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Biomedical subjects

C M Stein

Publications and source records attributed to C M Stein.

At least 19 recordsLinked to original sources
PubMed2006

Cardiovascular risk scores and the presence of subclinical coronary artery atherosclerosis in women with systemic lupus erythematosus.

The Framingham risk score is widely used to identify patients at increased cardiovascular risk, and women with systemic lupus erythematosus (SLE) have a marked increased prevalence of cardiovascular events. Thus, we examined the hypothesis that cardiovascular risk scores would identify women with SLE who had asymptomatic coronary atherosclerosis. Ninety-three women with SLE and 65 control subjects were studied. The Framingham score and a score for younger populations developed from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study were compared in both groups. Coronary atherosclerosis was ascertained by electron beam computed tomography. There were no significant differences in the median (interquartile range) Framingham [5 (2-10) compared to 7 (0-10), P = 0.88] and PDAY [15 (14-18) compared to 16 (13-18), P = 0.99] scores in patients with SLE and controls, respectively. Coronary atherosclerosis was associated with higher Framingham [12 (3-15) compared to 4 (1-8), P = 0.008] and PDAY [17 (15-19 compared to 15 (12-18), P = 0.03)] scores in patients with SLE; however, 99% of patients were classified as low-risk with a 10-year predicted risk of 1% (<1-3%). Our data indicate that cardiovascular risk scores are not adequate for risk stratification in women with SLE. Measurement of coronary calcification may add information to identify asymptomatic women with lupus who might benefit from aggressive preventive measures.

Adult↗
PubMed2003

A common beta1-adrenergic receptor polymorphism (Arg389Gly) affects blood pressure response to beta-blockade.

BACKGROUND: A common polymorphism of the beta(1)-adrenergic receptor Arg389Gly markedly affects function in vitro, but little is known about its in vivo significance. METHODS AND RESULTS: Resting and exercise hemodynamic responses were measured in subjects homozygous for Arg389 (n = 21) or Gly389 (n = 13) alleles before and 3 hours after administration of a beta-blocker, atenolol. Demographic characteristics and atenolol concentrations were similar in the two genotypic groups. Genotype had a marked effect on resting hemodynamic responses to atenolol, with Arg389-homozygous subjects having a larger decrease in resting systolic blood pressure (8.7 +/- 1.3 mm Hg versus 0.2 +/- 1.7 mm Hg, P < .001) and mean arterial blood pressure (7.2 +/- 1.0 mm Hg versus 2.0 +/- 1.7 mm Hg, P = .009). Attenuation of exercise-induced hemodynamic responses by atenolol was not affected by genotype. CONCLUSIONS: There is reduced sensitivity of Gly389 homozygotes to a beta-adrenergic receptor antagonist, and this polymorphism may be an important determinant of variability in response to beta-blockade.

Adrenergic beta-Antagonists↗
PubMed2001

The effect of common polymorphisms of the beta2-adrenergic receptor on agonist-mediated vascular desensitization.

BACKGROUND: With continuous exposure to beta2-adrenergic agonists, vascular tissue becomes desensitized to agonist-mediated vasodilatation. We studied the effects of two common polymorphisms of the beta2-adrenergic receptor, one at codon 16 and one at codon 27, on agonist-mediated vasodilatation and desensitization in the vascular bed. METHODS: We studied 26 healthy subjects who were selected to represent three genotypes: 7 were homozygous for the alleles encoding Arg16 and Gln27, 8 were homozygous for the alleles encoding Gly16 and Gln27, and 11 were homozygous for the alleles encoding Gly16 and Glu27. Vascular responses were assessed by measuring changes in the diameter of a dorsal hand vein. A dose-response curve of the effect of the beta2-adrenergic-receptor agonist isoproterenol was constructed (dose range, 4 to 480 ng per minute). Desensitization was then induced by a 2-hour continuous infusion of isoproterenol, and venodilatation was measured 30, 60, 90, and 120 minutes after the start of the infusion. RESULTS: Subjects who were homozygous for Arg16 had almost complete desensitization; venodilatation in response to isoproterenol in this group decreased from a mean (+/-SE) of 44+/-11 percent to 8+/-4 percent (P=0.006). In contrast, subjects who were homozygous for Gly16 did not have significant desensitization, irrespective of the amino acid encoded by codon 27. Subjects who were homozygous for Glu27 had higher maximal venodilatation in response to isoproterenol than those who were homozygous for Gln27 (86+/-13 percent vs. 54+/-8 percent, P=0.03). CONCLUSIONS: The Arg16 polymorphism of the beta2-adrenergic receptor is associated with enhanced agonist-mediated desensitization in the vasculature, and the Glu27 polymorphism is associated with increased agonist-mediated responsiveness. Therefore, polymorphisms of the beta2-adrenergic receptor are potentially important determinants of the vascular response to stress.

