Biomedical subjects

M L Tuck

Publications and source records attributed to M L Tuck.

At least 37 records · Page 2Linked to original sources

PubMed1997

Sympathetic nerve hyperactivity precedes hyperinsulinemia and blood pressure elevation in a young, nonobese Japanese population.

To evaluate the relationships between sympathetic nerve activity, insulin sensitivity, and blood pressure (BP) elevation, we examined BP, fasting blood glucose, plasma insulin, and norepinephrine (NE) levels in age- and body mass index (BMI)-matched 662 normotensive (NT) and 188 borderline hypertensive (BHT) subjects every year for 10 years. All measurements were taken in the supine position after an overnight fast. BP elevation (BP-E) during 10 years was defined as 10% or more elevation of mean BP when compared with BP at entry. BP-E was noted in 186 (28%) of NT and in 52 (28%) of BHT. Fasting insulin level at entry in BHT with BP-E was significantly greater than that in subjects without BP-E (P < .01), although fasting insulin level in NT with BP-E at entry was similar to that in NT without BP-E. Supine plasma NE level at entry period and year 10 in NT with BP-E was significantly greater than that in subjects without BP-E (P < .05, P < .01, respectively). Supine NE in BHT regardless of BP-E was significantly greater than that in NT at both entry and year 10. These results demonstrate that sympathetic nerve hyperactivity appears to precede hyperinsulinemia and resultant BP elevation in a young, nonobese Japanese population.

Adult↗

PubMed1997

Metabolic effects of long-term treatments with nifedipine-retard and captopril in young hypertensive patients.

The objective of this study was to clarify potential differences in the metabolism of glucose and lipids in a long-term treatment (for 5 years) for hypertension among nifedipine-retard and captopril in young, nonobese hypertensive men (HT). In 78 previously untreated HT who were given nifedipine-retard and in 81 HT given captopril, blood pressure (BP), pulse rate, blood glucose, and plasma insulin levels were measured every 30 min for 2 h after 75 g oral glucose ingestion, every year for 5 years. Twenty-six age- and body mass index (BMI)-matched normotensive men (NT) were measured for the same variables for 5 years. They were also measured for total cholesterol, triglyceride levels, and lipids fractions after an overnight fast, every year for 5 years without any kinds of lipid lowering agents. At 1 year after treatment with nifedipine-retard or captopril, BP decreased significantly, and the reductions in BP did not differ between HT treated with nifedipine-retard and captopril. In the entry period, fasting insulin (P < .05), the area under the curve (AUC) of insulin (P < .01), AUC of blood glucose (P < .05) after 75 g oral glucose ingestion, fasting total cholesterol (P < .05), and triglyceride levels (P < .05) in HT were significantly greater than those in NT. In HT treated with captopril, AUC of insulin (P < .01), AUC of blood glucose (P < .05), and total cholesterol (P < .05) decreased significantly after 1 year of treatment for HT, and triglyceride (P < .05) decreased significantly after the 2 year treatment. Although in HT treated with nifedipine-retard, AUC of insulin (P < .01) and AUC of blood glucose levels (P < .05) decreased significantly after 1 year of treatment, triglyceride and total cholesterol levels did not decrease throughout the 5 years. These results indicate that captopril has ameliorative effects in hyperinsulinemia or reduced insulin sensitivity, hypercholesterolemia, and hypertriglyceridemia starting at 1 year after the treatment for HT, whereas nifedipine-retard has an ameliorative effect in the metabolism of glucose but not in the metabolism of lipids. Therefore, ACE inhibitor has additional ameliorative effects on insulin sensitivity to the vasodilatory action.

Adult↗

PubMed1997

Prevalence of hyperinsulinemia in young, nonobese Japanese men.

