Effects of low dose versus conventional dose thiazide diuretic on insulin action in essential hypertension.

OBJECTIVE--To see whether low dose thiazide diuretics given to patients with essential hypertension might avoid the adverse metabolic consequences seen with conventional doses. DESIGN--Double blind randomised crossover study of two 12 week treatment periods with either low dose (1.25 mg) or conventional dose (5.0 mg) bendrofluazide given after a six week placebo run in period. SETTING--Outpatient clinics serving the greater Belfast area. SUBJECTS--16 white non-diabetic patients (9 male) under 65 with essential hypertension recruited from general practices within the greater Belfast area. MAIN OUTCOME MEASURES--Systolic and diastolic blood pressure and peripheral and hepatic insulin action. RESULTS--One man failed to complete the study. There were no differences between doses in their effects on systolic and diastolic blood pressure. Bendrofluazide 1.25 mg had substantially less effect on serum potassium concentration than the 5.0 mg dose. There were no intertreatment differences in fasting glucose, insulin, cholesterol, and triglyceride concentrations. Bendrofluazide 5.0 mg significantly increased postabsorptive endogenous glucose production compared with baseline (mean 10.9 (SD 1.2) v 10.0 (0.8) mumol/kg/min), whereas bendrofluazide 1.25 mg did not. Postabsorptive endogenous glucose production was significantly higher with bendrofluazide 5.0 mg compared with 1.25 mg (10.9 (1.2) v 9.9 (0.8) mumol/kg/min) but was suppressed to a similar extent after insulin (bendrofluazide 5.0 mg 2.8 (1.5) mumol/kg/min v bendrofluazide 1.25 mg 2.2 (1.5) mumol/kg/min). Exogenous glucose infusion rates required to maintain euglycaemia were not significantly different between doses and were similar to baseline. CONCLUSIONS--Bendrofluazide 1.25 mg is as effective as conventional doses but has less adverse metabolic effect. In contrast with conventional doses, low dose bendrofluazide has no effect on hepatic insulin action. There is no difference between low and conventional doses of bendrofluazide in their effect on peripheral insulin sensitivity.     

Interaction of biofeedback-assisted relaxation and diuretic in treatment of essential hypertension

Thirty patients with essential hypertension participated in a study designed to compare two treatments: diuretic medication alone (n=10) and biofeedback assisted relaxation combined with diuretic (n=20). One of 10 patients lowered BP with diuretic alone and 11 of 20 patients lowered BP with diuretic combined with biofeedback-assisted relaxation. The addition of the behavioral intervention to the diuretic therapy produced a decrease in blood pressure beyond that associated with the diuretic alone. The decreases in BP mediated by diuretic were related to high entry levels of BP, low anxiety, forehead muscle tension, anger expression and plasma renin activity. The BP decrease mediated by combined diuretic and biofeedback-assisted relaxation was associated with high pretreatment BP, anger controlled, low finger temperature and high/normal plasma renin activity.This work supported by the Northwestern Ohio Heart Association under grant No. 93132 to Dr. McGrady.     

Interaction of biofeedback-assisted relaxation and diuretic in treatment of essential hypertension.

Thirty patients with essential hypertension participated in a study designed to compare two treatments: diuretic medication alone (n = 10) and biofeedback assisted relaxation combined with diuretic (n = 20). One of 10 patients lowered BP with diuretic alone and 11 of 20 patients lowered BP with diuretic combined with biofeedback-assisted relaxation. The addition of the behavioral intervention to the diuretic therapy produced a decrease in blood pressure beyond that associated with the diuretic alone. The decrease in BP mediated by diuretic were related to high entry levels of BP, low anxiety, forehead muscle tension, anger expression and plasma renin activity. The BP decrease mediated by combined diuretic and biofeedback-assisted relaxation was associated with high pretreatment BP, anger controlled, low finger temperature and high/normal plasma renin activity.     

