Blood Pressure Control In Humans Research Articles

Pharmacophore modelling, docking and molecular dynamic simulation studies in the discovery of potential human renin inhibitors

Hypertension is the main cause of human death and the Renin- Angiotensin- Aldosterone System (RAAS) has a key role in the control of human blood pressure. In this research a multi-step virtual screening strategy was applied in order to find new potential renin inhibitors. The crystal structure of renin-aliskiren complex was explored and receptor-ligand pharmacophore model was developed and validated using pharmit. ZINC database was screened by pharmacophore model and Lipinski's rule of five. Thereafter, the retrieved hits were docked in the active site of renin by using Vina. ADME parameters and toxicity of the filtered compounds were approximated using in silico methods and the selected compounds were subjected to high performance docking in order to improve the accuracy of screening. The non-bond interactions of the hit molecules with renin were explored and the compounds with the highest affinity and appropriate interactions were selected. In the last step, molecular dynamic simulation studies were performed on the complex of renin with aliskiren and three top-ranked structures including ZINC6085004, ZINC426421106, and ZINC5481346. RMSD, RMSF, Rg and number of hydrogen bonds were calculated. The binding free energy was calculated using the MM/PBSA method. The result of MD simulation indicated the stable binding of ZINC426421106 and ZINC5481346 with the active site of renin. According to this in-silico study these two compounds are drug-like, nontoxic, and have a high potential for inhibiting renin and could serve as appropriate lead molecules for the development of renin inhibitors as antihypertensive agents.

Abstract P199: Circadian Contributions To Blood Pressure Variation Under Constant Conditions

The circadian clock is an endogenous biological timekeeper that responds to environmental changes and governs various physiological processes over a 24-hour cycle. Blood pressure (BP) variation is thought to be controlled by the circadian clock, but few studies have examined circadian control of BP in humans. Moreover, it is unknown whether nighttime BP dipping is driven by the circadian system or by external factors. We investigated whether the circadian system drives 24-hour rhythms in BP, including nighttime BP dipping, using a 30-hour constant routine (CR) protocol. The CR protocol controls for external factors, allowing circadian rhythms to be isolated and measured, by having participants lie in a semi-recumbent posture in dim light (<10 lux) at a constant temperature, consume isocaloric snacks every 2 hours, and maintain wakefulness. To measure the BP rhythm, ambulatory BP was measured every 30 minutes (SpaceLabs 90227), and to measure the central circadian rhythm, core body temperature was measured every 10 seconds using an ingestible, wireless sensor (HQInc Core Body Temperature Wireless Data Record and Sensor). To date, 17 normotensive African American participants (13 females and 4 males), with a mean age of 37 (± 11.3) years and body mass index (BMI) of 32.5 kg/m 2 , have completed the study. Approximately 59% of participants (10 of 17) had non-dipping systolic BP at screening, defined as a <10% decrease in mean systolic BP from daytime to nighttime. Under constant conditions, 94% of participants (16 of 17) had a non-dipping BP phenotype. Median systolic BP dipping was 0.8% for females and 2.2% for males. There was a robust rhythm in participants’ core body temperature but not BP, suggesting that the circadian clock may not contribute substantially to a nighttime decrease in BP in normotensive African Americans. Instead, the non-dipping BP phenotype is likely more so a result of behavioral and/or physiological sleep-related processes. Future research and interventions for non-dipping BP may need to target these underlying behavioral and physiological processes.

Lifelong high‐altitude hypoxia induces arterial baroreflex adaptations: new insights and future directions

Lifelong high‐altitude hypoxia induces arterial baroreflex adaptations: new insights and future directions

The Role of Calcitonin Gene Related Peptide (CGRP) in Neurogenic Vasodilation and Its Cardioprotective Effects.