OBJECTIVE: To clarify the prevalence of hyperinsulinemic subjects among young, nonobese, Japanese men, and to evaluate characteristics, in particular, of sympathetic nerve system activity and lipid fractions in hyperinsulinemic subjects. METHODS: Norepinephrine, plasma insulin, and lipid fractions were measured in 512 normotensive, 124 borderline hypertensive (BHT) and 88 established hypertensive (EHT) subjects, matched for age and body mass index, after they had fasted overnight. RESULTS: Hyperinsulinemia defined as mean fasting plasma insulin + 2SD in normotensives or more was found in 8% of all subjects (normotensive and hypertensive subjects, P = 0.018), 6% of normotensives, 10% of BHT (P = 0.28, versus normotensives), 18% of EHT (P = 0.005, versus normotensives), and 12% of hypertensives (P = 0.019, versus normotensives). The hyperinsulinemic (fasting insulin > or = mean + 2SD in normotensive) subjects had higher plasma norepinephrine levels in all blood pressure groups than did nonhyperinsulinemic (< mean + 2SD) subjects (normotensives P < 0.05, BHT P < 0.01, and EHT P < 0.05). Hyperinsulinemic normotensives had higher blood pressure levels than did nonhyperinsulinemic ones (P < 0.05); however, blood pressure levels in hyperinsulinemic BHT and EHT were similar to those in nonhyperinsulinemic subjects. Triglyceride in BHT and EHT was greater than that in normotensives (P < 0.05), and that in hyperinsulinemic subjects was greater than that in nonhyperinsulinemic subjects (P < 0.05). On the other hand, high-density lipoprotein cholesterol in hyperinsulinemic BHT and EHT was significantly lower than that in nonhyperinsulinemic BHT (P < 0.05) and EHT (P < 0.01). CONCLUSION: These results demonstrated that the prevalence of hyperinsulinemia among the present sample of young, nonobese, Japanese men was 12% and that the prevalence increased with blood pressure elevation. Furthermore, hypertriglyceridemia and sympathetic nerve hyperactivity appear to be related to hyperinsulinemia and the emergence of hypertension.

Adult↗

PubMed1997

Lisinopril versus hydrochlorothiazide in obese hypertensive patients: a multicenter placebo-controlled trial. Treatment in Obese Patients With Hypertension (TROPHY) Study Group.

Because obesity-associated hypertension has unique hemodynamic and hormonal profiles, certain classes of antihypertensive agents may be more effective than others as monotherapy. Thus, we compared the efficacy and safety of the angiotensin-converting enzyme inhibitor lisinopril and the diuretic hydrochlorothiazide in a 12-week, multicenter, double-blind trial in 232 obese patients with hypertension. Patients with an office diastolic pressure between 90 and 109 mm Hg were randomized to treatment with daily doses of lisinopril (10, 20, or 40 mg), hydrochlorothiazide (12.5, 25, or 50 mg), or placebo. Mean body mass indexes were similar for all patients. At week 12, lisinopril and hydrochlorothiazide effectively lowered office diastolic (-8.3 and -7.7 versus -3.3 mm Hg, respectively; P<.005) and systolic (-9.2 and -10.0 versus -4.6 mm Hg, respectively; P<.05) pressures compared with placebo. Ambulatory blood pressure monitoring confirmed that lisinopril and hydrochlorothiazide effectively lowered 24-hour blood pressure compared with placebo (P<.001). Significant dose-response differences were observed between treatments. Sixty percent of patients treated with lisinopril had an office diastolic pressure <90 mm Hg compared with 43% of patients treated with hydrochlorothiazide (P<.05). Responses to therapies differed with both race and age. Neither treatment significantly affected insulin or lipid profiles; however, plasma glucose increased significantly after 12 weeks of hydrochlorothiazide therapy compared with lisinopril (+0.31 versus -0.21 mmol/L; P<.001). Hydrochlorothiazide also decreased serum potassium levels by 0.4 mmol/L from baseline. In conclusion, lisinopril was as effective as hydrochlorothiazide in treating obese patients with hypertension. Treatment with angiotensin-converting enzyme inhibitors may show greater efficacy as monotherapy at lower doses compared with thiazide diuretics, may have a more rapid rate of response, and may offer advantages in patients at high risk of metabolic disorders.

Adult↗

PubMed1997

Impaired in vivo adrenergic responses in diet-induced hypertensive rats.

