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Biomedical subjects

C M Stein

Publications and source records attributed to C M Stein.

At least 37 records · Page 2Linked to original sources
PubMed1999

Genetic polymorphism of (S)-mephenytoin 4'-hydroxylation in populations of African descent.

AIMS: The frequency of CYP2C19 poor metabolizers (PMs) in populations of African descent has been reported to range from 1.0% to 35.4%. In order to determine with greater certainty the frequency of CYP2C19 PMs in such black populations we have performed a meta-analysis of the studies. METHODS: Relevant data on the frequency of both the PM phenotype of probe drugs (mephenytoin, omeprazole, and proguanil), and the distribution frequencies of CYP2C19 alleles and genotypes in black populations were summarized and reanalysed using a meta-analytical approach. RESULTS: Of nine reported studies two were excluded because of significant heterogeneity (chi2=115, P<0.0001). The combined data from the remaining seven studies showed that the frequency of the PM phenotype in 922 healthy unrelated black Africans and black Americans ranged from 1.0% to 7.5% (n=7 for combined data) with an overall frequency being 3.9% (36 of 922; 95%CI: 2.7%-5.2%). The frequency of the PM genotypes in blacks was 3.7% (36 of 966; 95%CI: 2.5%-4.9%), in agreement with the frequency of the PM phenotype. In the extensive metabolizers (EMs) 29% (271 of 930) were heterozygotes (wt/m ). The observed frequencies of the three Mendelian genotypes were 0.68 for wt/wt, 0.28 for wt/m, and 0.04 for m/m. The allelic distribution was appropriate at 82.3% (95%CI: 80.5%-83.9%) for CYP2C19*1, 17.3% (95%CI:15.7%-19.0%) for CYP2C19*2 (m1 ), and 0.4% (95%CI: 0.1%-0.7%) for CYP2C19*3 (m2 ) in these populations. CONCLUSIONS: We conclude that subjects of African ancestry have a low frequency of the CYP2C19 PM phenotype and genotype; that the defective CYP2C19 alleles are uncommon, and that a small proportion of heterozygotes exists in the EM subpopulation.

Africa↗
PubMed1999

Bradykinin stimulates tissue plasminogen activator release in human vasculature.

Bradykinin stimulates tissue plasminogen activator (tPA) release in isolated perfused animal tissues. The present study tests the hypothesis that bradykinin increases tPA release in humans through local effects on the vasculature. Graded doses of sodium nitroprusside (0.8 to 3.2 micrograms/min), acetylcholine (ACh) (7.5 to 60 micrograms/min), and bradykinin (100 to 400 ng/min) were administered intra-arterially in random order in 10 salt-depleted (10 mmol/d of Na) normotensive volunteers. None of the drugs altered mean arterial pressure or heart rate. Forearm blood flow (FBF) was measured by strain-gauge plethysmography. All 3 drugs caused a dose-dependent increase in FBF, although ACh was less potent than either nitroprusside or bradykinin (maximum FBF 7.5+/-2.4 versus 10.0+/-1.5 and 11.9+/-2.1 mL. 100 mL-1. min-1, respectively). Bradykinin caused a significant, dose-dependent increase in venous (effect of dose F=9. 9, P=0.028 by ANOVA), but not arterial (F=0.154, P=0.92) tPA antigen in the infused arm. Thus, net tPA release increased significantly in response to bradykinin (50.6+/-13.3 at the highest dose versus 0. 9+/-0.4 ng. 100 mL-1. min -1 at baseline, P=0.014). In contrast, bradykinin did not affect plasminogen activator inhibitor antigen. Neither nitroprusside nor ACh altered plasma levels of tPA or plasminogen activator inhibitor antigen. Bradykinin increased tPA release across the forearm in the absence of systemic effects. This effect could not be attributed to changes in blood flow because doses of equivalent potency of the vasodilator nitroprusside did not increase tPA. These data demonstrate that bradykinin stimulates tPA release in the human vasculature.