Calcitonin gene-related peptide (CGRP) is a highly potent vasoactive peptide released from sensory nerves, which is now proposed to have protective effects in several cardiovascular diseases. The major α-form is produced from alternate splicing and processing of the calcitonin gene. The CGRP receptor is a complex composed of calcitonin like receptor (CLR) and a single transmembrane protein, RAMP1. CGRP is a potent vasodilator and proposed to have protective effects in several cardiovascular diseases. CGRP has a proven role in migraine and selective antagonists and antibodies are now reaching the clinic for treatment of migraine. These clinical trials with antagonists and antibodies indicate that CGRP does not play an obvious role in the physiological control of human blood pressure. This review discusses the vasodilator and hypotensive effects of CGRP and the role of CGRP in mediating cardioprotective effects in various cardiovascular models and disorders. In models of hypertension, CGRP protects against the onset and progression of hypertensive states by potentially counteracting against the pro-hypertensive systems such as the renin-angiotensin-aldosterone system (RAAS) and the sympathetic system. With regards to its cardioprotective effects in conditions such as heart failure and ischaemia, CGRP-containing nerves innervate throughout cardiac tissue and the vasculature, where evidence shows this peptide alleviates various aspects of their pathophysiology, including cardiac hypertrophy, reperfusion injury, cardiac inflammation, and apoptosis. Hence, CGRP has been suggested as a cardioprotective, endogenous mediator released under stress to help preserve cardiovascular function. With the recent developments of various CGRP-targeted pharmacotherapies, in the form of CGRP antibodies/antagonists as well as a CGRP analog, this review provides a summary and a discussion of the most recent basic science and clinical findings, initiating a discussion on the future of CGRP as a novel target in various cardiovascular diseases.

Intermittent hypoxia and arterial blood pressure control in humans: role of the peripheral vasculature and carotid baroreflex

Intermittent hypoxia (IH) occurs in association with obstructive sleep apnea and likely contributes to the pathogenesis of hypertension. The purpose of this study was to examine the putative early adaptations at the level of the peripheral vasculature and carotid baroreflex (CBR) that may promote the development of hypertension. Ten healthy male participants (26 ± 1 yr, BMI = 24 ± 1 kg/m(2)) were exposed to 6 h of IH (1-min cycles of normoxia and hypoxia) and SHAM in a single-blinded, counterbalanced crossover study design. Ambulatory blood pressure was measured during each condition and the following night. Vascular strain of the carotid and femoral artery, a measure of localized arterial stiffness, and hemodynamic shear patterns in the brachial and femoral arteries were measured during each condition. Brachial artery reactive hyperemia flow-mediated vasodilation was assessed before and after each condition as a measure of endothelial function. CBR function and its control over leg vascular conductance (LVC) were measured after each condition with a variable-pressure neck chamber. Intermittent hypoxia 1) increased nighttime pulse pressure by 3.2 ± 1.3 mmHg, 2) altered femoral but not brachial artery hemodynamics, 3) did not affect brachial artery endothelial function, 4) reduced vascular strain in the carotid and possibly femoral artery, and 5) shifted CBR mean arterial pressure (MAP) to higher MAP while blunting LVC responses to CBR loading. These results suggest limb-specific vascular impairments, reduced vascular strain, and CBR resetting combined with blunted LVC responses are factors in the early pathogenesis of IH-induced development of hypertension.

Cutaneous control of blood pressure.

Textbook theory holds that blood pressure (BP) is regulated by the brain, by blood vessels, or by the kidney. Recent evidence suggests that BP could be regulated in the skin. The skin holds a complex capillary counter current system, which controls body temperature, skin perfusion, and apparently systemic BP. Epidemiological data suggest that sunlight exposure plays a role in controlling BP. Ultraviolet A radiation produces vasodilation and a fall in BP. Keratinocytes and immune cells control blood flow in the extensive countercurrent loop system of the skin by producing nitric oxide, a key regulator of vascular tone. The balance between hypoxia-inducible factor-1α and hypoxia-inducible factor-2α activity in keratinocytes controls skin perfusion, systemic thermoregulation, and systemic BP by nitric oxide-dependent mechanisms. Furthermore, the skin accumulates Na which generates a barrier to promote immunological host defense. Immune cells control skin Na metabolism and the clearance of Na via the lymphatic system. Reduced lymphatic clearance increases BP. Apart from the well-known role of the brain, blood vessels, and the kidney, the skin is important for systemic BP control in humans and in experimental animals.

