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- Pharmacokinetic-Pharmacodynamic Modeling of the Antihypertensive Effect of Eprosartan in Black and White Hypertensive Patients. [JOURNAL ARTICLE]
- Clin Pharmacokinet 2013 May 22.
BACKGROUND AND OBJECTIVE:It is well recognized that many antihypertensive drugs exhibit large interindividual variability in effect and that this wide range of patient response to antihypertensive drugs is a major problem in achieving blood pressure (BP) control. Variability in both drug concentration and drug effect may cause the heterogeneity in antihypertensive drug response. However, for most antihypertensive drugs, no clear relationship between drug concentration and its effect on BP has been reported. This study aimed to describe the relationship between eprosartan exposure and its effect on the systolic blood pressure (SBP) using population pharmacokinetic-pharmacodynamic modeling. Interindividual variability in pharmacokinetics and pharmacodynamics was quantified and the influence of covariates on this relationship was evaluated.
PATIENTS AND METHODS:Eprosartan plasma concentrations and SBP measurements were determined in 86 mildly hypertensive patients from the ROTATE study aged 48.1 ± 7.6 years with different ethnic backgrounds (33 White Dutch, 41 Creole Surinamese, 12 Hindustani Surinamese). In 12 of these patients, pharmacokinetics were densely sampled and 24-h ambulatory BP measurements were obtained. Data were analyzed using nonlinear mixed effects modeling.
RESULTS:Eprosartan concentration-time profiles were adequately described with a two-compartment pharmacokinetic model with zero-order absorption. A log-linear relationship was used to describe the relationship between concentration and the decrease in SBP. A hypothetical effect compartment was used to describe hysteresis in the drug effect. Approximately 80 % of the maximum decrease in SBP was observed after 24 days. Interindividual variability in drug response was 65 % and decreased to 14 % when ethnicity was added as covariate. Creole Surinamese exhibited no drug response in contrast to White Dutch and Hindustani Surinamese [-2.6 mm Hg per (ng/ml)].
CONCLUSIONS:The developed pharmacokinetic-pharmacodynamic model allows the quantification and explanation of variability in SBP between individuals with ethnicity as a useful determinant of responsiveness to eprosartan.
- Sustained in vivo blockade of alpha1-adrenergic receptors prevented some of stress-triggered effects on steroidogenic machinery in Leydig cells. [JOURNAL ARTICLE]
- Am J Physiol Endocrinol Metab 2013 May 21.
This study was designed to systematically analyze and evaluate the effects of in vivo blockade of α1-adrenergic receptors (α1-ADRs) on the stress-induced disturbance of steroidogenic machinery in Leydig cells. Parameters followed: (1) steroidogenic enzymes/proteins, transcription factors and cAMP/testosterone production; (2) the main hallmarks of stress (adrenaline, glucocorticoids); transcription profiles ADRs and oxydases with high affinity to inactivate glucocorticoids. Results showed that sustained blockade of α1-ADRs prevented stress-induced: (1) decrease of the transcripts/proteins for main steroidogenic CYPs (CYP11A1, CYP17A1); (2) decrease of Scarb1 & Hsd3b1 transcripts; (3) decrease of transcript for Nur77, one of the main activator of the steroidogenic expression; (4) increase of Dax1 and Arr19, the main steroidogenic repressors in Leydig cells. In the same cells, the expression of steroidogenic stimulatory factor Creb1, StAR and androgen receptor increased. In this signaling scenario, stress-induced stimulation of Adra1a/Adra1b/Adrbk1 and Hsd11b2 (the unidirectional oxydase with high affinity to inactivate glucocorticoids) was not changed. Blockade additionally stimulated stress-increased transcription of most abundantly expressed ADRs Adra1d/Adrb1/Adrb2 in Leydig cells. In the same cells, stress-decreased testosterone production, the main marker of Leydig cells functionality was completely prevented, while reduction of cAMP, the main regulator of androgenesis, was partially prevented. Accordingly, presented data provide new molecular/transcriptional base for "fight/adaptation" of steroidogenic cells and new molecular insights into the role of α1-ADRs in stress-impaired Leydig cells steroidogenesis. The results are important in term of wide use of α1-ADRs selective antagonists, alone/in combination, to treat high blood pressure, nightmares associated with posttraumatic stress disorder and disrupted sexual health.
- Effect of cuff type on arterial occlusion. [Journal Article]
- Clin Physiol Funct Imaging 2013 Jul; 33(4):325-7.