Acetylcholine↗
PubMed1999

Inhibition of stimulated interleukin-2 production in whole blood: a practical measure of cyclosporine effect.

BACKGROUND: Prediction of cyclosporine (CSA) efficacy and toxicity in individual patients is difficult. There is no practical, biologically relevant, pharmacodynamic measure of CSA effect. A major effect of CSA is to decrease interleukin-2 (IL-2) production; however, measurement of this effect in isolated lymphocytes as a marker of response to CSA has been problematic. METHODS: CSA inhibition of phytohemagglutinin-P (PHA)-stimulated IL-2 production, measured by ELISA, was studied ex vivo in whole blood drawn before, and after subjects received 4 mg/kg oral CSA. RESULTS: Four hours after CSA was administered, the mean (+/- SD) CSA concentration was 702 +/- 196 microg/L and PHA-stimulated IL-2 production decreased by 68.7% +/- 17.2% (P <0.0001; n = 17). Twenty-four hours after CSA was administered, concentrations were low (64 +/- 24 microg/L), with no inhibition of IL-2 production. A rapid, concentration-dependent response occurred. Maximum CSA concentrations (944 +/- 187 microg/L) and maximum inhibition of IL-2 production (86.9% +/- 13.7%) occurred 90 min after subjects received CSA. In vitro, 32.5-1200 microg/L CSA also inhibited PHA-stimulated IL-2 production in whole blood in a dose-dependent fashion with a similar IC(50) (approximately 300-400 microg/L) ex vivo and in vitro. CONCLUSION: In the search for a pharmacodynamic marker to better guide immunosuppressive therapy, the relationship between this simple, biologically relevant measure of CSA effect and clinical outcome should be determined.

Biomarkers↗
PubMed1999

Allelic, genotypic and phenotypic distributions of S-mephenytoin 4'-hydroxylase (CYP2C19) in healthy Caucasian populations of European descent throughout the world.

Impaired S-mephenytoin 4'-hydroxylation is a well-described genetic polymorphism affecting drug metabolism in humans. The reported population prevalence of the CYP2C19 poor metabolizer phenotype in Caucasians of European descent has been described as ranging from 0.9% to 7.7%. To address the question of whether the difference in the frequency of poor metabolizers represents an ethnic genetic microheterogeneity in the structure and expression of the CYP2C19 gene in Caucasian individuals, we performed a pooled analysis of available studies. Combined data from the 22 homogeneous studies showed that the frequency of poor metabolizers in healthy unrelated Caucasians determined by phenotyping was 2.8% (110 of 3990; 95% confidence interval 2.3-3.3). Data obtained from eight homogeneous studies that determined the frequency of poor metabolizers by genotyping showed that the genotypic frequency of poor metabolizers was 2.1% (28 of 1356; 95% confidence interval 1.3-2.8), consistent with the poor metabolizer frequency determined by phenotyping. In the extensive metabolizers, 26% (471 of 1786; 95% confidence interval 24.4-28.4) were heterozygotes. The observed frequencies of the three Mendelian genotypes were 73% for wt/wt, 26% for wt/m, and 2.1% for m/m. Based on the overall phenotypic poor metabolizer frequency of 2.8%, the expected genotypic frequencies were 69% for wt/wt, 28% for wt/m and 2.8% for m/m, which are in good agreement to the observed values. However, in the 84 Caucasian phenotyped and genotyped poor metabolizers, approximately 10% of the putative poor metabolizer alleles (17 of 168) were unknown. This study provides a systematic overview of the population distribution of the CYP2C19 poor metabolizer phenotype and CYP2C19 alleles and genotypes in healthy Caucasians living in different geographical areas, and shows a similar polymorphic pattern in the structure and expression of the CYP2C19 gene in the worldwide Caucasian populations.

Alleles↗
PubMed1999

Alpha1A-adrenergic receptor polymorphism: association with ethnicity but not essential hypertension.