Vestibulo-sympathetic reflexes in humans: evidence from natural stimulation and its impact on orthostasis

Sympathetic activation is important for postural blood pressure regulation. Historically, the baroreflexes have been considered the primary mechanism responsible in regulating blood pressure during standing in humans. Data from natural head movement studies indicate that the vestibular system contributes to muscle sympathetic activation and contributes to postural blood pressure changes in humans. The otolith organs and not the semicircular canals are responsible for increases in muscle sympathetic nerve activity. A number of factors can modify the vestibulosympathetic reflex including aging, bed rest, exercise training, and hydration status. All these factors, which attenuate the vestibulosympathetic reflex, are associated also with decrease orthostatic tolerance. This presentation will examine the relation between the vestibulosympathetic reflex and postural blood pressure control in humans.

A common hypofunctional genetic variant of GPER is associated with increased blood pressure in women.

Activation of vascular GPER has been linked to vasodepressor effects in animals. However, the significance of GPER regulation on chronic blood pressure control in humans is unknown. To examine this question we determined the functional significance of expression of a common missense single nucleotide variant of GPER, P16L in vascular smooth muscle cells, and its association with blood pressure in humans. Further, to validate the importance of carrying GPER P16L in the development of hypertension we assessed allele frequency in a cohort of hard-to-treat hypertensive patients referred to a tertiary care clinic. Expression of the GPER P16L variant (V) vs. wild type (WT) in rat aortic vascular smooth muscle cells, was associated with a significant decrease in G1 (1 μm, a GPER agonist)-mediated ERK phosphorylation (slope of the function of G1-stimulated ERK phosphorylation: GPER content WT: 16.2, 95% CI 9.9, 22.6; V: 5.0, 95% CI 1.0, 9.0; P < 0.005) and apoptosis (slope of the function of G1-stimulated apoptosis: GPER content: WT: 4.4, 95% CI: 3.4, 5.4; V: 2.5, 95% CI 1.6, 2.3 P < 0.005). Normotensive female subjects, but not male subjects, carrying this hypofunctional variant (allele frequency 22%) have increased blood pressure [mean arterial pressure: P16/P16: 80 ± 1 mmHg (n = 204) vs. P16L carriers: 82 ± 1 mmHg (n = 127), 95% CI for difference: 0.6, 4.0 mmHg, P < 0.05], [systolic blood pressure: P16/P16: 105 ± 1 mmHg vs. P16L carriers: 108 ± 1 mmHg, 95% CI for difference:1.0, 5.1 mmHg, P < 0.05], [diastolic blood pressure: P16/P16: 66 ± 0.5 mmHg vs. P16L carriers 68 ± 0.7, 95% CI for difference: 0.2, 3.6 mmHg, P < 0.05]. Further, the P16L allele frequency was almost two-fold higher in female vs. male hypertensive patients (31% vs. 16%, allele ratio 0.5, 95% CI 0.32, 0.76, P < 0.05). The common genetic variant, GPER P16L, is hypofunctional and female carriers of this allele have increased blood pressure. There was an increased prevalence in a population of hard-to-treat hypertensive female patients. Cumulatively, these data suggest that in females, impaired GPER function might be associated with increased blood pressure and risk of hypertension.