Adrenergic alpha-Agonists↗
PubMed2001

Cyclosporine pharmacokinetics and pharmacodynamics in African American and white subjects.

BACKGROUND: Renal allograft survival is lower in African American patients compared with white patients. Interethnic differences in cyclosporine (INN, ciclosporin) pharmacokinetics in renal transplant recipients have been described but have not been well characterized. Pharmacodynamic responses to cyclosporine have not been compared among ethnic groups. METHODS: Healthy men were studied after 5 days on a controlled diet. Cyclosporine concentrations were determined in whole blood drawn at intervals over 24 hours after administration of a microemulsion cyclosporine formulation (4 mg/kg; 9 African American subjects and 9 white subjects) and after a standard cyclosporine formulation (4 mg/kg; 10 African American subjects and 10 white subjects). Inhibition of phytohemagglutinin-P-stimulated interleukin-2 production in whole blood drawn 4 hours after cyclosporine was used as a pharmacodynamic measure to compare the effect of cyclosporine in African American and white subjects. RESULTS: The microemulsion cyclosporine formulation (area under the cyclosporine concentration-time curve, 7432 +/- 560 ng. h/mL in African American subjects and 7043 +/- 454 ng. h/mL in white subjects) was more bioavailable than the standard formulation (area under the cyclosporine concentration-time curve, 4828 +/- 319 ng. h/mL in African American subjects and 4538 +/- 301 ng. h/mL in white subjects); this resulted in an approximately 50% greater area under the cyclosporine concentration-time curve (P < .001 in both ethnic groups). There were no differences between African American subjects and white subjects in any pharmacokinetic measurement, with both the standard and the microemulsion cyclosporine formulations. Inhibition of phytohemagglutinin-P-stimulated interleukin-2 production 4 hours after the administration of cyclosporine was similar in African American subjects (70% +/- 5% inhibition) and white subjects (64% +/- 7% inhibition; P = .5). CONCLUSIONS: The pharmacokinetics and pharmacodynamics of cyclosporine were similar in a matched group of African American and white subjects studied under controlled conditions. Environmental factors may contribute more than genetic variability to the lower bioavailability of cyclosporine reported in African American renal transplant recipients.

Administration, Oral↗
PubMed2001

The effect of sildenafil on nitric oxide-mediated vasodilation in healthy men.

