The reverse-phase separation of neuropeptides using isocratic conditions is described. Each component of the mobile phase was examined for its ability to influence the separation of complex mixtures of neuropeptides. Manipulation of buffer strength, pH, organic modifier and column type provided sufficient flexibility to resolve closely related neuropeptides. Amperometric detection of oxidizable amino acids in the peptide sequence of a number of endogenous neuropeptides proved suitable for the identification of peptide standards and quantification of neural lobe arginine vasopressin and striatal methionine enkephalin.

Animals↗

PubMedDate not supplied

Dietary salt reduction in hypertension--what is the evidence and why is it still controversial?

The link between sodium intake and hypertension remains controversial because of inconsistency between early epidemiologic studies, which showed a strong positive relationship between salt intake and blood pressure/incidence of hypertension, and more recent studies, which showed only modest decreases in blood pressure with sodium reduction, particularly in the normotensive population. In addition, there is clinical evidence that sodium is related to target organ damage such as left ventricular hypertrophy and renal disease. Although the evidence available linking sodium intake and blood pressure in the general population is weak, sodium reduction has been shown to be useful in hypertensive patients, particularly salt-sensitive patients. Whether dietary sodium reduction should be recommended for the general population remains questionable because of marginal benefit and the suggestion of possible deleterious effects on cardiovascular outcomes independent of blood pressure. This paper will review the definition and methods used in determining salt sensitivity, the evidence linking sodium intake and target organ damage, and modern studies of salt and blood pressure.

Animals↗

PubMedDate not supplied

The efficacy and safety of valsartan compared with placebo in the treatment of patients with essential hypertension.

A multicenter, randomized, placebo-controlled, double-masked, parallel-group study was performed to compare the efficacy and safety of valsartan 20, 80, 160, and 320 mg with placebo in the treatment of patients with essential hypertension. A total of 736 adults with uncomplicated essential hypertension stages 1 to 3 were randomized to receive placebo or valsartan 20, 80, 160, or 320 mg daily for 8 weeks. Assessments were made at baseline, after 4 and 8 weeks of treatment, and 2 to 3 days after stopping treatment. The primary efficacy variable was change from baseline in mean sitting diastolic blood pressure (MSDBP). Other variables included change from baseline in mean sitting systolic blood pressure (MSSBP) and responder rates (ie, MSDBP < 90 mm Hg or decrease of > or = 10 mm Hg from baseline). All doses of valsartan produced statistically significant reductions in both MSDBP and MSSBP at end point compared with placebo. A dose-response effect was seen, although the incremental reduction in blood pressure with doses of valsartan > 80 mg was relatively small. Statistically significant differences in responder rates at end point were seen for doses of valsartan of 80 mg and above compared with placebo, whereas the responder rates for valsartan 20 mg was not significantly different from that for placebo. Safety and tolerability variables included data on adverse experiences, rebound hypertension, and clinical laboratory evaluations. Tolerability was good, with headache being the most common complaint and occurring most frequently in placebo patients. The incidence of dizziness was similar among the placebo (5.4%) and valsartan 20-mg to 160-mg groups (2.1% to 3.4%); there was an increase in the incidence of dizziness in the 320-mg group (9.3%). No cases of symptomatic orthostatic hypotension occurred. Analysis of rebound showed that 11.6% of patients receiving placebo and 16.6% receiving valsartan had an increase in MSDBP to baseline levels or above 2 to 3 days after stopping treatment. No clinically significant adverse experiences were noted after stopping treatment. There were no clinically or statistically significant changes in laboratory values during treatment. Thus valsartan proved to be both effective and safe in reducing blood pressure in adults with essential hypertension. The optimal dose range is 80 to 160 mg, given once daily.

Adult↗

PubMedDate not supplied

Efficacy, tolerability, and effects on quality of life of losartan, alone or with hydrochlorothiazide, versus amlodipine, alone or with hydrochlorothiazide, in patients with essential hypertension.