Solubilization and partial purification of the thiazide diuretic receptor from rabbit renal cortex

This study was designed to solubilize, characterize and begin to purify the thiazide-sensitive Na/Cl transporter from mammalian kidney. Metolazone, a thiazide-like diuretic drug, binds to receptors in rat renal cortex closely related to the thiazide-sensitive Na/Cl transport pathway of the renal distal tubule. In the current study, [3H]metolazone bound to receptors in rabbit renal cortical microsomes. The portion of [3H]metolazone binding that was inhibited by hydrochlorothiazide reflected binding to a high-affinity class of receptor. The affinity (Kd 2.0 +/- 0.1 nM) and number (Bmax = 0.9 +/- 0.4 pmol/mg protein) of high-affinity receptors in rabbit renal cortical membranes were similar to values reported previously for rat. When proximal and distal tubule fragments were separated by Percoll gradient centrifugation, receptors were restricted to the fraction that contained distal tubules. When compared with cortical homogenates, receptor density was enriched 12-fold by magnesium precipitation and differential centrifugation. The zwitterionic detergent CHAPS solubilized 25-35% of the receptors (at 6 mM). Chloride inhibited and Na stimulated binding of [3H]metolazone to solubilized high-affinity receptors. The receptors could be purified significantly by hydroxyapatite chromatography and size exclusion high performance liquid chromatography (HPLC). The combination of magnesium precipitation and differential centrifugation, hydroxyapatite chromatography, and size exclusion HPLC resulted in a 213-fold enrichment of receptors, compared to renal cortical homogenate. The current results indicate that thiazide receptors from rabbit kidney share characteristics with receptors from rat, and that rabbit receptors can be solubilized in CHAPS and purified significantly by hydroxyapatite chromatography and size exclusion HPLC.     

Influence of non-steroidal anti-inflammatory drugs on diuretic treatment of mild to moderate essential hypertension.

In an open triple crossover study in 10 patients with mild to moderate essential hypertension the influence was investigated of adding indomethacin 50 mg, naproxen 250 mg, or sulindac 200 mg, each twice daily for four weeks, to diuretic treatment with hydrochlorothiazide 50 mg a day. After two weeks'' treatment with indomethacin a slight increase in blood pressure was observed, whereas both sulindac and naproxen tended to enhance the antihypertensive effect of hydrochlorothiazide. After treatment for four weeks, however, the effects of all three drugs on blood pressure appeared to be blunted. Furthermore, body weight increased significantly during treatment with indomethacin but not during treatment with naproxen or sulindac. No significant changes were found for various biochemical variables, including concentrations of plasma electrolytes and serum creatinine and albumin, plasma renin activity, plasma aldosterone concentration, and 24 hour urinary excretion of sodium and potassium, with the exception, however, of an increase in plasma potassium concentration during treatment with indomethacin. These observations suggest that the interaction of indomethacin, naproxen, and sulindac with diuretic treatment in mild to moderate essential hypertension is transient and of minor clinical importance.     

The pathophysiology of hyperuricemia in essential hypertension: a pilot study

We have examined whether hyperuricemia in essential hypertension may be related to an increased insulin secretion thereby enhancing the tubular reabsorption of sodium and thus uric acid. Insulin hypersecretion, as elicited by the oral glucose tolerance test (OGTT), increased a mean of 5-fold in 12 essential hypertensive patients. Urinary uric acid to creatinine ratio significantly diminished by a mean of 62% after the OGTT. Simultaneously, urinary sodium to creatinine ratio decreased by a mean of 54%. These results suggest that insulin may mediate uric acid underexcretion due to its tubular sodium retaining effect in essential hypertensive patients.     

Biobehavioral treatment of essential hypertension: a group outcome study

In a group outcome and follow-up study of 77 patients with essential hypertension, significant reductions were seen in systolic and diastolic blood pressure (BP) and in hypotensive medication requirement. A multimodality biobehavioral treatment was used which included biofeedback-assisted training techniques aimed at teaching self-regulation of vasodilation in the hands and feet. Of the 54 medicated patients, 58% were able to eliminate hypotensive medication while at the same time reducing BP an average of 15/10 mm Hg. An additional 19 (35%) of the medicated patients were able to cut their medications approximately in half while reducing BP by 18/10 mm Hg. The remaining 4 (7%) medicated patients showed no improvement in either BP or medication requirement. Similar reductions in BP were seen in initially unmedicated patients. Seventy percent of the 23 unmedicated patients achieved average pressures below 140/90 mm Hg, with an additional 22% of these patients making clinically significant reductions in pressure without becoming normotensive, and with 8% unsuccessful at lowering pressures to a clinically significant extent. Follow-up data available on 61 patients over an average of 33 months indicated little regression in these results with 51% of the total patient sample remaining well-controlled off medication, an additional 41% partially controlled, and 8% unsuccessful in lowering either medications and/or blood pressures to a clinically significant extent.     