This study was conducted to investigate whether altered vascular responsiveness to vasoactive compounds contributes to the development of hypertension in diet-induced hyperinsulinemic rats. Male Sprague-Dawley rats were randomly assigned to receive high fructose, high sucrose, or standard rat chow for 13-18 wk. Blood pressure was monitored by indirect (tail-cuff) measurements at regular intervals during the diet treatment. Vascular responses to various vasoactive agents were studied both in vivo and in vitro. Blood pressure response, as assessed by direct (intra-arterial) measurement, to graded dose infusions of norepinephrine or angiotensin II or bolus infusion of acetylcholine were determined. In vitro vascular responses of the tail arteries to exogenous norepinephrine were also studied. The fructose- and the sucrose-fed rats had significantly higher blood pressure than controls. Serum insulin levels were also significantly higher in fructose- and sucrose-fed rats than in controls. The blood pressure responses to graded infusions of norepinephrine were significantly less in the fructose-fed rats than in controls. The blood pressure responses to angiotensin II and acetylcholine infusion were not significantly different among the three groups of rats. In vitro studies of vascular reactivity in the tail arteries revealed than the concentration of norepinephrine that produced half-maximal contraction (NE EC50) was significantly higher in the fructose group than control. Thus, impaired vascular responses to exogenous norepinephrine were observed in fructose-fed rats both in vivo and in vitro. This may be due to an adaptation to increased sympathetic nervous activity, or may be a compensatory response to other structural or functional changes that produce hypertension in this model.

Acetylcholine↗

PubMed1997

Elevated 12-lipoxygenase activity in the spontaneously hypertensive rat.

We have previously demonstrated that administration of inhibitors of the lipoxygenase (LO) pathway of arachidonic acid metabolism lowers blood pressure in hypertensive rats. In addition, we have shown that LO inhibition attenuates pressor agonist-induced vascular reactivity in vitro and calcium mobilization in cultured vascular smooth muscle cells (VSMC). To further elucidate the relationship between elevated LO activity and hypertension, 4, 8, and 12 week old hypertensive SHR were compared with age-matched Wistar-Kyoto (WKY) rats for plasma 12(S)-hydroxyeicosatetraenoic acid (12-HETE) concentration. 12-HETE levels were significantly elevated in the SHR compared to the WKY (SHR elevated by 154%, 159%, and 272% compared to WKY at 4, 8, and 12 weeks, respectively, P < .01 for all ages). There were no differences in plasma potassium levels between SHR and WKY at any of the ages tested. Plasma aldosterone levels and plasma renin activity were in the normal range at the three ages. At 12 weeks of age, both serum (4.72 +/- 0.23 v 2.18 +/- 0.33 microg/mL, P < .01), and aortic smooth muscle 12-HETE levels (0.94 +/- 0.09 v 0.66 +/- 0.08 microg/mg protein, P < .05) were elevated in SHR compared with WKY. The 12 week old SHR were given a bolus of the LO inhibitor 5,8,11-eicosatriynoic acid (ETI, 7 mg/kg, intravenously) and blood pressure measured after 20 min. ETI reduced mean systolic blood pressure from 175.8 +/- 4.2 to 141.6 +/- 5.9 mm Hg (P < .05). To investigate these effects of HETEs, cultured vascular smooth muscle cells were pretreated for 1 min with 12(S)HETE and then challenged with angiotensin II (AngII). The addition of 12(S)HETE increased AngII-induced intracellular calcium levels in normal cultured rat vascular smooth muscle cells by 78% compared to vehicle (P < .05). Thus, LO products, which are high in SHR, may contribute to vascular tone through alterations in the intracellular calcium signal by potentiating calcium responses to pressors such as Ang II.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗

PubMed1996

Do reduced insulin sensitivity and dyslipidemia exist in borderline hypertensive patients?

To evaluate the relationship between insulin resistance, dyslipidemia, and blood pressure (BP), we measured BP, blood glucose, plasma insulin (INS) levels, total cholesterol (T-ch), and triglyceride after an overnight fast in 454 Japanese young, nonobese, nondiabetic factory workers, including 226 normotensive (NT), 120 borderline hypertensive (BHT), and 108 essential hypertensive (EHT) subjects. Age and body mass index were strictly matched among the three groups. Fasting INS and T-ch were greater in BHT > EHT > NT (BHT v NT, P < .05; EHT v NT, P < .05). We also recognized significantly positive correlations between T-ch and mean BP (R = 0.39, P = .021), and between fasting INS and mean BP (r = 0.56, P = .013). These results suggest that insulin resistance and dyslipidemia are associated with hypertension in its early stage.

Adult↗

PubMed1996

Mechanisms mediating postprandial blood pressure reduction in young and elderly subjects.