BACKGROUND: Sildenafil, a treatment for erectile dysfunction, is a specific phosphodiesterase type 5 (PDE 5) inhibitor that enhances nitric oxide (NO)-mediated vasodilation in the corpus cavernosum by inhibiting cyclic guanosine monophosphate breakdown. Since PDE 5 is widely expressed in the vasculature, we examined the hypothesis that sildenafil could enhance NO-mediated vasodilation in other vascular beds and improve endothelial function. METHODS: NO-mediated responses to acetylcholine (endothelium-dependent) and nitroglycerin (endothelium-independent) were measured in healthy men in the dorsal hand vein (n = 13), after the administration of either sildenafil 50 mg or placebo. Flow-mediated dilation of the brachial artery and forearm postischemic reactive hyperemia were measured before and after sildenafil 50 mg, isosorbide dinitrate 5 mg, and placebo in a double-blind, randomized, crossover study (n = 11). RESULTS: In the hand vein, sildenafil administration increased sensitivity to local nitroglycerin. The 50% effective dose decreased approximately 4-fold from 13.5 ng/min (range, 6.9-26.6 ng/min) to 2.7 ng/min (range, 1.1-6.4 ng/min) (P =.025). Sildenafil decreased the maximum venoconstriction induced by phenylephrine from 81% +/- 3% to 74% +/- 3% (P =.025). Sildenafil did not significantly affect the maximal venodilatory response to acetylcholine (35% +/- 7% after placebo versus 32% +/- 8% after sildenafil) (P =.7). In the arterial vasculature, flow-mediated dilation before (2.4% +/- 1%) and after (2.8% +/- 1.4%) sildenafil (P =.8) and postischemic reactive hyperemia area under the curve before (1807 +/- 393 mL. min. s/100 mL) and after (1467 +/- 257 mL. min. s/100 mL) sildenafil were not different (P =.8). Resting heart rate, blood pressure, and resting brachial artery diameter were unchanged after sildenafil administration. Isosorbide dinitrate, an endothelium-independent vasodilator, caused a significant increase in resting brachial artery diameter from 0.53 +/- 0.01 cm to 0.56 +/- 0.02 cm (P =.005), without altering flow-mediated dilation. CONCLUSIONS: In healthy men sildenafil increased sensitivity to nitroglycerin, an exogenous NO donor, approximately 4-fold but did not affect endothelium-dependent, NO-mediated responses in either the hand vein or forearm vasculature. Differential vascular responses to sildenafil may localize its enhancement of endogenous NO-mediated vasodilation to vascular beds such as the corpus cavernosum.

Acetylcholine↗
PubMed2001

Educational program for physicians to reduce use of non-steroidal anti-inflammatory drugs among community-dwelling elderly persons: a randomized controlled trial.

CONTEXT: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most frequently prescribed drugs for patients 65 years of age or older, primarily for musculoskeletal symptoms of osteoarthritis. Because NSAIDs frequently cause serious gastrointestinal (GI) and other complications among elderly patients, expert guidelines for osteoarthritis recommend acetaminophen-based regimens, which are safer and often as effective as NSAIDs. OBJECTIVE: Evaluate a physician education program that communicated guidelines for management of osteoarthritis in elderly patients that emphasized avoidance of NSAIDs when possible. The program reviewed NSAID risks and benefits and recommended: re-evaluating continuous NSAID users, considering substitution of up to 4 g/d of acetaminophen for the NSAID, and trying topical agents and nonpharmacologic measures. DESIGN AND SETTING: Randomized controlled trial among community-dwelling Tennessee Medicaid enrollees. SUBJECTS: Study physicians had 5 or more patients who: were community-dwelling Medicaid enrollees 65 years of age or older; had used NSAIDs regularly for at least 180 days; had had no medical care encounters during this period suggesting an indication other than osteoarthritis; and had 1 year of baseline and follow-up data. The study thus included 209 physicians (103 intervention/106 control) with 1,566 qualifying regular NSAID users (768/798). INTERVENTIONS: Face-to-face visit to study physicians by another physician, and reminder placements in the charts of patients eligible to have NSAID use reevaluated. OUTCOMES: Change between baseline and follow-up years in: days of prescribed NSAIDs, acetaminophen, other drugs for musculoskeletal disorders, and GI drugs; outpatient visits and inpatient days of stay; SF36 measures of general health, physical function, and bodily pain (from 40% random patient sample); and over-the-counter NSAIDs (from the sample). RESULTS: Intervention-attributable reduction of 7% (95% CI, 3% to 11%) in days of prescribed NSAIDs use with concomitant increase in acetaminophen use. No significant changes in other study endpoints. The intervention effect was greater among 75 physicians with a completed study visit, whose 564 patients had a 10% (95% CI, 6% to 14%) attributable reduction in NSAID use. CONCLUSIONS: The educational program modestly reduced NSAID exposure in community-dwelling elderly patients without undesirable substitution of other medications or detectable worsening of musculoskeletal symptoms.

Acetaminophen↗
PubMed2001

Educational program for nursing home physicians and staff to reduce use of non-steroidal anti-inflammatory drugs among nursing home residents: a randomized controlled trial.