Urotensin-II System in Genetic Control of Blood Pressure and Renal Function

Urotensin-II controls ion/water homeostasis in fish and vascular tone in rodents. We hypothesised that common genetic variants in urotensin-II pathway genes are associated with human blood pressure or renal function. We performed family-based analysis of association between blood pressure, glomerular filtration and genes of the urotensin-II pathway (urotensin-II, urotensin-II related peptide, urotensin-II receptor) saturated with 28 tagging single nucleotide polymorphisms in 2024 individuals from 520 families; followed by an independent replication in 420 families and 7545 unrelated subjects. The expression studies of the urotensin-II pathway were carried out in 97 human kidneys. Phylogenetic evolutionary analysis was conducted in 17 vertebrate species. One single nucleotide polymorphism (rs531485 in urotensin-II gene) was associated with adjusted estimated glomerular filtration rate in the discovery cohort (p = 0.0005). It showed no association with estimated glomerular filtration rate in the combined replication resource of 8724 subjects from 6 populations. Expression of urotensin-II and its receptor showed strong linear correlation (r = 0.86, p<0.0001). There was no difference in renal expression of urotensin-II system between hypertensive and normotensive subjects. Evolutionary analysis revealed accumulation of mutations in urotensin-II since the divergence of primates and weaker conservation of urotensin-II receptor in primates than in lower vertebrates. Our data suggest that urotensin-II system genes are unlikely to play a major role in genetic control of human blood pressure or renal function. The signatures of evolutionary forces acting on urotensin-II system indicate that it may have evolved towards loss of function since the divergence of primates.

Abstract 352: A Common Hypofunctional Genetic Variant of GPER: Increased Blood Pressure in Female Carriers and Increased Expression in Female Hypertensive Patients

Activation of the aldosterone/estrogen GPCR, GPER, has been linked to vasodepressor effects. Further, genetic deletion of GPER in one mouse model has been linked to increased blood pressure in female but not male mice. However, the significance of GPER regulation for chronic blood pressure control in humans is unknown. To examine this question we determined the functional significance of expression of a common missense single nucleotide variant of GPER, P16L, and the impact of its expression on blood pressure and in the development of hypertension. Expression of the GPER P16L variant in rat aortic vascular smooth muscle cells vs. expression of wild type (WT) GPER, was associated with a significant decrease in G1 (1μM, a GPER agonist)-mediated ERK activation and G1-mediated inhibition of apoptosis. In normotensive subjects, expression of this hypofunctional GPER variant (allele frequency=22%) paralleled an increase in mean arterial blood pressure in females [P16/P16: 80±1 mmHg (n=236) vs P16L carriers: 82±1 mmHg (n=156), p&lt;0.05] but not in males. To validate the importance of expression of the GPER P16L variant on the development of hypertension, we compared the allele frequency in normotensive vs. hypertensive subjects, the latter recruited from patients referred to a tertiary care level hypertension clinic (n=151). In this hypertensive patient population, the P16L allele frequency was increased in female patients with hypertension (1.4 fold, p&lt;0.05 vs. allele frequency in normotensives) but was not increased in hypertensive males. In summary, we have determined that the common genetic variant, P16L GPER, is hypofunctional and that expression of this missense single nucleotide polymorphism is associated with increased blood pressure in normotensive subjects and with an increased frequency in hypertensive female but not male patients. Cumulatively, these data suggest that in females, impaired GPER function is associated with increased blood pressure and risk of hypertension.

Antihypertensive effect of passion fruit peel extract and its major bioactive components following acute supplementation in spontaneously hypertensive rats

Extracts from leaves, peels or flowers of Passiflora are noted for their medicinal effects. Passiflora edulis peel extract (PFPE) has been proposed to lower blood pressure (BP); however, only indirect measurement techniques have been employed. To more accurately measure the effect of PFPE on hemodynamic parameters and determine the minimal effective dose, hemodynamic parameters were directly measured in spontaneously hypertensive rats (SHR) implanted with radiotelemeters. PFPE was given orally at 0, 2.5, 50 or 200 mg/kg body weight (BW) to determine the minimal effective dose. Once this dose was determined, the potential active components, edulilic acid (EA), anthocyanin fraction (AF) or γ-aminobutyric acid (GABA), were tested to determine which may contribute to the reductions in BP. The 50 mg PFPE/kg BW dose was the lowest dose that significantly reduced all hemodynamic parameters from baseline when compared to control. When the potential actives were provided at equivalent doses to those found in 50 mg PFPE/kg BW, the EA and AF significantly reduced all measured hemodynamic parameters from baseline when compared to control. GABA did not significantly affect any hemodynamic parameters compared to control and significantly increased heart rate. These direct measurements indicate that PFPE can decrease hemodynamic parameters in SHR and indicate that EA and AF are active compounds that contribute to the antihypertensive effects of PFPE supplementation. While these results are encouraging, detailed mechanistic studies are needed to determine the putative value of PFPE for blood pressure control in humans.

