Essential hypertension in blacks: is it a metabolic disorder?
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Black People↗
Biomedical subjects
M L Tuck
Publications and source records attributed to M L Tuck.
Increased Na/H antiport activity and abundance in uremic red blood cells.
Alterations in red blood cell sodium (Na) transport have been described in chronic renal failure. This study examines the possible impact of uremia on two ouabain-insensitive pathways, the Na/H antiporter and the Cl-/NaCO3- anion exchanger. The Vmax of Na/H antiporter measured as Na influx driven by outward H gradient in acid loaded red blood cells was significantly higher in uremic red blood cells versus controls (60.5 +/- 16.5 vs. 24.5 +/- 5.4 mmol/liter cells/hr, P < 0.025). This increase in activity was associated with an increased abundance of the Na/H antiporter as determined by immunologic analysis using an affinity purified polyclonal antibody to the human NHE-1 isoform of the antiporter. By contrast, the activity of the anion exchanger measured as the DIDS-sensitive lithium (Li) influx was similar in uremic versus control red blood cells (2.10 +/- 0.18 vs. 2.14 +/- 0.20 mmol/liter cells/hr). These experiments, when considered in conjunction with prior studies showing normal Na/Li countertransport in uremia indicate that there is a selective increase in the number of functional Na/H antiporters in uremic red blood cells and that Na/Li countertransport measurements may not be a valid marker for Na/H antiporter activity in red blood cells in patients requiring dialysis for end-stage renal failure.
Aged↗
Racial differences in platelet cytosolic calcium and calcitropic hormones in normotensive subjects.
Elevated levels of serum parathyroid hormone (PTH) and platelet cytosolic free calcium ([Ca2+]i) have been reported in subjects with essential hypertension. In addition, there is a positive correlation between serum PTH and platelet [Ca2+]i in white subjects with essential hypertension. Black normotensive subjects have relatively higher levels of serum PTH when compared to white normotensive subjects. To investigate the possibility that elevated serum PTH levels in black normotensives may contribute to elevated platelet [Ca2+]i, calcitropic hormone profiles and platelet [Ca2+]i were determined in 31 black normotensive subjects and 34 age-matched white normotensive subjects. There was no difference between the two groups in total serum calcium, plasma ionized calcium, or creatinine clearance. However, serum PTH was significantly elevated (P < .02) in the black normotensive group. Serum 1,25(OH)2 vitamin D levels were similar between the two groups whereas serum 25(OH) vitamin D levels were significantly lower (P < .001) in the blacks. The 24 h urinary excretion of Ca was also lower (P < .05) in the black normotensive group. Basal platelet [Ca2+]i was significantly lower (P < .05) in black normotensive than in white normotensive subjects. Serum PTH levels did not correlate with platelet [Ca2+]i in either group, or in the groups combined. These results demonstrate that the higher serum PTH concentrations in black normotensives is not associated with higher platelet [Ca2+]i, as is the case in white hypertensive patients.
Adult↗
The lipoxygenase inhibitor phenidone is a potent hypotensive agent in the spontaneously hypertensive rat.
Previous studies from our laboratory indicated that the lipoxygenase inhibitor phenidone markedly attenuates angiotensin II (AII) induced vascular contractility. Phenidone was also shown to inhibit the formation of vascular lipoxygenase products and to reduce blood pressure in the AII-dependent renovascular hypertensive rat. We have now examined the effects of phenidone in the spontaneously hypertensive rat (SHR). A single dose of phenidone lowered intraarterial systolic pressure in a dose dependent manner in both SHR and Wistar-Kyoto (WKY) [(max 74 +/- 15 and 22 +/- 3 mm Hg, respectively; P < .001)], but the effect was substantially greater in SHR. Long-term oral phenidone administration arrested the evolution of hypertension in 6 week old SHR treated over a period of 4 weeks (control 190 +/- 2 mm Hg; phenidone treated rats 164 +/- 4 mm Hg; P < .01). To assess the role of AII related mechanisms in the hypotensive effect of phenidone, the acute effect was studied in SHR on high and low sodium intake. In addition, the effect of captopril was compared to that of phenidone alone or captopril and phenidone in salt restricted SHR. While a single dose of phenidone (30 mg/kg, intraperitoneally) elicited similar maximal effects in SHR on high and low sodium intake (54 +/- 6 and 52 +/- 5 mm Hg compared to basal blood pressure, respectively), the hypotensive effect in sodium restricted rats was more sustained. Phenidone had no further hypotensive effect in captopril treated, salt restricted SHR.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Insulin attenuates agonist-mediated calcium mobilization in cultured rat vascular smooth muscle cells.