The alpha1-adrenergic receptor (alpha1-AR) mediates vasoconstriction and plays an important role in the regulation of vascular tone. Increased alpha1-AR-mediated vasoconstrictor sensitivity, increased vascular reactivity to stress, and an increased prevalence of hypertension occur in African-Americans. The human alpha1A-AR is the predominant alpha1-AR subtype in vascular smooth muscle. The potential relevance of alpha1A-AR genetic variation to ethnic differences in vascular response and to the pathogenesis of hypertension prompted us to determine the frequency distribution of a recently identified polymorphism (Arg492 to Cys) in the alpha1A-AR in normotensive and hypertensive black and white American individuals. Polymerase chain reaction-based PstI restriction fragment length polymorphisms in the human alpha1A-AR gene were determined in 231 African-American and 282 Caucasian individuals, both with and without hypertension. There were marked differences in the genotypic and allelic distributions of the Arg492 to Cys alpha1A-AR polymorphism between African-American and Caucasian individuals (Cys492/Cys492 genotype, normotensive: 7.6% versus 30.1%; hypertensive: 7.1% versus 26.2%; Cys492 allele, normotensive: 29.5% versus 53.8%; hypertensive: 28.8% versus 55.2%; blacks versus whites, P < 0.0001). The frequency of the variant Cys492 allele was similar in normotensive and hypertensive individuals, both in African-Americans (29.5% versus 28.8%) and Caucasians (53.8% versus 55.2%). There were no significant intergenotypic differences in blood pressure (all P > 0.05). The data indicate that this polymorphism is not associated with essential hypertension in black or white Americans, but that the frequency of the alpha1A-AR Arg492 allele occurs significantly more commonly in African-Americans than in Caucasians. The potential role of the Arg492 to Cys alpha1A-AR polymorphism in ethnic differences in vascular alpha1-adrenergic response requires further investigation.

Adult↗
PubMed1999

Frequency of functionally important beta-2 adrenoceptor polymorphisms varies markedly among African-American, Caucasian and Chinese individuals.

There are ethnic differences in the prevalence and severity of hypertension and asthma and in beta-2 adrenergic receptor (BAR2)-mediated vascular responses. Two common polymorphisms of the human BAR2, Arg16 to Gly and Gln27 to Glu, are associated with alterations in BAR2 response, both in vitro and in vivo. Ethnic differences in disease manifestations and responses to treatment may be explained by the altered frequency of BAR2 polymorphisms. To determine the relative frequencies of the Arg16 to Gly and Gln27 to Glu BAR2 polymorphisms in different ethnic groups we studied 415 (123 African-American, 188 Caucasian-American and 104 Chinese) healthy individuals. There was a marked interethnic difference in the frequency of the BAR2 polymorphisms among the ethnic groups. The Glu27 allele was more frequent in Caucasian-American (34.8%) than in African-American individuals (20.7%) (P = 0.0001) and much less frequent in Chinese individuals (7.2%) (P = 0.0001 versus African-American or Caucasian-American). The homozygous Glu27 genotype was more frequent in Caucasian-American (15.4%) than African-American individuals (4.9%) (P = 0.003) and was not observed in Chinese. The Gly16 allele (54.3% versus 41.3%) and homozygous genotype (35.1% versus 18.3%) were more common in Caucasian-American than Chinese individuals (P = 0.003 for both). There is a marked ethnic difference in the frequency of these two common BAR2 polymorphisms among African-American, Caucasian-American and Chinese individuals, with a markedly reduced frequency of the Glu27 polymorphism, the polymorphism associated with resistance to desensitization and increased BAR2 responses, in African-American and Chinese individuals. Such ethnic genotypic differences may explain previously observed alterations in the response to the BAR agonists in different ethnic groups.

Black or African American↗
PubMed1998

Regulation of local tissue-type plasminogen activator release by endothelium-dependent and endothelium-independent agonists in human vasculature.