CONTENT: The risk for serious gastrointestinal complications due to nonsteroidal anti-inflammatory drugs (NSAIDs) is high in the elderly. Acetaminophen-based regimens are safer and may be as effective as NSAIDs for the treatment of osteoarthritis in many patients. OBJECTIVE: To determine the effects of an educational program on NSAID use and clinical outcomes in nursing homes. DESIGN AND SETTING: Randomized controlled study. Ten pairs of Tennessee nursing homes with > or = 8% of residents receiving NSAIDs were randomized to intervention or control. SUBJECTS: Nursing home residents (intervention n = 76 and control n = 71) aged 65 years and older taking NSAIDs regularly. INTERVENTIONS: An educational program for physicians and nursing home staff that included the risks and benefits of NSAIDs in the elderly and an algorithm that substituted acetaminophen, topical agents, and nonpharmacologic measures for the treatment of noninflammatory musculoskeletal pain. Intervention and control subjects were assessed at baseline and 3 months later. MAIN OUTCOME MEASURES: Differences in NSAID and acetaminophen use, and pain, function, and disability scores in intervention and control nursing home subjects. RESULTS: The intervention was effective resulting in markedly decreased NSAID use and increased acetaminophen use. Mean number of days of NSAID use in the 7 day periods before the baseline and 3 month assessments decreased from 7.0 to 1.9 days in intervention home subjects compared with a decrease from 7.0 to 6.2 days in control homes (P = 0.0001). Acetaminophen use in the 7 days immediately before the 3 month assessment increased by 3.1 days in intervention home subjects compared with 0.31 days in control homes (P = 0.0001). A similar proportion of subjects in control (32.5%) and intervention (35.4%) groups had worsening of their arthritis pain score (P = 0.81). CONCLUSIONS: An educational intervention effectively reduced NSAID use in nursing homes without worsening of arthritis pain.

Acetaminophen↗
PubMed2001

Hypertension in black people: study of specific genotypes and phenotypes will provide a greater understanding of interindividual and interethnic variability in blood pressure regulation than studies based on race.

Hypertension is more frequent and more severe in some Black populations. Although many studies have focused on hypertension in black people in an attempt to understand the genetic and environmental factors that regulate blood pressure, this approach has not been productive. Study of the relationship between specific phenotypes and genotypes, both within and across ethnic groups, is more likely to advance our understanding of the regulation of blood pressure than studies focused on race and blood pressure.

Black People↗
PubMed2001

Arg389Gly beta 1-adrenoceptor polymorphism varies in frequency among different ethnic groups but does not alter response in vivo.

There are marked interethnic differences in beta 1-adrenoceptor-mediated responsiveness, with sensitivity decreased in African-Americans and increased in Chinese compared with Caucasians. Therefore, the frequency of a common naturally occurring polymorphism of the human beta 1-adrenoceptor gene (Arg389Gly), which has functional importance in vitro, was determined in 194 African-Americans, 316 Caucasian-Americans, 221 Hispanic-Americans and 142 Chinese. African-Americans were found to have a significantly lower frequency of the Arg389 allele than the other three ethnic groups (all P < 0.01). In the populations studied, the order of the distribution of the Arg389 allele was: Chinese (74%) > Caucasians (72%) > Hispanics (67%) > African-Americans (58%). To determine the functional significance of the Arg389Gly beta 1-adrenoceptor polymorphism, in-vivo heart rate responses to exercise were compared in healthy subjects homozygous for the Arg (n = 9) and Gly (n = 8) alleles. Heart rate response to exercise was not affected by genotype (P = 0.4). Although ethnic differences in the frequency of the beta 1-adrenoceptor Arg389Gly polymorphism exist, the polymorphism does not appear to have functional significance in healthy subjects and therefore may not contribute to ethnic differences in response to drugs acting through the beta 1-adrenoceptor.

Alleles↗
PubMed2001

In-vivo effects of Glu298Asp endothelial nitric oxide synthase polymorphism.