The objective of this study was to clarify potential differences in hormonal, neurogenic and hemodynamic mechanisms mediating postprandial blood pressure (BP) reduction. In 12 age- and body mass index-matched young normotensive (NT) subjects, 21 elderly NT, 17 young hypertensive (EH) patients, and 32 elderly EH, we measured BP, blood glucose, plasma insulin (IRI), and norepinephrine (NE) levels before and every 30 min for 3 h after a 75 g oral glucose solution ingestion. Cardiac output (CO) and total systemic resistance (TSR) were also measured before and 1 h after oral glucose ingestion. Postprandial BP reduction, defined as 10% or more decline in mean BP was recognized in 3/12 (25%) young NT, 9/21 (43%) elderly NT, 5/17 (29%) young EH, and 20/32 (63%) elderly EH. The most consistent finding was that the IRI response to glucose was high in all subjects with postprandial BP reduction regardless of age or level of BP, although changes in blood glucose levels showed no major differences. The NE level was low in young and elderly NT with postprandial BP reduction, but in EH the level was not different. Increases in CO in elderly subjects with postprandial BP reduction was significantly less than that in subjects without postprandial BP reduction. In addition, the decrease in TSR in young subjects with postprandial BP reduction was significantly greater than that in subjects without postprandial BP reduction, while the decrease in elderly subjects was not different between the subjects with and without postprandial BP reduction. In conclusion, postprandial BP reduction in elderly EH appears to be associated with hyperinsulinemia independent of age and BP status. The vasodilator effects of insulin may contribute to postprandial BP reduction. A second conclusion is that impairment of sympathetic nervous system responses to insulin may also contribute to altered postprandial hemodynamic responses especially in EH, suggesting multiple mechanisms in origin of postprandial BP reduction.

Adult↗

PubMed1996

Changes in frequency of orthostatic hypotension in elderly hypertensive patients under medications.

To evaluate changes in frequency of orthostatic blood pressure (BP) reduction (orthostatic hypotension; OH) in elderly hypertensive patients (HT) before and after treatment for hypertension, we measured BP after supine for 10 min and standing position for 2 min, before and after treatment for 2 years by five kinds of antihypertensive drugs in 50 elderly normotensive subjects (NT) and each of 50 HT in double-blind study. Orthostatic hypotension was defined as 10% or more decline of supine mean BP, and the frequency of OH was in 27% of HT following BP reduction by any kinds of antihypertensive drugs. In conclusion, the reducing or normalized BP by treatment for hypertension in elderly HT decreases the prevalence of orthostatic hypotension.

Aged↗

PubMed1996

Differences in insulin and sympathetic responses to glucose ingestion due to family history of hypertension.

To evaluate the relationship of metabolic and neural factors in familial hypertension, we examined blood pressure (BP), blood glucose, and plasma insulin and norepinephrine (NE) levels before and every 30 min for 120 min after glucose ingestion in six groups with 20 subjects each: normotensive subjects (NT) with and without a family history of hypertension; borderline hypertensive patients (BHT) with and without a family history of hypertension; and established hypertensive patients (EH) with and without a family history of hypertension. The changes in blood glucose were similar in the six groups. In the subjects with a positive family history of hypertension regardless of BP levels, the basal levels and changes in insulin levels after glucose ingestion were significantly greater than those in the subjects without a family history of hypertension (F = 13.32, P = .0001). In BHT and EH subjects, regardless of family history, changes in insulin were greater than in NT (F = 16.00, P = .0001). Basal levels and changes in plasma NE were higher in BHT and EH (F = 26.55, P = .0001) than NT and changes in plasma NE were greater in subjects with a family history than those in subjects without a family history (F = 18.32, P = .0001). Thus, abnormal insulin and NE responses to glucose appear to aggregate in subjects with a history of familial hypertension, regardless of the level of BP. Furthermore, the ratio of delta NE/ delta insulin (changes from basal to peak) in NT and BHT, and in subjects with a family history were significantly greater than in EH and in subjects without a family history. Thus, we demonstrated that concomitant abnormalities in the glucose-insulin regulatory system and the sympathetic nervous system characterize the early phase in the development of hypertension and these abnormalities have an apparent genetic basis.

Adult↗

PubMed1996

Increased inward passive permeability in vitro to sodium in uraemic erythrocytes.