A randomized, double-masked, parallel-group, multicenter clinical trial was conducted to compare the efficacy, tolerability, and effects on quality of life associated with treatment regimens including the angiotensin II receptor antagonist losartan, with hydrochlorothiazide (HCTZ) added as needed, with regimens including the dihydropyridine calcium channel blocker amlodipine with HCTZ added as needed. The trial included patients whose sitting diastolic blood pressure (SiDBP) measurements were between 95 and 114 mm Hg, inclusive, at placebo baseline. Patients were randomized to receive either losartan or amlodipine in a double-masked, double-dummy fashion. A 4-week placebo washout period was followed by a 12-week active treatment period. Patients in the losartan arm (n = 97) were initially given 50 mg of oral (PO) losartan once a day (QD); the medication could be titrated to 50-mg losartan/ 12.5-mg HCTZ PO QD after 4 weeks, followed by 50-mg losartan plus 25-mg HCTZ PO QD after 8 weeks as necessary. Patients in the amlodipine group (n = 93) received 5-mg amlodipine PO QD, which could be titrated to 10 mg PO QD after 4 weeks, followed by 10 mg plus 25-mg HCTZ PO QD after 8 weeks. Medication was titrated upward as necessary to achieve trough SiDBP < 90 mm Hg. Efficacy, tolerability, and quality-of-life scores were assessed after 12 weeks of therapy with each regimen. Trough SiDBP reductions after 4, 8, and 12 weeks of therapy were clinically comparable (losartan group: 7.3, 10.4, and 11.1 mm Hg, respectively; amlodipine group: 7.9, 11.2, and 11.8 mm Hg, respectively). Similar reductions in systolic blood pressure were also seen for both treatment groups. The percentage of patients reaching goal SiDBP (defined as trough SiDBP < 90 mm Hg or SiDBP > or = 90 mm Hg with a > or = 10 mm Hg drop from placebo baseline) was comparable for the two groups, with 68% of patients in the losartan group and 71% of patients in the amlodipine group reaching goal. Significantly more patients in the amlodipine group had drug-related adverse experiences (27% vs 13%). In particular, drug-related edema was more common in patients receiving the amlodipine regimen than in those receiving the losartan regimen (11% vs 1%). Patients in the amlodipine arm reported significantly more bother due to edema, regardless of whether edema was present at baseline, than did patients in the losartan arm (12% vs 2%), although overall quality of life was not different in the two treatment groups. This study demonstrates that a regimen of losartan with HCTZ added as needed, when compared with a regimen of amlodipine with HCTZ added as needed, provides comparable efficacy and superior tolerability and less bother to patients with respect to edema.

Adult↗

PubMedDate not supplied

An elective-titration study of the comparative effectiveness of two angiotensin II-receptor blockers, irbesartan and losartan. Irbesartan/Losartan Study Investigators.

This multicenter, randomized, double-masked, elective-titration study was designed to compare the effectiveness, safety, and tolerability of irbesartan and losartan, two angiotensin II subtype AT1-receptor blockers, in the treatment of patients with mild-to-moderate hypertension. After a 3-week, single-masked, placebo lead-in period, 432 patients with a mean seated diastolic blood pressure (SeDBP) of 95 to 115 mm Hg were randomly allocated to receive either irbesartan 150 mg once daily (n = 213) or losartan 50 mg once daily (n = 219). At week 4, if SeDBP at trough (i.e., 24 +/- 3 hours after the previous dose) was > or = 90 mm Hg, the daily dose was doubled (to irbesartan 300 mg or losartan 100 mg). At week 8, if trough SeDBP was > or = 90 mm Hg, hydrochlorothiazide 12.5 mg once daily was added to the regimen; consistent with the prescribing information for losartan, the dose of losartan was reduced to 50 mg once daily on the addition of hydrochlorothiazide. A total of 370 patients (178 irbesartan and 192 losartan) were evaluable for efficacy. The mean change in trough SeDBP at week 8, the primary efficacy end point, was significantly greater in patients receiving irbesartan monotherapy than in those receiving losartan monotherapy (-10.2 mm Hg vs -7.9 mm Hg, respectively). At week 12, reductions in trough SeDBP and seated systolic blood pressure were greater with irbesartan treatment than with losartan treatment (-13.8 mm Hg vs -10.8 mm Hg and -18.0 mm Hg vs -13.9 mm Hg, respectively), and a greater proportion of irbesartan patients responded to therapy (i.e., trough SeDBP < 90 mm Hg or reduction in trough SeDBP > or = 10 mm Hg) compared with losartan patients (78% vs 64%, respectively). Both regimens were well tolerated.