Randomised controlled comparative study of methyldopa and oxprenolol in treatment of hypertension in pregnancy.

One hundred pregnant women with hypertension (defined as diastolic blood pressure at or above 95 mm Hg) were allocated at random to treatment with methyldopa or oxprenolol and were compared with nonhypertensive controls matched according to parity and gestation at delivery. The patients were also stratified into those entering the study early (before 32 weeks'' gestation) and those entering late (after 32 weeks'' gestation). Although there were no differences in diastolic blood pressure between the hypertensive groups before or during treatment, in the early entry group the systolic blood pressure at entry of those allocated to oxprenolol was significantly higher than that of those receiving methyldopa; this difference remained throughout the treatment period. Also in the early entry group further increments of drug treatment were required to control blood pressure of patients receiving oxprenolol than in those receiving methyldopa. The eventual fetal outcome for all patients treated with methyldopa was the same as that for those treated with oxprenolol; birth weight, placental weight, head circumference, and Apgar score were not significantly different and there were no stillbirths in either group.     

Raynaud's phenomenon as side effect of beta-blockers in hypertension.

A series of 102 hypertensive patients were assessed for the frequency of symptoms of Raynaud''s phenomenon and absent peripheral pulses. Out of 21 patients receiving methyldopa alone only one had cold hands and feet whereas among patients on beta-blockers the incidence was 50%. The frequency of both symptoms and absent pulses was highest in patients taking propranolol compared with those taking atenolol or oxprenolol. Patients without a foot pulse were much more likely to have cold hands. A change from propranolol to oxprenolol in some symptomatic patients resulted in improvement. In two patients the skin temperature fell after an 80-mg dose of propranolol. The mechanism by which beta-blockers induce Raynaud''s phenomenon is still not clear.     

Lack of effect of beta-blocker on flat dose response to thiazide in hypertension: efficacy of low dose thiazide combined with beta-blocker.

Increasing the dose of a thiazide diuretic used alone in patients with essential hypertension has little further effect on blood pressure but increases the deleterious metabolic consequences of the diuretic. The effect of a beta-blocker on this flat dose response is not known. In two randomised crossover studies the effect of 12.5 mg, 25 mg, and 50 mg hydrochlorothiazide combined with 400 mg acebutolol was assessed. The mean fall in supine blood pressure was about 15% and was the same whatever dose of thiazide was used with the beta-blocker. As the dose of hydrochlorothiazide was increased, however, there was evidence of increasing metabolic consequences of the diuretic. The study did not define the minimum dose of diuretic, and doses of hydrochlorothiazide lower than 12.5 mg might be as effective. These results suggest that many patients who are being treated with a combination of a beta-blocker and a diuretic are receiving unnecessarily large amounts of the diuretic without benefit to their blood pressure and with adverse metabolic consequences.     

"Third drug" trial: comparative study of antihypertensive agents added to treatment when blood pressure remains uncontrolled by a beta blocker plus thiazide diuretic.

Hydralazine, labetalol, methyldopa, minoxidil, prazosin, and placebo were compared when added by random allocation to atenolol 100 mg and bendrofluazide 5 mg daily in a series of 238 hypertensive patients inadequately controlled by the beta blocker-diuretic combination. Atenolol was withdrawn in those allocated to labetalol, and minoxidil was given only to men. The order of acceptability was: placebo, hydralazine, prazosin, methyldopa, minoxidil, labetalol. Minoxidil was more effective than the other active drugs, which had similar potency to one another. All the active agents were more effective than placebo. Hydralazine was the most generally suitable third drug, with prazosin a close second. Minoxidil was especially effective in patients with less severe hypertension but the same regimen caused fluid retention in those with more severe disease. Labetalol should probably be introduced at a low dose (150 mg daily) even when replacing full doses of a previously administered beta blocker.     