Endothelial nitric oxide synthase catalyses the formation of the vasodilator nitric oxide, a major regulator of vascular tone. The Asp298 polymorphism of the nitric oxide synthase gene is associated with altered function and expression of the enzyme in vitro and myocardial infarction and coronary artery spasm in vivo. We examined the effect of the Glu298Asp polymorphism on: (1) local vascular responses to phenylephrine, acetylcholine, glyceryl trinitrate and prostaglandin E1 in the dorsal hand vein; (2) changes in forearm blood flow during mental stress, a measure of nitric oxide-mediated effect on resistance vessels; (3) excretion of urinary nitrite/nitrate as a measure of total body nitric oxide production; and (4) F2-isoprostane metabolite, a measure of oxidative stress, in healthy Glu298 (n = 12) and Asp298 (n = 13) homozygotes. There were no significant differences in acetylcholine dose responses (P = 0.29) in Glu298 and Asp298 homozygotes. Responses to glyceryl trinitrate, prostaglandin E1 and the alpha-adrenergic agonist phenylephrine did not differ by genotype. Forearm blood flow was similar at rest and increased significantly (from 7.5 ml/min/100 ml to 12.2 ml/min/100 ml; P = 0.003), but similarly (P = 0.2), during mental stress in both genotypes. Asp298 homozygotes excreted significantly less nitrate/nitrite than Glu298 homozygotes (nitrate + nitrite/creatinine ratio 0.05 +/- 0.01 vs. 0.09 +/- 0.01, respectively; P < 0.005). Urinary F2-isoprostane metabolite excretion did not differ (Glu298, 2.04 +/- 0.25 ng/mg creatinine; Asp298, 1.85 +/- 0.37 ng/mg creatinine; P = 0.7). We conclude that in healthy volunteers the Glu298Asp polymorphism affects endogenous nitric oxide production without affecting nitric oxide-mediated vascular responses. This polymorphism may only have clinical significance in the presence of endothelial dysfunction.

Adult↗
PubMed2001

Identification and functional characterization of a new CYP2C9 variant (CYP2C9*5) expressed among African Americans.

CYP2C9 is a polymorphic gene for which there are four known allelic variants; CYP2C9*1, CYP2C9*2, CYP2C9*3, and CYP2C9*4. In the present study, DNA from 140 European Americans and 120 African Americans was examined by single-strand conformational polymorphism and restriction fragment length polymorphism analyses, resulting in the identification of a new CYP2C9 variant, CYP2C9*5. This variant is derived from a C1080G transversion in exon 7 of CYP2C9 that leads to an Asp360Glu substitution in the encoded protein. The CYP2C9*5 variant was found to be expressed only in African Americans, such that approximately 3% of this population carries the CYP2C9*5 allele. The variant was expressed in, and purified from, insect cells infected with a recombinant baculovirus. Comparative kinetic studies using the purified wild-type protein CYP2C9*1; the Ile359Leu variant, CYP2C9*3; and the Asp360Glu variant, CYP2C9*5 were carried out using (S)-warfarin, diclofenac, and lauric acid as substrates. The major effect of the Asp360Glu mutation was to increase the K(m) value relative to that of CYP2C9*1 for all three substrates: 12-fold higher for (S)-warfarin 7-hydroxylation, 5-fold higher for the 4'-hydroxylation of diclofenac, and 3-fold higher for the omega-1 hydroxylation of lauric acid. V(max) values differed less than K(m) values between the CYP2C9*1 and CYP2C9*5 proteins. In vitro intrinsic clearances for CYP2C9*5, calculated as the ratio of V(max)/K(m), ranged from 8 to 18% of CYP2C9*1 values. The corresponding ratio for CYP2C9*3 was 4 to 13%. Accordingly, the in vitro data suggest that carriers of the CYP2C9*5 allele would eliminate CYP2C9 substrates at slower rates relative to persons expressing the wild-type protein.

Black or African American↗
PubMed2001

Molecular basis of ethnic differences in drug disposition and response.

Ethnicity is an important demographic variable contributing to interindividual variability in drug metabolism and response. In this rapidly expanding research area many genetic factors that account for the effects of ethnicity on pharmacokinetics, pharmacodynamics, and drug safety have been identified. This review focuses on recent developments that have improved understanding of the molecular mechanisms responsible for such interethnic differences. Genetic variations that may provide a molecular basis for ethnic differences in drug metabolizing enzymes (CYP 2C9, 2C19, 2D6, and 3A4), drug transporter (P-glycoprotein), drug receptors (adrenoceptors), and other functionally important proteins (eNOS and G proteins) are discussed. A better understanding of the molecular basis underlying ethnic differences in drug metabolism, transport, and response will contribute to improved individualization of drug therapy.