Insulin has been shown to attenuate pressor-induced vascular contraction, but the mechanism for this vasodilatory action is unknown. This study examines the effect of insulin on angiotensin II (ANG II)-induced increments in cytosolic calcium in cultured rat vascular smooth muscle cells (VSMC). 20-min incubations with insulin (10 microU/ml to 100 mU/ml) did not alter basal intracellular calcium concentration ([Ca2+]i), but inhibited the response to 100 nM ANG II in a dose-dependent manner (ANG II alone, 721 +/- 54 vs. ANG II + 100 mU/ml insulin, 315 +/- 35 nM, P < 0.01). A similar effect of insulin on ANG II action was observed in calcium poor buffer. Moreover, insulin did not effect calcium influx. ANG II receptor density and affinity were not affected by 24-h incubation with insulin. To further clarify the mechanisms of these observations, we measured ANG II-induced production of inositol 1,4,5-triphosphate (IP3), and IP3-releasable 45Ca. Insulin treatment did not alter ANG II-stimulated IP3 production. However, IP3-stimulated release of 45Ca in digitonin permeabilized cells was significantly reduced after 5-min incubations with 100 mU/ml insulin. Thapsigargin induced release of calcium stores was also blocked by insulin. Thus, insulin attenuates ANG II-stimulated [Ca2+]i primarily by altering IP3-releasable calcium stores. Insulin effects on ANG II-induced [Ca2+]i were mimicked by preincubation of VSMC with either sodium nitroprusside or 8-bromo-cGMP. As elevations in cGMP in vascular tissue lower [Ca2+]i, it is possible that insulin affects IP3 release of calcium by a cGMP-dependent mechanism that would contribute to its vasodilatory effects.
Angiotensin II↗
Diabetes and hypertension.
Arterial hypertension is more common in diabetes mellitus than in nondiabetic subjects, and many metabolic and hemodynamic features of diabetes mellitus contribute to the etiology of hypertension. Control of hypertension in diabetes mellitus is extremely important as high blood pressure accelerates both macrovascular and microvascular complications of this disease. Most classes of antihypertensive agents are effective in blood pressure control in diabetes mellitus, so the choice of antihypertensive therapy is based on the differences in adverse effects of these agents on metabolic control and their effect on other cardiovascular risks.
Animals↗
Obesity, the sympathetic nervous system, and essential hypertension.
There is ample evidence that the sympathetic nervous system is important in the etiology of essential hypertension. Plasma catecholamines such as norepinephrine and epinephrine are the most common indexes of sympathetic function used in studies of essential hypertension. Plasma norepinephrine is higher in young essential hypertensive patients than in normotensive subjects. Other methods to examine sympathetic activity, such as blood pressure response to sympatholytic agents, measurement of regional sympathetic activity, vascular reactivity to sympathetic agonists, power spectral analysis, and microneurography, have all provided further evidence for enhanced sympathetic activity in essential hypertension, especially in younger subjects. Certain groups that make up a substantial part of the essential hypertensive population, such as obese subjects, have heightened sympathetic activity that could contribute to hypertension. Plasma norepinephrine levels are significantly higher in obese compared with nonobese subjects, and the remarkable fall in blood pressure with weight loss in obese subjects is correlated with reductions in plasma norepinephrine. Antihypertensive agents have variable effects on sympathetic activity; some agents (diuretics and direct vasodilators) have elevating effects, some agents (centrally acting agents and alpha-antagonists) have lowering effects, and others (converting enzyme inhibitors, calcium blockers, and beta-blockers) have mixed effects. Tailoring therapy toward agents that reduce sympathetic activity for specific groups perceived as having neurogenic hypertension, such as obese subjects, is a goal yet to be attained.