1. We have reported a normal sodium (Na) pump, but decreased loop-diuretic-sensitive Na efflux in erythrocytes from patients with chronic renal failure on haemodialysis, suggesting a different mode of co-transport in uraemia. 2. The present work extends these findings and examines in vitro simultaneous unidirectional and radiolabelled Na and K fluxes through the Na/K/Cl co-transport and the Na/K pump in washed erythrocytes from seven subjects with chronic renal failure and seven controls. Erythrocyte cytosolic calcium was also examined. 3. Ouabain-sensitive 86Rb influx was similar in patients and controls (1.76 +/- 0.19 versus 1.72 +/- 0.13 mmol h-1 litre-1 of erythrocytes) as was ouabain-sensitive 22Na efflux (3.62 +/- 0.36 versus 4.04 +/- 0.39 mmol h-1 litre-1 of erythrocytes). 4. Bumetanide-sensitive 86Rb and 22Na influx and 22Na efflux were measured at three concentrations (4, 8 and 12 mmol/l) of external K. In chronic renal failure, mean bumetanide-sensitive 22Na efflux was decreased at all external K concentrations compared with controls, and at physiological concentrations (4 mmol/l) external K was lower than controls (0.14 +/- 0.01 versus 0.38 +/- 0.05 mmol h-1 litre-1 of erythrocytes, P < 0.01). Mean bumetanide-sensitive 86Rb influx was also reduced in chronic renal failure at all external K concentrations, and at 4 mmol/l external K was lower than controls (0.13 +/- 0.04 versus 0.34 +/- 0.04 mmol h-1 litre-1 of erythrocytes, P < 0.01). Conversely, bumetanide-sensitive 22Na influx was markedly increased at all external K levels in chronic renal failure, and at 4 mmol/l external K values were elevated compared with controls (0.64 +/- 0.18 versus 0.34 +/- 0.04 mmol h-1 litre-1 of erythrocytes, P < 0.001). The mean cytosolic calcium concentration was higher in erythrocytes in chronic renal failure than controls (134.4 +/- 8.6 versus 63.7 +/- 5.8 nmol/l, P < 0.001). 5. Thus, in washed erythrocytes incubated in artificial media there is a markedly increased ouabain-insensitive Na influx in subjects with chronic renal failure which might be explained in part by the higher levels of cytosolic calcium. In vivo, this cell defect combined with suppression of the Na/K pump could lead to intracellular Na accumulation and play a role in uraemic complications.

Adult↗

PubMed1996

Glucose and insulin metabolism in hypertension.

Individuals with abnormal glucose and insulin metabolism have a higher incidence of hypertension, and recent interest has focused on the fact that patients with untreated essential hypertension have higher than normal plasma insulin concentrations, are resistant to insulin-stimulated glucose uptake and often have accompanying lipid disorders. The pathophysiological significance of these observations lies in the findings that insulin has mitogenic properties and can potentiate vascular smooth muscle growth, thus promoting structural changes in vessels and atherosclerosis. Insulin could also promote high blood pressure via its effect in increasing sodium reabsorption and sympathetic nervous system activity. A variety of therapies is available for treatment of hypertension in patients with metabolic complications. Lifestyle modification is considered to be the initial approach, with weight management the most important component. Although diuretics and beta-blockers have a proven record in reducing morbidity and mortality, they may have adverse effects on glucose, insulin and lipids and should be used with caution in hypertensive subjects with metabolic risks. alpha-adrenergic blockers have favorable effects on lipids and glucose. Calcium antagonists have no adverse effect on glucose or insulin in patients with essential hypertension or diabetic patients with hypertension. ACE inhibitors, on the other hand, have neutral or beneficial effects on glucose, insulin and lipid metabolism, improving insulin sensitivity, insulin secretion, potassium balance and intermediary metabolism. Finally, oral hypoglycemic agents, which improve glucose metabolism and insulin sensitivity, can reduce blood pressure in obese, hypertensive subjects.

Animals↗

PubMed1996

Tonic inhibition of renin secretion by the 12 lipoxygenase pathway: augmentation by high salt intake.