Animals↗
PubMed2000

Human beta2-adrenergic receptor polymorphisms: no association with essential hypertension in black or white Americans.

BACKGROUND AND OBJECTIVES: The most common polymorphisms of the human beta2-adrenergic receptor--Arg16-->Gly and Gln27-->Glu--are associated with alterations in beta2-adrenergic receptor responses, both in vitro and in vivo. beta2-Adrenergic receptor-mediated vascular responses are affected by ethnicity, blood pressure, and genotype. We tested the hypothesis that these two common beta2-adrenergic receptor genetic variants are associated with essential hypertension in black or white Americans. SUBJECTS AND METHODS: In a population-based case-control association study, the relationship between beta2-adrenergic receptor genotypes and hypertension was examined in 307 normotensive subjects (128 black and 179 white) and 356 hypertensive subjects (155 black and 201 white). A polymerase chain reaction-based single-stranded conformational polymorphism method with direct sequencing of the bands of interest was used to detect the two frequently occurring beta2-adrenergic receptor variants (Arg16-->Gly, Gln27-->Glu). RESULTS: No significant differences in the distributions of alleles and genotypes of the tested beta2-adrenergic receptor variants were found between normotensive and hypertensive groups from either black or white Americans (all P > .05). There was a marked interethnic difference in the frequency of the Gln27-->Glu beta2-adrenergic receptor polymorphism in both normotensive and hypertensive subjects. In normotensive white subjects, the variant Glu27 allele (35.2% versus 18.0%; P < .0001) and Glu27 homozygous genotype (14.0% versus 4.7%; P < .01) were more common than in black subjects. Similarly, in hypertensive white subjects, the variant Glu27 allele (35.8% versus 18.4%; P < .0001) and the Glu27 homozygous genotype (15.9% versus 2.6%; P < .0001) were more common than in black subjects. CONCLUSIONS: These data suggest that although there are marked ethnic differences in their distribution, the common genetic polymorphisms of the human beta2-adrenergic receptor gene do not cosegregate with the presence of hypertension in either black or white Americans.

Adult↗
PubMed2000

CYP3A activity in African American and European American men: population differences and functional effect of the CYP3A4*1B5'-promoter region polymorphism.

OBJECTIVE: Cytochrome P4503A (CYP3A) activity exhibits considerable interindividual variability. Possible differences in CYP3A activity were investigated in European American and African American men with the use of midazolam as an in vivo probe. METHODS: Midazolam was simultaneously administered intravenously (1 mg, [15N3]-labeled) and orally (2 mg, unlabeled in capsule form) to 15 young healthy European American men and a similar group of men of African American descent. Plasma concentration-time curves were measured. The subjects were subsequently genotyped with respect to the CYP3A4*B1 polymorphism (A-290G) in the 5'-promoter (nifedipine-specific element) region. RESULTS: The oral bioavailability of midazolam was about equally determined by intestinal and hepatic extraction with CYP3A activity at the former site exhibiting greater variability. Oral bioavailability was related to intestinal metabolism (r = 0.98), whereas hepatic CYP3A activity contributed little to the interindividual variability (r = 0.03). A lower systemic clearance (265+/-54 versus 310+/-56 mL/min; P = .04), but not oral clearance, was observed in African Americans. With one exception, the African Americans possessed a variant CYP3A4*1B allele (4 heterozygotes A/G and 10 homozygote G/G), whereas all of the European Americans were wild-type homozygotes (A/A). Hepatic CYP3A activity and the systemic clearance of midazolam were about 30% lower in G/G homozygotes than in A/A homozygotes (252+/-53 versus 310+/-54 mL/min; P = .02), and a gene-dose effect was present (P = .01). There was no genotype/phenotype relationship with respect to the oral clearance of midazolam. CONCLUSION: Comparison of CYP3A activity between populations is complicated by frequency distribution differences in the regulatory CYP3A4*1B polymorphism and lower hepatic CYP3A activity associated with the variant allele. However, this reduction is modest; therefore no major and clinically important difference in CYP3A activity is present between Americans of African or European descent.