OBJECTIVES: This study sought to define the local regulation of vascular tissue-type plasminogen activator (t-PA) release. BACKGROUND: The vascular endothelium, through the production of t-PA and plasminogen activator inhibitor (PAI-1), is an important regulator of fibrinolysis. Plasma t-PA levels increase in response to adrenergic stimulation; however, it is unclear whether this increase is the result of systemic reflex responses or direct effects on the vascular endothelium. METHODS: Forearm blood flow dose responses were generated to low doses of agonist infused directly into the brachial artery in 15 normotensive men (mean [+/-SE] age 28.9 +/- 2.2 years). Simultaneous arterial and venous blood samples were drawn at baseline and in response to the intraarterial administration of isoproterenol (400 ng/min), methacholine (8 microg/min) and sodium nitroprusside (SNP) (8 microg/min). PAI-1 and t-PA antigen levels were measured by enzyme-linked immunosorbent assay, and the net release across the forearm was calculated. RESULTS: Forearm plasma flow increased significantly from baseline (1.4 +/- 0.2 ml/100 ml per min) after administration of isoproterenol, methacholine and SNP (9.7 +/- 1.9, 8.7 +/- 1.9 and 6.7 +/- 1.1 ml/100 ml per min, respectively) (p < 0.001 by analysis of variance). Baseline net t-PA release (0.7 +/- 0.3 ng/100 ml per min) increased significantly after administration of isoproterenol (26.2 +/- 11.6 ng/100 ml per min, p = 0.005) and methacholine (15.3 +/- 5.5 ng/100 ml per min, p = 0.001) but not after administration of SNP (1.8 +/- 2.2 ng/100 ml per min, p = 0.84). There was no net release of PAI-1 across the vascular bed. CONCLUSIONS: Marked, rapid local t-PA release occurred in response to isoproterenol, a beta-adrenoceptor agonist, and methacholine, an endothelium-dependent nitric oxide agonist, in the human forearm. This effect was selective and independent of the effects of shear stress due to increased flow because SNP induced similar increases in forearm blood flow without affecting t-PA release. Vascular t-PA release may be a potentially valuable tool for evaluating endothelial function in diseases associated with increased risk of thrombosis.

Adult↗
PubMed1998

Angiotensin II mediates systemic rebound hypertension after cessation of prostacyclin infusion in sheep.

Prostacyclin (or epoprostenol), an arachidonic acid metabolite, is an effective treatment for patients with primary pulmonary hypertension. Interruption of chronic prostacyclin infusion can result in recurrent symptoms of dyspnea and fatigue. The etiology of this phenomenon is unknown. We hypothesized that sympathoadrenal activation could lead to increased vascular tone after abrupt termination of the infusion. To evaluate this effect, we monitored six chronically instrumented, awake sheep during and after infusion of prostacyclin. Prostacyclin decreased mean arterial pressure (MAP) by 14% and increased cardiac output by 33%. After the infusion ceased, MAP rebounded 23% above baseline, and cardiac output decreased by 28% from peak values within 10 min. We were unable to demonstrate an increase in norepinephrine levels after cessation of prostacyclin, nor did alpha-adrenergic blockade affect postinfusion hemodynamics. However, plasma renin activity increased >10-fold at peak infusion and remained elevated for up to 2 h after discontinuation of prostacyclin. Coinfusion of the angiotensin II-receptor antagonist L-158,809 resulted in complete abrogation of the postcessation rise in MAP. We conclude that renin-angiotensin system activation is primarily responsible for systemic hypertension occurring after abrupt cessation of prostacyclin infusion in sheep and that angiotensin II receptor blockade prevents this response. Our data do not support a role for sympathetic nervous system activation in the systemic pressor response after prostacyclin infusion.

Adrenergic alpha-Antagonists↗
PubMed1998

Basal and stimulated sympathetic responses after epinephrine: no evidence of augmented responses.