Device-guided breathing exercises in the control of human blood pressure

To evaluate whether device-guided breathing (DGB) lowers blood pressure (BP) in adults. Systematic review and meta-analysis. We searched Medline (1950-2010), Embase (1980-2010), the Cochrane Library including the Cochrane Central register of Controlled Trials (CENTRAL), AMED (1985-2010), CINAHL (1980-2010) and the Current Controlled Trials registry (as of October 2010). Primary outcomes included the mean change in SBP and DBP. Secondary outcomes included change in heart rate, quality of life, compliance with the device and any side effects of the device. We included eight trials of the Resperate device (InterCure Ltd, Lod, Israel), consisting of 494 adult patients. Use of this device resulted in significantly reduced SBP by 3.67 mmHg [95% confidence interval (CI) = -5.99 to -1.39; P = 0.002] and decreased DBP by 2.51 mmHg (95% CI = -4.15 to -0.87; P = 0.003). However, sensitivity analysis was carried out excluding the five trials sponsored by or involving the manufacturers of the device, which revealed no overall effect on BP using the device. The maximum trial duration was 9 weeks and no overall effect was seen on heart rate or quality of life using the device. There is evidence that short-term use of DGB may reduce both DBP and DBP. However, five of the eight trials were sponsored by or involved the manufactures of the device. When these trials were excluded we found no overall effect. We conclude that longer term, independent trials are required to validate this intervention.

Is blood pressure control in humans mediated by the peripheral chemoreceptors?

Peripheral chemoreceptors in the carotid bodies (CB) mediate sympathetic outflow to hypoxia and hypoglycemic counterregulation. With the developing understanding of the CB as multi-modal sensors, we tested the hypothesis that the CB also play a role in the sympathetic control of blood pressure. Five young healthy subjects (3M/2F) were exposed to normoxia or hyperoxia to blunt cellular activation in the CB glomus cells during a hyperinsulinemic-hypoglycemic clamp (60 mg/dl). Mean blood pressure during hypoglycemia was significantly lower with hyperoxia than with normoxia (delta reduction from baseline: −5.4 ± 3.4 mmHg normoxia vs. −13.8 ± 1.9 mmHg hyperoxia). Paradoxically, even though blood pressure was low, hypoglycemia with hyperoxia resulted in a significant reduction in plasma levels of norepinephrine (50.7% normoxia) and epinephrine (62.3% normoxia). The typical baroreflex-mediated rise in sympathetic activity with lower blood pressure did not occur when the CB were silenced. These findings support the concept that peripheral chemoreceptors may modulate sympathetic control of blood pressure though interactions with the arterial baroreflexes. T32 DK07352, F32 DK84624-01A1, CTSA 1 UL1 RR024150, DK 29953

CYP3A5 and ABCB1 Genes and Hypertension

Hypertension is the first single modifiable cause of disease burden worldwide. Genes encoding proteins that are involved in the metabolism (CYP3A5) and transport (ABCB1) of drugs and hormones might contribute to blood pressure control in humans. Indeed, recent data have suggested that CYP3A5 and ABCB1 gene polymorphisms are associated with blood pressure in the rat as well as in humans. Interestingly, the effects of these genes on blood pressure appear to be modified by dietary salt intake. This review summarizes what is known regarding the relationships of the ABCB1 and CYP3A5 genes with blood pressure, and discusses the potential underlying mechanisms of the association. If the role of these genes in blood pressure control is confirmed in other populations and other ethnic groups, these findings would point toward a new pathway for blood pressure control in humans.