Humans↗
12-Lipoxygenase products modulate calcium signals in vascular smooth muscle cells.
Previous studies have shown that inhibition of the lipoxygenase pathway of arachidonic acid metabolism can prevent the development of elevated blood pressure in renin-dependent models of hypertension. Agents that inhibit the lipoxygenase pathway such as phenidone and the flavonoid baicalein can selectively attenuate contractile responses to angiotensin II in vivo as well as in isolated vascular tissue. In the present study, the effects of lipoxygenase inhibitors on pressor-induced changes in cytosolic calcium were examined in cultured rat vascular smooth muscle cells using the fluorescent dye fura-2. Two structurally unrelated lipoxygenase inhibitors, baicalein and 5,8,11-eicosatriynoic acid, attenuated angiotensin II-stimulated increases in cytosolic calcium in both normal and calcium-poor buffer. The addition of 5-, 12-, or 15(S)-hydroxyeicosatetraenoic acid alone to the cells had no acute effect on intracellular calcium concentration. However, the addition of 12(S)-hydroxyeicosatetraenoic acid but not 5- or 15(S)-hydroxyeicosatetraenoic acid restored the initial calcium response to angiotensin II in vascular smooth muscle cells pretreated with both inhibitors; 5,8,11-eicosatriynoic acid also reduced [Arg8]-vasopressin and endothelin-stimulated increases in intracellular calcium. The attenuation of vasopressor-induced calcium transients by agents that inhibit lipoxygenase may explain their observed hypotensive effects in vivo. Moreover, lipoxygenase products, in particular 12(S)-hydroxyeicosatetraenoic acid, may act as mediators for the intracellular actions of angiotensin II and possibly other pressor hormones in vascular tissue by regulation of intracellular calcium metabolism.
Angiotensin II↗
Flavonoid potentiation of contractile responses in rat blood vessels.
Certain bioflavonoids and phenolic compounds have long been known to enhance catecholamine responses, in vivo and in vitro. In the present studies the flavone, baicalein, potentiated nerve-stimulated contractions in vitro in rat tail and femoral artery isometric ring preparations. Inhibition of catecholamine reuptake with cocaine or catecholamine metabolism with tropolone and parglyine (monoamine oxidase and catecholamine-O-methyl transferase inhibitors, respectively) did not alter baicalein's ability to potentiate contractile responses to nerve stimulation. Baicalein (10(-5) M), the prototype flavone, also increased sensitivity to exogenous norepinephrine, serotonin, arginine vasopressin and to the noncatecholamine alpha-1 and alpha-2 adrenergic agonists, cirazoline and tramazoline. Structure-function studies indicated that flavone potentiation required three contiguous A or B ring hydroxylations. Several nonflavone phenol derivatives with three contiguous hydroxyls also potentiated nerve stimulation responses. As baicalein is a potent lipoxygenase inhibitor, comparisons were made between potentiating ability and lipoxygenase inhibitory activity in a series of flavonoids. There was no direct correlation between inhibition of 12-hydroxy-5,8,10,14-eicosatetraenoic acid levels in thrombin stimulated human platelets and potentiation of contractile responses in the femoral artery. Additionally, the specific substrate analog lipoxygenase inhibitor, 5,8,11-eicosatriynoic acid, and the cyclooxygenase inhibitor, ibuprofen, were nonpotentiating. Ibuprofen pretreatment did not alter the potentiating action of baicalein. It is concluded that flavonoids with three contiguous hydroxyls on either the A or B ring increase in vitro vascular responsiveness via a post-synaptic process, independent of cyclooxygenase, lipoxygenase, monoamine oxidase or catecholamine-O-methyl transferase activity.
12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
Pathophysiology and management of hypertension in diabetes.