Blood flow restriction (BFR) by itself or in combination with exercise has been shown to be beneficial for skeletal muscle. Despite most of the literature showing positive effects of BFR on skeletal muscle, not all studies show a benefit of BFR exercise compared with exercise without BFR. Some of the discrepancy can be explained by differences in methodology. For example, wide (13·5 cm) nylon cuffs result in arterial occlusion at a much lower pressure than narrow elastic (5 cm) cuffs. However, although it is evident that there are differences between elastic narrow (5 cm) cuffs and nylon wide (13·5 cm) cuffs, it is presently unclear whether or not there are differences between two cuffs of similar size (5 cm) but different material (nylon versus elastic). We hypothesized that although the cuffs are of similar size, there would be significant differences in arterial occlusion between two cuff materials. With the participants supine, in a randomized order, either the nylon (5 × 83 cm) or elastic (5 × 135 cm) cuffs were applied to the most proximal portion of each leg. Arterial blood flow was detected using a hand-held bidirectional Doppler probe placed on the posterior tibial artery. A paired sample t-test found no difference between cuff types for arterial occlusion pressure. In conclusion, arterial occlusion pressure is not different between two cuffs of a similar size but different material. This suggests that either elastic or nylon cuffs of the same width should restrict blood flow similarly at the same pressure during resting conditions.
- Baroreflex sensitivity analysis: spontaneous methodology vs. Valsalva's maneuver. [JOURNAL ARTICLE]
- Clin Auton Res 2013 May 16.
INTRODUCTION:Spontaneous analysis techniques and Valsalva's maneuver (VM) are often used as a non-pharamcological approach to assess both sympathetic (sBRS) and cardiovagal (cBRS) baroreflex sensitivity. Despite their wide utilization, no studies have assessed the intra-individual reliability between these analysis techniques. Accordingly, we hypothesized that spontaneous BRS would be positively correlated to VM BRS.
METHODS:Heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA) were measured in 26 healthy subjects (age, 22 ± 1 year; 14 men and 12 women) during 10 min supine rest and 3 VM at 40 mmHg expiratory pressure (15 s, 1 min recoveries). For spontaneous BRS, relations between diastolic BP and MSNA were used to determine sBRS, while relations between systolic BP and R-R interval were used to determine cBRS. During VM, sBRS was the ratio of MSNA and the maximum diastolic BP reduction during early phase II, and cBRS was derived from linear relations between systolic BP and R-R interval during early phase II (i.e., hypotensive stimulus) and phase IV (i.e., hypertensive stimulus).
RESULTS:Spontaneous sBRS was significantly correlated to VM sBRS (r = 0.516, p = 0.036). In contrast, spontaneous cBRS from up-up sequence was not correlated to VM phase IV cBRS (r = 0.274, p = 0.109). Similarly, spontaneous cBRS from down-down sequence was not correlated to VM phase II cBRS (r = 0.199, p = 0.207).
CONCLUSION:In conclusion, our findings demonstrate positive association between spontaneous sBRS and VM sBRS, but there is no correlation between spontaneous and VM cBRS.
- Estimating 24-Hour Urinary Sodium Excretion From Casual Urinary Sodium Concentrations in Western Populations: The INTERSALT Study. [JOURNAL ARTICLE]
- Am J Epidemiol 2013 May 14.
High intakes of dietary sodium are associated with elevated blood pressure levels and an increased risk of cardiovascular disease. National and international guidelines recommend reduced sodium intake in the general population, which necessitates population-wide surveillance. We assessed the utility of casual (spot) urine specimens in estimating 24-hour urinary sodium excretion as a marker of sodium intake in the International Cooperative Study on Salt, Other Factors, and Blood Pressure. There were 5,693 participants recruited in 1984-1987 at the ages of 20-59 years from 29 North American and European samples. Participants were randomly assigned to test or validation data sets. Equations derived from casual urinary sodium concentration and other variables in the test data were applied to the validation data set. Correlations between observed and estimated 24-hour sodium excretion were 0.50 for individual men and 0.51 for individual women; the values were 0.79 and 0.71, respectively, for population samples. Bias in mean values (observed minus estimated) was small; for men and women, the values were -1.6 mmol per 24 hours and 2.3 mmol per 24 hours, respectively, at the individual level and -1.8 mmol per 24 hours and 2.2 mmol per 24 hours, respectively, at the population level. Proportions of individuals with urinary 24-hour sodium excretion above the recommended levels were slightly overestimated by the models. Casual urine specimens may be a useful, low-burden, low-cost alternative to 24-hour urine collections for estimation of population sodium intakes; ongoing calibration with study-specific 24-hour urinary collections is recommended to increase validity.
- [Genetic factors of hypertension]. [English Abstract, Journal Article]
- Rinsho Byori 2013 Feb; 61(2):144-9.