Recent evidence suggests that lipoxygenase (LO) metabolites inhibit renin production in vitro. However, the physiological significance of this effect has not been determined. This study examined the role of the LO pathway in the regulation of plasma renin concentration (PRC) in vivo. The acute administration of two structurally unrelated LO inhibitors, phenidone (30 and 60 mg/kg) and esculetin (60 mg/kg), resulted in suppression of platelet 12 hydroxyeicosatetraenoic acid (12HETE) production, reduction in systemic arterial pressure and a 2- to 3-fold increase in PRC. To determine whether the esculetin-induced increase in PRC was secondary to hypotension, esculetin was also administered to rats preinfused with a pressor dose of norepinephrine. In these acutely hypertensive rats, esculetin still induced a 2.5-fold increase in PRC, whereas blood pressure remained over 40 mm Hg above basal levels. Further, esculetin (10(-6)M) increased renin release in renal slices from 150 +/- 10 to 310 +/- 20 ng/ml.h (P < 0.05) and this rise was entirely blocked in the presence of 12HETE (10(-7)M; 130 +/- 40 ng/ml.h). In rats placed on high salt intake, 12HETE concentration in renal slices from the outer cortex was considerably higher than in renal slices from salt-restricted rats (116.5 +/- 15.7 vs. 65 +/- 12 pg/mg protein; P < 0.05). Chronic administration of the LO inhibitor phenidone also resulted in an increase of PRC, which was independent of changes in blood pressure. On either high salt (3.15%0 or low salt (0.05%) diet phenidone-treated rats had higher PRC levels than the respective control groups [high salt 9.7 +/- 3.5 vs. 1.9 +/- 1.4 ng/ml.h; P < 0.05; low salt 33.2 +/- 5.3 vs. 19.4 +/- 3.10 ng/ml.h; P < 0.05]. The finding that LO blockers are potent stimulators of PRC in vivo suggests the existence of a physiological tonic inhibition of renin secretion by LO products that is operative under a wide range of salt intake. High salt intake enhances this inhibitory tone by increasing renal cortical 12 LO activity and, in fact, normal suppression of PRC during high salt diet does not occur in LO-blocked animals. Thus, the LO pathway exerts a tonic inhibitory effect on renin release, which appears particularly important for renin suppression during high salt intake.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗

PubMed1996

Platelet lipoxygenase inhibitors attenuate thrombin- and thromboxane mimetic-induced intracellular calcium mobilization and platelet aggregation.

Platelets metabolize arachidonic acid via cyclooxygenase and lipoxygenase (LO) enzymatic pathways. Although platelets produce large amounts of arachidonic acid metabolites via the LO pathway, little is known regarding the physiological significance of these products. We used three structurally dissimilar LO inhibitors, 5,8,11-eicosatriynoic acid (ETI), baicalein and phenidone, and found that LO inhibition attenuated thrombin- and U46619 (a thromboxane mimetic)-induced increases of platelet intracellular calcium ([Ca++]i) in washed human platelets. LO inhibitors also reduced platelet aggregation induced by thrombin and U46619. The effect of ETI on reducing the thrombin-induced [Ca++]i elevation persisted even when cation channels were blocked, suggesting that LO inhibitors modify release of Ca from intracellular stores. Stimulating endogenous LO product formation potentiated thrombin-induced [Ca++]i responses and aggregation, and these effects were eliminated by ETI. ETI did not alter inositol 1,4,5-trisphosphate production in stimulated platelets, but increased platelet cyclic AMP production in thrombin- or forskolin-stimulated platelets. These results suggest that LO products are regulators of platelet [Ca++]i mobilization and aggregation in response to some agonists, and that LO inhibitors may work in part by modifying platelet cyclic AMP metabolism.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗

PubMed1995

Secondary aldosteronism.

Conditions of secondary aldosteronism are common in clinical medicine, occurring in normotensive and hypertensive settings. In some conditions such as edema disorders, this represents a partially beneficial response to restore volume and Na at the expense of hypokalemia. In RVH and malignant hypertension, the aldosteronism may be beneficial, but most evidence shows a detrimental impact. In both situations, aldosterone does not compensate fully for Na degradation and facilitates K loss. In pregnancy, aldosterone's effects is more successful for volume conservation, and the action on K is almost completely overridden by other K-sparing factors. Chronic renal failure seems to best benefit from hyperaldosteronism, but the response is limited because aldosterone must act on extrarenal targets. In iatrogenic causes of secondary aldosteronism, the effects of aldosterone are mostly detrimental. The overall conclusion supports the hypothesis that aldosterone functions best in physiologic situations, but in pathophysiologic settings it does not perfectly compensate for the basic defect. This implies that in these complex conditions, successful therapy should address the disorder in aldosterone and also the other underlying pathophysiologic mechanisms.

Aldosterone↗

PubMed1994

Dexamethasone enhances active cation transport in cultured aortic smooth muscle cells.

