differences in free (1)-propranolol concentrations between the groups; however, propranolol decreased resting heart rate in the white group more than in the black group (P less than 0.05). Cardiac index decreased less in the black group compared to the white group (P less than 0.05). Following the second isoproterenol challenge, there again were greater increases in systolic BP in the black group at both the 10- and the 20-micrograms isoproterenol dose (P less than 0.05). Our study has highlighted the importance of cross-racial studies in evaluating drug effects.

Adult↗
PubMed1991

Effect of age on lymphocyte beta 2-adrenergic responsiveness.

Beta-adrenergic receptor agonists and antagonists are among the most widely used classes of agents in the US today. Heterogeneity in pharmacologic response among humans exists. This article reviews the influence of age on lymphocyte beta 2-adrenergic receptor responses. Evidence obtained in humans indicates that beta-adrenergic receptor numbers on peripheral blood cells may differ, although the direction of the change is not consistent among laboratories. Drug-induced regulation of receptors either up or down appears to be similar among age groups. The affinity of beta-adrenoceptor binding sites for isoproterenol decreases with aging. Events distal to the receptor recognition site itself exhibit age-related differences, presumably due to a decrease in the coupling of beta-adrenoceptors to adenylate cyclase. Mechanisms of decreased catecholamine responsiveness during aging remain to be defined. The precise definition of these alterations may contribute useful insights into the changes that occur with aging in response to catecholamines, other hormones, and neurotransmitters.

Adult↗
PubMed1990

Racial differences in baseline cyclic adenosine monophosphate concentrations per million T-lymphocytes and protein concentrations.

beta-Adrenergic blockers are less efficacious as monotherapy for the treatment of hypertension in blacks as compared with whites. Because beta-adrenergic stimulation and blockade differ between racial groups, biochemical differences in the beta-adrenergic pathway may exist. It is the intent of this report to show underlying similarities and differences, at least in part, in the beta-adrenergic pathway (e.g., baseline cAMP and protein concentrations) using the T-lymphocyte as the model system. A total of 20 (n = 10 black, n = 10 white) normotensive male volunteers were recruited, begun on a low-sodium diet to normalize serum catecholamines, and blood was collected for lymphocyte beta-receptor isotherm binding experiments and cAMP determination. There were no differences in Bmax, sites per cell, or kd. Basal cAMP concentrations were significantly higher in the black group (16.0 +/- 9.8 pmol/10(6) cells) compared with the white group (7.0 +/- 1.8 pmol/10(6) cells) (p less than 0.05). Protein levels from the lymphocyte suspension were also higher in the black group (1,081.0 +/- 367.7 micrograms/ml) compared with the white group (766.8 +/- 220.4 micrograms/ml) (p less than 0.05). Normalization of cAMP for protein yielded 83.2 +/- 55.4 fmol/micrograms protein in the black group and 56.6 +/- 29.8 fmol/micrograms protein in the white group (p = 0.11). Altered protein levels may be a confounding variable in studies of this type. Further work is necessary to identify the nature and significance of this protein elevation, its relationship to the adenylate cyclase system in lymphocytes, and the source of the cAMP elevation noted herein.

Adrenergic beta-Antagonists↗
PubMed1989

Rapid high-performance liquid chromatographic method for the measurement of the enantiomers of metoprolol in serum using a chiral stationary phase.

Metoprolol, a beta-adrenergic blocker, is only available as a racemic mixture for clinical use. A high-performance liquid chromatographic method for the separation of the optical isomers (enantiomers) in human serum is described utilizing a commercially available column with a cellulose tris (3,5-dimethylcarbamate) chiral stationary phase. Separation of the enantiomers is accomplished without precolumn derivatization using a mobile phase of hexane-2-propanol-diethylamine (91:8:1, v/v). The method can be successfully applied to pharmacokinetic studies in man.

Adult↗
PubMed1989

Racial differences in drug response: isoproterenol effects on heart rate in healthy males.

It was the purpose of this study to investigate racial alterations in beta-adrenoceptor response. Two groups of healthy, male volunteers gave their consent. There were eight black Americans (mean age, 26.1 +/- 2.5 years) and eight white/Caucasian Americans (mean age 24.4 +/- 1.8 years). Each subject underwent an isoproterenol sensitivity test. There was a significant (P less than 0.05) decrease in the ratio of Emax to ED50 in the white group (25.3 +/- 6.4) compared with the black group (37.1 +/- 12.4). Over the dose range of 0.1 to 1.0 micrograms there was a significant increase in response at both the 0.25- and the 0.5-microgram dose (P less than 0.05), with the black American group appearing to respond with a greater rate of rise in heart rate following the initial doses.

Adult↗
PubMed1989

Racial differences in drug response: isoproterenol effects on heart rate following intravenous metoprolol.

Healthy young black men and white men received single intravenous doses of metoprolol (0.07 mg/kg) or participated in an isoproterenol sensitivity study before and after metoprolol (0.07 mg/kg followed by 50 micrograms/min) in a randomized, crossed-over fashion. Noncompartmental pharmacokinetic parameters were calculated. The dose of isoproterenol versus change in heart rate response curves were constructed, and comparisons of dose ratio, ED50, Emax, and Ka, with the apparent association constant for metoprolol binding to beta 1-receptors, were made. There were no pharmacokinetic differences observed between the groups. The predicted Emax for the black group was 52.7 +/- 8.7 beats/min at a metoprolol concentration of 29.8 +/- 6.1 ng/ml, which was higher (p less than 0.05) than that in the white group, i.e., 43.7 +/- 7.3 beats/min at a concentration of 27.6 +/- 9.1 ng/ml. There were no differences in dose ratio, ED50, or Ka. The racial differences in beta 1-receptor responses to exogenous isoproterenol following metoprolol can simply be explained by an increase in beta 1-receptor activity in the black subjects, assuming homogeneity in cardiac beta 2-receptor responses.

Adult↗
PubMed1989

Determination of metoprolol and its alpha-hydroxide metabolite in serum by reversed-phase high-performance liquid chromatography.

A high-performance liquid chromatographic (HPLC) method for the simultaneous quantitation of metoprolol and alpha-hydroxymetoprolol concentrations in serum is developed. Analysis is performed on a C18 column using a 70:30 mixture of two solutions, A and B respectively. Solution A is 1 L of a 1% acetic acid solution with 25 mL of 0.005 M 1-heptanesulfonic acid. Solution B is 1 L of acetonitrile with 25 mL of 0.005 M 1-heptanesulfonic acid. Column effluent is monitored by fluorescence detection at an excitation wavelength of 225 nm. A 320-nm band pass filter is employed. The limit of sensitivity is approximately 2 ng/mL for both compounds. No potential sources of interference are identified. A coefficient of variation of less than 10% is observed on replicate determinations at 10 ng/mL for both compounds and at 300 and 180 ng/mL for metoprolol and alpha-hydroxymetoprolol, respectively. The method has the advantages of complete resolution of the metabolite of metoprolol, a high degree of reproducibility, adequate sensitivity, and an easily accessible internal standard.

Chromatography, High Pressure Liquid↗