Essential hypertension (EH) is thought to be a multifactorial disease. In Japan, there are more than 20 million cases of EH, which accounts for 80 to 90% of hypertension cases in Japan. It is very difficult to isolate the susceptibility genes of EH in familial linkage analysis such as sib-pair analysis and association studies such as case-control studies of candidate genes. Over the past few years, genome-wide association studies (GWAS) have begun to identify the primary genetic mechanisms of hypertension. For example, GWAS have identified many loci in or near genes that generally were not expected to be associated with the level of blood pressure or essential hypertension. Considering the high expectations for the studies and the billions of dollars spent to conduct these studies, however, progress has been slow. We believe that next-generation research technologies, such as the whole genome sequencing, may remedy some of these problems encountered thus far. The present paper contains a review of issues and progress in isolation of susceptibility genes of EH, and an introduction to an effective novel method for isolation of susceptibility genes of EH.
- Renal sympathetic denervation: hypertension therapy and beyond. [Journal Article]
- Expert Rev Med Devices 2013 May; 10(3):329-38.
Hypertension is one of the most important treatable causes of mortality and morbidity in the world, but despite the wide availability of pharamacological therapy, blood pressure is poorly controlled in many patients. Renal sympathetic denervation (RSD) is a novel therapeutic option whereby the renal sympathetic nerves, which lie within and around the wall of the renal arteries, are ablated using a catheter placed within the arterial lumen. The Symplicity HTN-2 trial has shown that RSD reduces blood pressure to a clinically relevant degree; this finding has resulted in an explosion in interest in the procedure and RSD has the potential to become a standard therapy for many hypertensive patients. Many new devices are in development that will simplify the procedure, and several novel indications for RSD are currently being investigated in clinical trials.
- Silencing of Atp2b1 increases blood pressure through vasoconstriction. [JOURNAL ARTICLE]
- J Hypertens 2013 May 9.
BACKGROUND::Recent genome-wide association studies (GWASs) have identified 30 genetic loci that regulate blood pressure, increasing our understanding of the cause of hypertension. However, it has been difficult to define the causative genes at these loci due to a lack of functional analyses.
METHOD:: In this study, we aimed to validate the candidate gene ATP2B1 in 12q21, variants near which have the strongest association with blood pressure in Asians and Europeans. ATP2B1 functions as a calcium pump to fine-tune calcium concentrations - necessary for repolarization following muscular contractions. We silenced Atp2b1 using an siRNA complex, injected into mouse tail veins.
RESULTS::In treated mice, blood pressure rose and the mesenteric arteries increased in wall : lumen ratio. Moreover, the arteries showed enhanced myogenic responses to pressure, and contractile responses to phenylephrine increased compared with the control, suggesting that blood pressure is regulated by ATP2B1 through the contraction and dilation of the vessel, likely by controlling calcium concentrations in the resting state.
CONCLUSION:: These results support that ATP2B1 is the causative gene in the blood pressure-associated 12q21 locus and demonstrate that ATP2B1 expression in the vessel influences blood pressure.
- Multifactorial Model and Treatment Approaches of Refractory Hypotension in a Patient Who Took an ACE Inhibitor the Day of Surgery. [Journal Article]
- Case Rep Anesthesiol 2013.:723815.
In the field of anesthesiology, there is wide debate on discontinuing angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) therapy the day of noncardiac surgery. Although there have been many studies attributing perioperative hypotension to same-day ACEI and ARB use, there are many additional variables that play a role in perioperative hypotension. Additionally, restoring blood pressure in these patients presents a unique challenge to anesthesiologists. A case report is presented in which a patient took her ACEI the day of surgery and developed refractory hypotension during surgery. The evidence of ACEI use on the day of surgery and development of hypotension is reviewed, and additional variables that contributed to this hypotensive episode are discussed. Lastly, current challenges in restoring blood pressure are presented, and a basic model on treatment approaches for refractory hypotension in the setting of perioperative ACEI use is proposed.
- Advances in blood pressure genomics. [Journal Article]
- Circ Res 2013 May 10; 112(10):1365-79.
The elucidation of genes implicated in Mendelian forms of hypertension demonstrates rare variants with substantial effects are responsible, and often these genes lie within pathways managing sodium homeostasis. More recently with advances in affordable high-throughput genotyping strategies, multiple common genetic variants with modest effects on blood pressure (<1 mmHg systolic) have been discovered in the population. In aggregate, these common variants explain <3% of the variance of blood pressure. Although these findings may offer new mechanistic insights into the biology of blood pressure, a key question is can these findings translate into patient benefit? It is timely to reflect on recent advances in genomics, and the use of new resources, such as the 1000 Genomes Project and the Encyclopedia of DNA Elements, to annotate likely causal variants, and their relevance to cardiovascular disease. In this review, we discuss the advances in relation to our knowledge of the genetic architecture of blood pressure, and whether gene discoveries might influence cardiovascular risk assessment, help to stratify patient response to medicine, or identify new biological pathways for novel therapeutic targets.