Previous studies have indicated that ouabain-sensitive cation transport is increased in arteries obtained from rats with glucocorticoid-induced hypertension. However, it remained unclear whether this effect reflected direct glucocorticoid activation or rather depended on the elevated arterial pressure per se. In the present study, we examined the effect of dexamethasone on cultured rat aortic smooth muscle cells. Dexamethasone (10(-9) mol/L) increased ouabain-sensitive 86Rb uptake by about 50% (control: 16.5 +/- 1.6 pmol/mg protein/10 min; dexamethasone 10(-9) mol/L: 24.4 +/- 1.3 pmol/mg protein/10 min). The effect was not apparent until 18 h of incubation and was partly inhibited by the mineralocorticoid antagonist spironolactone. Dexamethasone also increased membrane potential in these cells by an average of 9.5 mV (control: -43.3 +/- 4 mV; dexamethasone: -52.8 +/- 4 mV), presumably reflecting increased intracellular K+ activity as a result of dexamethasone's effect on the Na,K pump. These results suggest a direct effect of glucocorticoids on arterial Na,K pump. The physiopathological significance of this effect remains to be determined.

Aldosterone↗

PubMed1994

Role of insulin and norepinephrine in the hypertension of obesity.

The present study compares plasma norepinephrine (PNE), renin activity (PRA), aldosterone (PA), and insulin (RIAI) levels between 13 normotensive and 42 hypertensive obese subjects during weight maintenance, and in 19 of the 42 obese hypertensive subjects, these variables were measured during 16 weeks on a very low calorie diet (VLCD). Mean values for baseline RIAI and PNE were elevated in the 55 obese subjects compared to nonobese controls. However, when the normotensive and hypertensive groups were compared, mean values for PNE, PRA, PA, and RIAI were not different. In the 19 obese hypertensive subjects studied on the VLCD, there were significant reductions from baseline in mean body weight, blood pressure, RIAI, and PNE, but not for PRA or PA. Two phases of blood pressure, RAIA, and PNE responses to weight loss were noted. In the early phase (days 1-7), blood pressure and RAIA decreased dramatically, whereas PNE, PRA, and PA increased. During the late phase (weeks 2-16), further significant decreases in blood pressure and weight were accompanied by reductions in PNE (604 +/- 50 to 403 +/- 43 pg/mL, P < .01) and in RIAI (13.9 +/- 1.7 to 10.3 +/- 1.6 microU/mL, P < .05). As levels of insulin and norepinephrine were similar in normotensive and hypertensive obese individuals during weight maintenance, they may not contribute to the hypertension associated with obesity. During weight loss, however, the temporal changes in blood pressure, insulin, and norepinephrine suggest their mediation of the hypotensive response.

Adult↗

PubMed1994

Parathyroid hormone analogues inhibit calcium mobilization in cultured vascular cells.

Parathyroid hormone and parathyroid hormone-related protein lower blood pressure and relax contracted arteries. Parathyroid hormone also attenuates angiotensin II-induced vasoconstriction. To determine the cellular mechanism or mechanisms by which parathyroid hormone analogues antagonize pressor effects, we examined the effect of these peptides on angiotensin II-induced calcium mobilization in fura 2-AM-loaded cultured rat vascular smooth muscle cells. Either 100 nmol/L parathyroid hormone or parathyroid hormone-related protein significantly reduced the amount of calcium mobilized by 100 nmol/L angiotensin II. The attenuating effect of these peptides was mimicked by 10 mmol/L forskolin and 10 mmol/L isobutylmethylxanthine and was not dependent on the presence of extracellular calcium. This effect of the parathyroid hormone analogues was reduced when cells were pretreated with 100 mmol/L 2',5'-dideoxyadenosine, an adenylate cyclase inhibitor. Combined inhibition of cyclic nucleotide-dependent protein kinases eliminated the inhibitory effect of parathyroid hormone, whereas protein kinase C inhibition had no effect. Parathyroid hormone analogues decreased the amount of calcium released by inositol 1,4,5-trisphosphate in digitonin-permeabilized vascular smooth muscle cells. This effect was inhibited by treatment with 2',5'-dideoxyadenosine. These results suggest that these peptides attenuate inositol 1,4,5-trisphosphate-sensitive calcium mobilized by angiotensin II via an adenylate cyclase-dependent mechanism. This may be a mechanism by which acute administration of parathyroid hormone or parathyroid hormone-related peptide antagonizes vasoconstriction.

Animals↗