Modulation of Blood Pressure by Central Melanocortinergic Pathways

Weight gain and weight loss are associated with changes in blood pressure through unknown mechanisms. Central melanocortinergic signaling is implicated in the control of energy balance and blood pressure in rodents, but there is no information regarding such an association with blood pressure in humans. We assessed blood pressure, heart rate, and urinary catecholamines in overweight or obese subjects with a loss-of-function mutation in MC4R, the gene encoding the melanocortin 4 receptor, and in equally overweight control subjects. We also examined the effects of an MC4R agonist administered for 7 days in 28 overweight or obese volunteers. The prevalence of hypertension was markedly lower in the MC4R-deficient subjects than in the control subjects (24% vs. 53%, P=0.009). After the exclusion of subjects taking antihypertensive medications, blood-pressure levels were significantly lower in MC4R-deficient subjects than in control subjects, with mean (+/-SE) systolic blood pressures of 123+/-14 mm Hg and 131+/-12 mm Hg, respectively (P=0.02), and mean diastolic blood pressures of 73+/-10 mm Hg and 79+/-7 mm Hg, respectively (P=0.03). As compared with control subjects, MC4R-deficient subjects had a lower increase in heart rate on waking (P=0.007), a lower heart rate during euglycemic hyperinsulinemia (P<0.001), and lower 24-hour urinary norepinephrine excretion (P=0.04). The maximum tolerated daily dose of 1.0 mg of the MC4R agonist led to significant increases of 9.3+/-1.9 mm Hg in systolic blood pressure and of 6.6+/-1.1 mm Hg in diastolic blood pressure (P<0.001 for both comparisons) at 24 hours, as compared with placebo. Differences in blood pressure were not explained by changes in insulin levels; there were no significant adverse events. Results of our genetic and pharmacologic studies implicate melanocortinergic signaling in the control of human blood pressure through an insulin-independent mechanism.

Genetic variation in the KCNMA1 potassium channel α subunit as risk factor for severe essential hypertension and myocardial infarction

The large conductance Ca2+ -dependent potassium channel plays a critical role in the control of vascular tone, coupling local increases in intracellular Ca2+ to membrane hyperpolarization and vascular relaxation. It also impacts blood pressure by modulating the renin-angiotensin-aldosterone system. Previous studies have shown that a polymorphism in the beta1 regulatory subunit of the Ca2+ -dependent potassium channel modulates the risk of diastolic hypertension in humans. We have studied polymorphisms in the pore-forming alpha subunit gene (KCNMA1) and their association to hypertension and myocardial infarction. Sequencing of the KCNMA1 gene revealed two genetic variants (polymorphisms C864T and IVS17) in population-based epidemiological studies (4786 participants). We detected a significant increase in the frequency of the IVS17+37T>C polymorphism with severe systolic hypertension (48.3% for normotensive vs. 69% for severe systolic hypertension, P=0.03) and with severe general hypertension (48.7 vs. 65.8%, P=0.04), although the adjusted odd ratios did not reach statistical significance. Four C864T/IVS17 haplotypes were identified. Haplotype 4 (encompassing the C allele of the IVS17 polymorphism and the T allele of the C864T polymorphism) was related with increased severity of systolic and general hypertension as well as increased risk of myocardial infarction. Our study provides genetic evidence that highlights the relevance of the Ca2+ -dependent potassium channel in the control of human blood pressure and its impact on cardiovascular disease.

An ancestral variant of Secretogranin II confers regulation by PHOX2 transcription factors and association with hypertension

Granins regulate secretory vesicle formation in neuroendocrine cells and granin-derived peptides are co-released with neurotransmitters as modulatory signals at sympathetic sites. We report evidence for association between a regulatory polymorphism in Secretogranin II (SCG2) and hypertension in African-American subjects. The minor allele is ancestral in the human lineage and is associated with disease risk in two case-control studies and with elevated blood pressure in a separate familial study. Mechanistically, the ancestral allele acts as a transcriptional enhancer in cells that express endogenous Scg2, whereas the derived allele does not. ARIX (PHOX2A) and PHOX2B are identified as potential transactivating factors by oligonucleotide affinity chromatography and mass spectrometry and confirmed by chromatin immunoprecipitation. Each of these transcription factors preferentially binds the risk allele, both in vitro and in vivo. Population genetic considerations suggest positive selection of the protective allele within the human lineage. These results identify a common regulatory variation in SCG2 and implicate granin gene expression in the control of human blood pressure and susceptibility to hypertension.