Arterial hypertension is more common in diabetes mellitus than in nondiabetic subjects, and many metabolic and hemodynamic features of diabetes mellitus contribute to the etiology of hypertension. Control of hypertension in diabetes mellitus is extremely important as high blood pressure accelerates both macrovascular and microvascular complications of this disease. Most classes of antihypertensive agents are effective in blood pressure control in diabetes mellitus, so the choice of antihypertensive therapy is based on the differences in adverse effects of these agents on metabolic control and other cardiovascular risks.
Antihypertensive Agents↗
Role of salt in the control of blood pressure in obesity and diabetes mellitus.
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Blood Pressure↗
Inhibition of lipoxygenase pathway reduces blood pressure in renovascular hypertensive rats.
To assess the potential role of the lipoxygenase (LO) pathway in the vasculature in an angiotensin II (ANG II)-dependent model of hypertension, we investigated the effect of LO pathway inhibition on blood pressure in the two-kidney, one-clip (2K,1C) Goldblatt hypertensive rat. The development of renovascular hypertension in 2K,1C rats was attenuated by oral administration of phenidone (Phe, 60 mg.kg-1.day-1), a nonselective LO inhibitor, throughout the 3 wk of observation after renal artery constriction. In contrast, the same treatment protocol had no effect on the evolution of hypertension in the deoxycorticosterone acetate-salt rat, which is considered to be an ANG II-independent form of hypertension. The hypotensive effect of Phe was not associated with changes in plasma renin or aldosterone concentration (PRC and PAC, respectively). In vitro synthesis of 12-hydroxyeicosatetraenoic acid (12-HETE) by aortic segments was increased in 2K,1C hypertensive rats compared with sham-operated rats. In addition, the synthesis of 12-HETE was suppressed by the in vitro addition of Phe (10(-4) M) to aortic-segment incubates obtained from 2K,1C rats and sham-operated rats. Acute administration of Phe (30 or 60 mg/kg) in 2K,1C hypertensive rats produced a rapid and sustained decrease in mean blood pressure (MBP). This decrease in MBP was accompanied by a brisk rise in PRC and PAC. In contrast, bolus administration of indomethacin, a selective cyclooxygenase inhibitor, did not affect MBP, PRC, or PAC.(ABSTRACT TRUNCATED AT 250 WORDS)
12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
Calcitropic hormones, platelet calcium, and blood pressure in essential hypertension.
Plasma ionized calcium, platelet cytosolic calcium (using the fura-2 method in gel-filtered platelets), parathyroid hormone (both the intact hormone and a midmolecule portion), calcitriol, and calcidiol were measured in 19 untreated male patients with essential hypertension and 19 age-matched normotensive male research subjects. Mean levels of platelet cytosolic calcium, parathyroid hormone, calcitriol, and calcidiol were all significantly higher, whereas plasma ionized calcium was significantly lower, in the hypertensive group compared with the normotensive group. Both platelet cytosolic calcium and intact parathyroid hormone were positively correlated with mean arterial pressure (r = 0.58, p less than 0.001; r = 0.54, p less than 0.001, respectively), whereas plasma ionized calcium was inversely correlated with mean arterial pressure (r = -0.60, p less than 0.001) in the combined group of all study subjects. All three of these correlations were significant in the hypertensive group alone but not in the normotensive group alone. When analyzed with plasma ionized calcium, body mass index, serum calcitriol, and calcidiol in a multivariable regression model, the significance of the partial regressions of platelet cytosolic calcium and parathyroid hormone with mean arterial pressure persisted. Intact parathyroid hormone was positively correlated to platelet cytosolic calcium (r = 0.43, p less than 0.01) and plasma ionized calcium was inversely correlated to platelet cytosolic calcium (r = -0.44, p less than 0.01). These results confirm previous reports of disturbances of calcium metabolism in essential hypertension and suggest that the elevated platelet cytosolic calcium observed in essential hypertension may be linked to one or more of these alterations of calcium metabolism.
Adult↗
Nifedipine gastrointestinal therapeutic system in the treatment of hypertension. Results of a multicenter trial. The Modern Approach to the Treatment of Hypertension (MATH) Study Group.