Delayed facilitation of norepinephrine release through the action of epinephrine (NE) at presynaptic beta-adrenoceptors has been postulated to account for the delayed hemodynamic effects of epinephrine and to be a mechanism causally related to the development of hypertension. To determine whether a short-term increase in epinephrine concentrations resulted in subsequent facilitation of sympathetic responses, 9 healthy subjects (age, 21+/-0.9 years) were studied at rest and during physiological stress on 2 occasions when they received an infusion of either saline or epinephrine (20 ng/kg per minute) in random order. Heart rate, blood pressure, forearm blood flow, epinephrine concentrations, and NE spillover were measured at rest, during mental stress (Stroop test), and during a cold pressor test. Measurements were performed before, during the 1-hour infusion of epinephrine or placebo, and 1 hour after the infusion. A radioisotope dilution method was used to measure NE spillover. Hemodynamic measurements and NE spillover were increased during the infusion of epinephrine, but 1 hour after discontinuation of epinephrine there was no significant augmentation of hemodynamic or sympathetic responses. NE spillover 1 hour after saline or epinephrine infusion was similar (0.85+/-0.2 versus 0. 87+/-0.2 microg/min; P=0.92). In addition, there was no delayed facilitation of stress-induced hemodynamic or NE responses after epinephrine. These findings do not support the hypothesis that epinephrine results in delayed facilitation of NE release.

Adult↗
PubMed1997

Determination of catecholamines in sheep plasma by high-performance liquid chromatography with electrochemical detection: comparison of deoxyepinephrine and 3,4-dihydroxybenzylamine as internal standard.

3,4-Dihydroxybenzylamine (DHBA) is commonly used as the internal standard in HPLC catecholamine assays. Sheep are frequently used in studies of cardiovascular physiology and in such studies measurement of catecholamines is important. The recovery of DHBA from sheep plasma is, however variable and poor. Therefore, we have developed a reliable and sensitive HPLC-ED method with alumina extraction for measurement of catecholamines in sheep plasma using deoxyepinephrine (epinine) as the internal standard. Separation was performed on a muBondapak C18 column (300x3.9 mm, 10 microm) with a mobile phase containing 2% acetonitrile and 98% buffer (0.05% sodium acetate-0.02% EDTA-0.013% sodium heptanesulfonate), pH 3.25. The extraction of epinine from water, human plasma, dog plasma and sheep plasma did not differ (p>0.05), but extraction of DHBA from sheep plasma was significantly impaired (p<0.0001). The R2 of regression curves (n=5) of norepinephrine (NE) (25.02 pg/ml-1.00 ng/ml) and epinephrine (E) (25.82 pg/ml-1.03 ng/ml), using epinine as internal standard were greater than 0.99. The intra- and inter-day coefficients of variation were 2.11-11.15 and 0.88-12.60% for NE and 1.12-10.91 and 2.88-12.60% for E, respectively. The detection limits for NE and E are 12 pg/ml. The technique described has the advantage that it allows the simultaneous determination of both endogenous and [3H]norepinephrine in sheep plasma using a sensitive and reproducible HPLC technique.

Animals↗
PubMed1997

Combination treatment of severe rheumatoid arthritis with cyclosporine and methotrexate for forty-eight weeks: an open-label extension study. The Methotrexate-Cyclosporine Combination Study Group.

OBJECTIVE: To determine whether the clinical benefit and favorable safety profile previously noted with the combination of cyclosporine (CSA) and methotrexate (MTX) given for 24 weeks in patients with rheumatoid arthritis (RA) would be maintained for a further 24 weeks, and whether the addition of CSA in patients who had previously been randomized to receive placebo + MTX would result in clinical benefit. METHODS: Eligible subjects from the initial study (weeks 0-24), in which the addition of placebo or CSA to MTX therapy was compared in patients with RA that was partially responsive to MTX, were enrolled. Patients who had received CSA + MTX continued this regimen for a further 24 weeks (weeks 24-48) (group 1; n = 48), and patients who had initially received placebo + MTX now received CSA + MTX for 24 weeks (weeks 24-48) (group 2; n = 44), in an open-label extension study. The primary outcome measures were the number of tender joints, number of swollen joints, physician and patient global assessments, pain, functional disability as measured by the modified Health Assessment Questionnaire, and erythrocyte sedimentation rate. RESULTS: Of the 92 patients enrolled, 80 (87%) completed the extension study. In patients in group 1, the clinically and statistically significant improvement in response outcomes previously noted at week 24, ranging from 25% to 50%, was maintained through week 48. In patients in group 2, the addition of CSA resulted in significant clinical improvement. By week 48, most outcome measures in group 2 patients were similar to those in group 1 patients. CSA treatment resulted in a small increase in serum creatinine levels, but only 1 patient was withdrawn from the study for this reason. CONCLUSION: The clinical improvement previously observed in patients treated with the CSA + MTX combination for 24 weeks was maintained for 24 subsequent weeks, without serious adverse effects, and was also observed in the patients whose treatment was switched from placebo + MTX to CSA + MTX.