Fine-mapping and comprehensive transcript analysis reveals nonsynonymous variants within a novel 1.17 Mb blood pressure QTL region on rat chromosome 10

The presence of blood pressure (BP) quantitative trait loci (QTL) on rat chromosome 10 has been clearly demonstrated by linkage analysis and substitution mapping. Using congenic strains containing the LEW rat chromosomal segments on the Dahl salt-sensitive (S) rat background, further iterations of congenic substrains were constructed and characterized to fine-map a chromosome 10 region (QTL1) linked to blood pressure. Comparison of seven congenic substrains refined QTL1 to a 1.17 Mb segment flanked by D10Mco88 and D10Mco89, which are located at 71,513,116 and 72,684,774 bp, respectively. The newly defined QTL1, containing 18 genes, is captured in its entirety within a single congenic substrain. A thorough transcript analysis revealed that 3 of these 18 genes, Ccl5, Ddx52, and RGD1559577, had nonsynonymous allelic variations between the S rat and the LEW rat. None of the detected transcripts within the newly defined QTL1 are implicated directly in BP control in humans or model organisms. Therefore, the present work defines a novel blood pressure QTL with three potential quantitative trait nucleotides.

Protective Effect of the KCNMB1 E65K Genetic Polymorphism Against Diastolic Hypertension in Aging Women and Its Relevance to Cardiovascular Risk

The E65K polymorphism in the beta1-subunit of the large-conductance, Ca2+-dependent K+ (BK) channel, a key element in the control of arterial tone, has recently been associated with low prevalence of diastolic hypertension. We now report the modulatory effect of sex and age on the association of the E65K polymorphism with low prevalence of diastolic hypertension and the protective role of E65K polymorphism against cardiovascular disease. We analyzed the genotype frequency of the E65K polymorphism in 3924 participants selected randomly in two cross-sectional studies. A five-year follow-up of the cohort was performed to determine whether cardiovascular events had occurred since inclusion. Estrogen modulation of wild-type and mutant ion channel activity was assessed after heterologous expression and electrophysiological studies. Multivariate regression analyses showed that increasing age upmodulates the protective effect of the K allele against moderate-to-severe diastolic hypertension in the overall group of participants (odds ratio [OR], 0.35; P=0.006). The results remained significant when analyses were restricted to women (OR, 0.18; P=0.02) but not men (OR, 0.46; P=0.09). This effect was independent of the reported acute modulation of BK channels by estrogen. A five-year follow-up study also demonstrated a reduced age- and sex-adjusted hazard ratio of 0.11, 95% CI, 0.01 to 0.79 of K-carriers for "combined cardiovascular disease" (myocardial infarction and stroke) compared with EE homozygotes. Our study provides the first genetic evidence for the different impact of the BK channel in the control of human blood pressure in men and women, with particular relevance in aging women, and highlights the E65K polymorphism as one of the strongest genetic factors associated thus far to protection against myocardial infarction and stroke.

Effects of elements in human blood pressure control.

This review enumerates and discusses the elements involved in the control of human blood pressure via a historical evolutionary form. The older and most recent element literature presentations were researched using MEDLINE and a manual review of documents cited. Independent data extraction and cross-referencing was performed. Of the 28 known elements that can influence blood pressure, 15 were found to be involved in human blood pressure regulation. The elements were divided into four groups: electrolyte, composed of sodium, potassium, calcium, and magnesium; metal, which included zinc, copper, and iron; toxic, made up of lead, mercury, cadmium, barium, thallium, arsenic; miscellaneous (lithium and selenium). Evolutionary historical data, possible mechanisms of actions, and interactions between elements that have been shown to influence blood pressure are discussed. Controversy exists over the therapeutic use of elements to alter blood pressure but is absent in the case of the toxic group where preventive control is a proven public health matter. The significance of these 15 elements in the regulation of human blood pressure has been established and ongoing studies will continue to reinforce their influence and importance.