Nifedipine, in the gastrointestinal therapeutic system (GITS) formulation, a controlled-release formulation for once-a-day administration, was evaluated in the Modern Approach to the Treatment of Hypertension (MATH) trial. In this study conducted at 127 centers, 1155 patients with mild-to-moderate hypertension representative of the spectrum seen in practice were included in the analyses of effectiveness. After a 2 week placebo period, nifedipine GITS therapy was started at 30 mg/day and was titrated to a maximum dose of 180 mg/day over 6 weeks. Response criteria were a sitting diastolic blood pressure less than 90 mm Hg and a decrease of greater than or equal to 10 mm Hg. After titration, patients were observed for 12 weeks during treatment. At the final visit, nifedipine GITS significantly (P less than .0001) reduced sitting systolic blood pressure 17 +/- 14 mm Hg (mean +/- SD), and sitting diastolic blood pressure 14 +/- 8 mm Hg. Similar highly significant reductions in standing blood pressure were observed. For all subjects, 76% achieved goal blood pressure response during titration. More than 50% were controlled on doses of 30 to 60 mg/day. At the final visit blood pressure reductions in men and women were similar, except for a significantly greater decrease in sitting systolic pressure for women. A similar proportion of blacks responded compared with whites, and reductions in sitting systolic and diastolic blood pressure were also similar in the 2 groups. Nifedipine GITS had no effect on renal function, serum potassium, or total, HDL, or LDL cholesterol. Uric acid was reduced by 0.5 mg/dL (P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Antihypertensive effectiveness of nifedipine gastrointestinal therapeutic system in the elderly. The Modern Approach to the Treatment of Hypertension (MATH) Study Group.
The Modern Approach to the Treatment of Hypertension (MATH) trial was conducted to determine the therapeutic safety and efficacy of the once-a-day nifedipine gastrointestinal therapeutic system (GITS) formulation in a large and diverse cohort of patients with mild-to-moderate hypertension. One of the goals of the MATH study was to evaluate the clinical utility of nifedipine GITS in elderly hypertensives. This analysis compares the safety and efficacy of nifedipine GITS in elderly patients (greater than or equal to 65 years of age) and nonelderly patients (adults less than 65 years of age). A total of 222 elderly and 933 nonelderly patients from 127 centers were evaluated. Following a 2 week placebo washout phase, patients were titrated over 1 to 6 weeks on nifedipine GITS 30 to 180 mg/day, increasing in 30 mg increments to achieve goal blood pressure, defined as sitting diastolic blood pressure of less than 90 mm Hg and a 10 mm Hg decrease from baseline. Therapy was maintained at the optimal dose for an additional 12 weeks. Hemodynamic and laboratory parameters were assessed at baseline and at the final treatment visit. Baseline parameters were comparable between patient groups except for systolic blood pressure, which was significantly greater in the elderly compared with nonelderly patients (164 +/- 18 v 150 +/- 14 mm Hg, respectively, P less than .0001). After 12 weeks of therapy with nifedipine GITS, sitting and standing systolic and diastolic blood pressure was significantly decreased from baseline for both elderly and nonelderly patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Endocrine and renal effects of nifedipine gastrointestinal therapeutic system in patients with essential hypertension. Results of a multicenter trial. The Modern Approach to the Treatment of Hypertension Study Group.
Use of thiazide diuretics and beta-blockers in the treatment of hypertension may result in metabolic derangements and/or disturbances in the parameters of renal function, which offset the benefits of blood pressure reduction by adversely affecting other cardiovascular risk factors, particularly in special patient groups such as the elderly or those with concomitant diseases. Newer agents including calcium channel blockers, which exert potent antihypertensive effects without adversely affecting metabolic parameters unfavorably, are used with increasing frequency in hypertensive patients, but their clinical utility has been limited by the need for multiple daily dosing with attendant fluctuations in plasma levels thought to be associated with nuisance side effects and possible gaps in therapeutic protection. The Modern Approach to the Treatment of Hypertension (MATH) trial was conducted to determine the efficacy and safety of the new once-daily nifedipine gastrointestinal therapeutic system (GITS) formulation in a large cohort of mild-to-moderate hypertensive patients overall, and to identify specific effects of therapy in the presence of complicating factors such as diabetes and obesity. A total of 1155 patients from 127 centers were treated with nifedipine GITS in the MATH trial, including 157 diabetic (fasting plasma glucose greater than 120 mg/dL or on hypoglycemic therapy) and 747 nondiabetic patients. There were 458 obese patients (body mass index [BMI] greater than 30), 489 overweight patients (BMI greater than or equal to 25 less than or equal to 30), and 206 patients of normal weight (BMI less than 25).(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Metabolic considerations in hypertension.