Adult↗
PubMed1997

Coadministration of glyburide and minoxidil, drugs with opposing effects on potassium channels.

INTRODUCTION: Adenosine triphosphate (ATP)-sensitive potassium (K+) channels are modulated by drugs, so that they are opened by vasodilators such as minoxidil but are closed by hypoglycemic agents such as glyburide (glibenclamide). Animal studies and in vitro evidence suggests that the coadministration of drugs with opposing effects on K+ channels attenuates their pharmacodynamic effects. METHODS: To investigate whether this important pharmacodynamic interaction occurs in humans, we administered 5 mg minoxidil, 2.5 mg glyburide or both in a double-blind fashion to nine healthy subjects. Glucose and insulin responses during an intravenous glucose tolerance test (0.3 gm/kg) were measured and blood pressure was recorded for 8 hours. In an additional four subjects the effect of 5 mg glyburide on the hypotensive effect of 5 mg minoxidil was examined. RESULTS: None of the parameters of glucose metabolism differed significantly when subjects received glyburide alone, minoxidil alone, or glyburide with minoxidil. Minoxidil or minoxidil in combination with 2.5 mg glyburide resulted in a similar significant decrease in blood pressure compared with the response to glyburide alone. The hypotensive effect of minoxidil was smaller in the four subjects who received the higher dose of glyburide, but significant hypoglycemia (blood glucose concentration < 60 mg/dl) occurred in three of the four subjects. CONCLUSION: We conclude that, in healthy volunteers, the coadministration of 2.5 mg glyburide and 5 mg minoxidil does not result in attenuation of the blood pressure-lowering effect of minoxidil. The smaller hypotensive response in four subjects who received 5 mg glyburide and 5 mg minoxidil suggests the possibility of a dose-related drug interaction. Studies with strict clamping of blood glucose concentrations will be required to address this possibility.

Adult↗
PubMed1997

Vasodilation in black Americans: attenuated nitric oxide-mediated responses.

BACKGROUND: Attenuated vasodilation in response to the intra-arterial administration of the beta-adrenergic agonist isoproterenol (INN, isoprenaline), an endothelium-independent vasodilator, has previously been observed in normotensive black Americans. To determine whether this reflected a more generalized attenuation of responses to vasodilators, we compared forearm blood flow responses to the endothelium-dependent vasodilator methacholine and the endothelium-independent vasodilator sodium nitroprusside in young normotensive black men and white men. METHODS: Forearm blood flow responses to the intra-arterial administration of isoproterenol (10 to 400 ng/min), methacholine (0.25 to 8 micrograms/min), and sodium nitroprusside (0.25 to 8 micrograms/min) were measured with use of venous occlusion plethysmography in 11 normotensive black men (mean +/- SE age, 30.5 +/- 2.2 years) and nine normotensive white men (mean age, 28.0 +/- 3.2 years). RESULTS: Baseline characteristics, including baseline forearm blood flow, were similar in the black and the white subjects. Vasodilation in response to isoproterenol, sodium nitroprusside, and methacholine was significantly attenuated in black subjects, resulting respectively in a 3.7-fold, 3.6-fold, and 5.0-fold increase in forearm blood flow in black subjects and a 7.5-fold, 5.2-fold, and 6.9-fold increase in forearm blood flow in white subjects (ANOVA; isoproterenol, p < 0.0001; sodium nitroprusside, p < 0.0001; methacholine, p = 0.01). CONCLUSIONS: Our finding of attenuated nitric oxide-mediated vasodilation in response to methacholine and sodium nitroprusside in healthy black American men suggests that attenuated vasodilation in black subjects is a relatively generalized phenomenon, resulting in attenuated responses to multiple vasodilators that act through different receptor- and nonreceptor-mediated mechanisms.