Administration, Oral↗
PubMed2000

Increased vascular adrenergic vasoconstriction and decreased vasodilation in blacks. Additive mechanisms leading to enhanced vascular reactivity.

Blood pressure reactivity is enhanced in young black subjects through mechanisms that are poorly understood. We compared alpha-adrenergic-mediated vasoconstrictor and ss-adrenergic vasodilator sensitivity and their relation to sympathetic activity in blacks and whites. Ten healthy black (age, 29.9+/-2.4 years) and 10 white (age, 28.3+/-1.9 years) men were studied. Forearm blood flow was measured with strain-gauge plethysmography after the intrabrachial artery administration of phenylephrine (1.25 to 20 microgram/min) and isoproterenol (60 and 400 ng/min) after application of lower-body negative pressure and after a cold pressor test. Forearm and systemic norepinephrine spillover were measured with a radioisotope dilution technique. alpha-Adrenergic vasoconstriction was markedly increased (ANOVA P=0.008) and ss-adrenergic vasodilation decreased (ANOVA P=0.02) in blacks. Phenylephrine (10 microgram/min) decreased forearm blood flow by 58.0+/-2.5% in blacks but only by 26.6+/-6.0% in whites (P<0.001). Vasoconstrictor response to endogenous norepinephrine, stimulated by a cold pressor test, resulted in a higher forearm vascular resistance in blacks than in whites (107.3+/-13 versus 64.8+/-13 mm Hg. mL(-)(1). 100 mL(-)(1), P=0.03). There were no significant ethnic differences in basal or stimulated forearm or systemic norepinephrine spillover. Increased vasoconstrictor and decreased vasodilator responses in blacks were not correlated. Increased sympathetically mediated vascular tone caused by enhanced vasoconstriction and attenuated vasodilation, effects that would be additive, and not increased sympathetic activity could enhance vascular reactivity and may play a role in the pathogenesis of hypertension in blacks.

Adrenergic alpha-Agonists↗
PubMed1999

Inhibition of P-glycoprotein-mediated drug transport: A unifying mechanism to explain the interaction between digoxin and quinidine [seecomments].

BACKGROUND: Although quinidine is known to elevate plasma digoxin concentrations, the mechanism underlying this interaction is not fully understood. Digoxin is not extensively metabolized, but it is known to be transported by the drug efflux pump P-glycoprotein, which is expressed in excretory tissues (kidney, liver, intestine) and at the blood-brain barrier. Accordingly, we tested the hypothesis that inhibition of P-glycoprotein-mediated digoxin transport by quinidine contributes to the digoxin-quinidine interaction. METHODS AND RESULTS: First, we demonstrated active transcellular transport of both digoxin and quinidine in cultured cell lines that express P-glycoprotein in a polarized fashion. In addition, 5 micromol/L quinidine inhibited P-glycoprotein-mediated digoxin transport by 57%. Second, the effect of quinidine on digoxin disposition was studied in wild-type and in mdr1a(-/-) mice, in which the gene expressing the major digoxin-transporting P-glycoprotein has been disrupted. Because the in vitro data showed that quinidine itself is a P-glycoprotein substrate, quinidine doses were reduced in mdr1a(-/-) mice to produce plasma concentrations similar to those in wild-type control animals. Quinidine increased plasma digoxin concentrations by 73.0% (P=0.05) in wild-type animals, compared with 19.5% (P=NS) in mdr1a(-/-) mice. Moreover, quinidine increased digoxin brain concentrations by 73.2% (P=0.05) in wild-type animals; by contrast, quinidine did not increase digoxin brain concentrations in mdr1a(-/-) mice but rather decreased them (-30.7%, P<0.01). CONCLUSIONS: Quinidine and digoxin are both substrates for P-glycoprotein, and quinidine is a potent inhibitor of digoxin transport in vitro. The in vivo data strongly support the hypothesis that inhibition of P-glycoprotein-mediated digoxin elimination plays an important role in the increase of plasma digoxin concentration occurring with quinidine coadministration in wild-type mice and thus support a similar mechanism in humans.

ATP Binding Cassette Transporter, Subfamily B, Mem↗