The frequent concurrence of other cardiovascular risk factors in hypertensive patients, such as obesity and diabetes mellitus, suggests that overlapping genetic and environmental factors may contribute to the common metabolic and cardiovascular derangements observed in these populations. Hypertension and hyperglycemia accelerate atherosclerosis in diabetics, and play an important role in associated morbidity and mortality. Several abnormalities in blood pressure regulatory systems such as the renin-angiotensin system, the sympathetic nervous system, and sodium/volume control have been described in diabetes mellitus. Sodium retention and cardiovascular hyperreactivity appear to occur early in the course of diabetes mellitus, even at normal blood pressure levels and before onset of renal failure, and could set the stage for the development of hypertension. The relationship between obesity and hypertension is also well-established, and may reflect metabolic and cardiovascular adaptations in obese subjects which predispose to blood pressure elevations. Obese subjects display changes in sympathetic nervous system activity, sodium metabolism, and vascular hemodynamics. Sodium-sensitive blood pressure responses in the obese may be secondary to increased cardiac output or fluid volume, and are directly related to circulating insulin levels. Certain metabolic and vascular characteristics of obesity and diabetes mellitus are found in patients with essential hypertension. It has been suggested that insulin and insulin resistance may be the common link between these risk factors. Improved understanding of metabolic considerations in the treatment of obese and diabetic hypertensives should lead to more careful selection of medications that avoid metabolic complications. Although diuretics and beta-blockers may be useful in some patients, there are several reasons not to recommend their use as initial therapy in obese and diabetic hypertensives. On the other hand, calcium channel blockers and angiotensin converting enzyme inhibitors are highly effective, with minimal effects on metabolic parameters, and are well-suited as first-line therapy in the treatment of obese and diabetic hypertensives.
Antihypertensive Agents↗
Stimulation by uraemic plasma of frusemide-sensitive sodium efflux in erythrocytes from normal women.
1. Reduced Na+,K+ pump activity has been reported in uraemic erythrocytes, and this has been attributed to the presence of a circulating ouabain-like inhibitor. Since we have previously reported marked suppression of Na+,K+ co-transport activity in erythrocytes from dialysis patients, we have now examined the effect of incubation with uraemic plasma on Na+ efflux through the Na+,K+ pump and the co-transport pathway in normal erythrocytes from both men and women. 2. The results show that Na+ efflux via the Na+,K+ pump is not different between men and women (3.14 +/- 0.14 vs 3.68 +/- 0.18 mmol h-1 litre-1 of cells) and is not inhibited by incubation with uraemic plasma. 3. In contrast, co-transport-mediated Na+ efflux is lower in erythrocytes from normal women when compared with normal men (0.17 +/- 0.02 vs 0.25 +/- 0.05 mmol h-1 litre-1 of cells, P less than 0.001). 4. Moreover, incubation with uraemic plasma causes stimulation of Na+ efflux through the co-transport pathway in erythrocytes of healthy women (0.17 +/- 0.02 vs 0.27 +/- 0.03 mmol h-1 litre-1 of cells, P less than 0.005), but not in erythrocytes of healthy men (0.27 +/- 0.03 vs 0.25 +/- 0.05 mmol h-1 litre-1 of cells). 5. Our data do not support the presence of either a Na+,K+ pump or a co-transport inhibitor in plasma from dialysed uraemic patients. Thus, the suppressed co-transport activity demonstrated in uraemic erythrocytes cannot be attributed to a circulating inhibitor, and may reflect an acquired membrane or transport defect.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