Adrenergic beta-Agonists↗
PubMed1997

Lack of correlation between arterial and venous beta-adrenergic receptor sensitivity.

The regulation of vascular beta-adrenoceptor responses in humans has been studied in vivo in both arteries and veins. Because venous responses can be studied less invasively than arterial responses, they are an attractive substitute for the measurement of arterial responses, provided that venous responses are representative of responses in resistance arteries. However, although venous, particularly hand vein response, has been extensively studied, arterial and venous beta-adrenergic sensitivities, in the same individuals, have not been compared. Measures of venous and arterial beta-adrenergic sensitivities were compared in 10 healthy normotensive subjects. Forearm blood flow, after administration of increasing doses of isoproterenol into the brachial artery, was measured by strain-gauge plethysmography and was used for determination of arterial beta-adrenoceptor sensitivity, expressed as the IP500 (the dose of isoproterenol resulting in a fivefold [500%] increase in baseline forearm blood flow). Venous sensitivity to isoproterenol, expressed as the IP15 (the dose of isoproterenol resulting in 15% venodilation), was measured in a dorsal hand vein using the linear variable differential transformer. Administration of isoproterenol into the hand vein and brachial artery resulted in venodilation and increased forearm blood flow, respectively. However, there was no correlation between the measures of venous (log IP15) and arterial (log IP500) measures of vascular beta-adrenergic sensitivity (r = -.12, P = .74). We conclude that since arterial and venous sensitivities to isoproterenol in healthy white men did not correlate, venous and arterial beta-adrenergic responses are regulated differently and that studies examining vascular beta-adrenoceptor sensitivity would most appropriately be performed in a vessel representative of the vascular bed of interest.

Adrenergic beta-Agonists↗
PubMed1997

Blunted blood pressure response to central sympathoinhibition in normotensive blacks: increased importance of nonsympathetic factors in blood pressure maintenance in blacks.

Enhanced sympathetic reactivity may predispose blacks to the development of hypertension and may occur because of increased sympathetic stimulation and/or attenuated sympathoinhibition. A potential site for such attenuated sympathetic inhibition may be at the level of central alpha2-adrenergic receptors, which play an important role in the feedback inhibition of norepinephrine release. We used cumulative doses (1, 2, and 3 microg/kg I.V.) of the centrally acting alpha2-adrenergic agonist clonidine to measure the sensitivity of alpha2-adrenoceptor-mediated sympathoinhibition and the resultant hypotensive response in 8 normotensive blacks and 10 normotensive whites. Sympathetic activity was determined by radioisotope dilution methodology. Basal norepinephrine spillover was similar in blacks (0.80+/-0.14 microg/min) and whites (0.73+/-0.19 microg/min, P=NS) and after clonidine decreased significantly in both blacks (0.21+/-0.07 microg/min, P<.0001) and whites (0.24+/-0.06 microg/min, P<.0001), with no difference between the groups (P=NS). Despite this similar degree of sympathoinhibition, the hypotensive response to clonidine was markedly blunted in blacks, such that mean arterial pressure decreased by only 10% in blacks but by 21% in whites (P<.0001). The smaller blood pressure decrement after clonidine in normotensive blacks, in the face of an equal degree of sympathoinhibition, suggests that even when sympathetic tone is decreased to the same level in blacks and whites, normotensive blacks have less reduction in blood pressure than whites, implying that nonadrenergic mechanisms contribute more to blood pressure maintenance in blacks than whites. Whether a similar interethnic difference in response to sympathoinhibition occurs in hypertensive patients is as yet unknown.

Adult↗