Common variation in KLKB1 and essential hypertension risk: tagging-SNP haplotype analysis in a case-control study

The human plasma kallikrein gene (KLKB1) encodes plasma kallikrein, a serine protease that catalyzes the release of kinins and other vasoactive peptides and may be involved in the pathogenesis of hypertension. In this study, we performed a haplotype-based study to assess the effect of common genetic variation in the KLKB1 gene on the risk of essential hypertension. Eight common single nucleotide polymorphisms (SNPs) were selected from the HapMap database and used to determine the pattern of linkage disequilibrium (LD) and haplotype structure within the KLKB1 gene. Four tag SNPs were then identified with over 85% power to predict both common haplotypes and remaining common SNPs, and genotyped in 1,317 cases with essential hypertension and 1,269 healthy controls. Single SNP analyses indicated that SNPs rs2304595 and rs4253325 were significantly associated with hypertension, adjusted for covariates. Compared with the most common Hap2 CAGC, Hap1 AGAC and Hap3 CGAC, which carry the susceptible rs2304595 G allele and rs4253325 A allele, were found to significantly increase the risk of essential hypertension with adjusted odds ratios equal to 1.37 and 1.17, respectively (P < 0.0001 and 0.028). A strongly significant interaction with gene-drinking was also observed. Among drinkers, the adjusted OR for Hap1 relative to Hap2 was increased to 2.50 (95% CI, 2.40 to 2.61; P < 0.0001). This was the first study to perform association analysis of the KLKB1 gene with essential hypertension. Our findings suggested that common genetic variation in the KLKB1 gene might contribute to the risk of hypertension in the northern Han Chinese population. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. Conflict of interests: None.     

Biobehavioral treatment of essential hypertension: A group outcome study

In a group outcome and follow-up study of 77 patients with essential hypertension, significant reductions were seen in systolic and diastolic blood pressure (BP) and in hypotensive medication requirement. A multimodality biobehavioral treatment was used which included biofeedback-assisted training techniques aimed at teaching self-regulation of vasodilation in the hands and feet. Of the 54 medicated patients, 58% were able to eliminate hypotensive medication while at the same time reducing BP an average of 15/10 mm Hg. An additional 19 (35%) of the medicated patients were able to cut their medications approximately in half while reducing BP by 18/10 mm Hg. The remaining 4 (7%) medicated patients showed no improvement in either BP or medication requirement. Similar reductions in BP were seen in initially unmedicated patients. Seventy percent of the 23 unmedicated patients achieved average pressures below 140/90 mm Hg, with an additional 22% of these patients making clinically significant reductions in pressure without becoming normotensive, and with 8% unsuccessful at lowering pressures to a clinically significant extent. Follow-up data available on 61 patients over an average of 33 months indicated little regression in these results with 51% of the total patient sample remaining well-controlled off medication, an additional 41% partially controlled, and 8% unsuccessful in lowering either medications and/or blood pressures to a clinically significant extent.This research was partially supported by grant HL-32136. The Authors wish to thank Sarah Bremer for her assistance in preparing this article.     

Gravitation in pathogeny of essential hypertension

The purpose of this research is the study of changes of a systemic hemodynamics under passive orthostatic test for a healthy persons and an ill with Essential Hypertension (EH) and analysis of a possible role of the gravitational factor in a Pathogeny of this disease. For an ill with EH reduction of Stroke Volume and Cardiac Output were reliably lower in an orthostatic position. Increasing of a Total peripheral vascular resistance was twice less for ill. Considerable differences in reaction of cardiovascular system to gravitational influence for an ill with Essential Hypertension are stipulated by changes in central regulation of circulation and in the structure of a vascular wall. It allows to assume influence of gravitation at early stages of a Pathogeny of the given disease. The detection of hyper reactivity of a cardiovascular system to influence of gravitation can indicate the first stage of the disease.     

Aldosterone and magnesium in essential arterial hypertension

Thirty mildly hypertensive patients and 27 patients with severe essential hypertension and high levels of aldosterone were selected for a study of the relationship between plasma aldosterone and magnesium in essential arterial hypertension; levels of calcium and potassium were also studied. Thirty-six individuals were used as a control group. Our findings indicate that as plasma aldosterone levels increase, serum magnesium levels decrease correspondingly: in mild hypertensives with low levels of plasma aldosterone p less than 0.05 and in the most severely hypertensive patients with high levels of plasma aldosterone p less than 0.001. In this latter group we also found an inverse correlation between serum magnesium and systolic arterial pressure (p less than 0.001) and diastolic pressure (p less than 0.01). In these patients a significant increase in urinary excretion of magnesium was found, with levels 3 times higher than in the control group. These findings suggest a close relationship between changes in plasma aldosterone and magnesium. Possibly the aldosterone contributes through this mechanism to maintaining the hypertensive state in essential arterial hypertension. This action is exercised directly through the kidney, leading to a small but constant urinary loss of magnesium. This in turn leads to a chronic depletion of magnesium in hypertensives who have high levels of plasma renin activity and highly elevated plasma aldosterone.