Adult↗

PubMedDate not supplied

Dose-responsive antihypertensive efficacy of valsartan, a new angiotensin II-receptor blocker.

Predictable dose-related efficacy is considered to be an important attribute of any antihypertensive agent. To determine the magnitude of dose-responsive efficacy for valsartan, a highly selective angiotensin II-receptor blocker, we conducted an integrated analysis of efficacy data from nine double-masked, randomized, placebo-controlled, parallel studies of similar design and of at least 4 weeks' duration. The intent-to-treat analysis included 4067 patients with mild-to-moderate hypertension who had received valsartan (n = 2901) 10, 20, 40, 80, 160, or 320 mg once daily or placebo (n = 1166). Blood pressure was assessed at trough (24 hours after the last dose). In all nine studies, valsartan doses > or = 80 mg produced statistically significant reductions in supine or seated diastolic blood pressure (SDBP) and systolic blood pressure (SSBP) compared with placebo (P < 0.05). The integrated analysis demonstrated a clear increase in blood-pressure-lowering efficacy with increasing dose across the range 10 to 320 mg (placebo-subtracted mean changes from baseline to end point for valsartan 10, 20, 40, 80, 160, and 320 mg, respectively: SDBP, -0.8, -2.8, -2.6, -3.9, -5.1, and -6.4 mm Hg; SSBP, -1.3, -5.7, -5.3, -6.8, -8.6, and -9.0 mm Hg). The data demonstrate that valsartan provides dose-responsive antihypertensive efficacy across the therapeutic dose range, with clinically relevant blood-pressure lowering at doses > or = 80 mg once daily.

Adult↗

PubMedDate not supplied

Hypertension in women.

Hypertension in women has received less attention than hypertension in men, and the major controlled trials of antihypertensive therapy have been carried out in populations made up predominantly of and have emphasised outcomes in men. Recently it has been recognised that women develop high blood pressure, particularly systolic hypertension, at an increased rate as they age, and that this age-related blood pressure increase is exaggerated by the menopause. The age-related rise in blood pressure, particularly systolic blood pressure and pulse pressure, contributes substantially to the age-related increase in risk of heart attack, heart failure, and stroke in middle-aged and elderly women. This article reviews aspects of hypertension epidemiology, pathophysiology, diagnosis and treatment that are important to women's health with particular emphasis on important concomitant cardiovascular disease risk factors such as type 2 diabetes and the menopause. The role of ovarian hormones and their withdrawal in the pathogenesis of hypertension and related target organ damage is considered, as are the results of drug treatment of high blood pressure in women. Blood pressure in pregnancy is discussed in a separate article by Broughton-Pipkin and Roberts.

Age Factors↗

PubMedDate not supplied

Treating hypertension in the elderly--whom to treat, when, and with what?

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Aged↗

PubMedDate not supplied

Primary aldosteronism: a practical approach to diagnosis and treatment.

Primary aldosteronism (PA) may account for as many as 10%-14% of hypertension cases. The plasma aldosterone concentration/plasma renin activity ratio is a simple screening test for PA that should be performed in all patients with refractory/severe hypertension, spontaneous or provoked (by diuretics) hypokalemia, or a requirement for excessive potassium supplementation to maintain normokalemia. PA can be confirmed by a fludrocortisone suppression test or 24-hour urine collection for aldosterone. Confirmatory testing should be followed by high-resolution computerized tomography of the adrenal glands to distinguish bilateral hyperplasia or an adenoma. A solitary tumor greater than 1 cm in size in a younger patient is an indication for surgery; all other (nondiagnostic) findings should be followed by bilateral adrenal venous sampling (if available) to identify a unilateral cause of PA. Treatment for a lateralizing positive study is surgical; spironolactone or another mineralocorticoid receptor antagonist is the treatment of choice for a nonlateralizing study. If adrenal venous sampling is not readily available, patients may be successfully treated pharmacologically.

Humans↗

PubMedDate not supplied

Comparative efficacy of olmesartan, losartan, valsartan, and irbesartan in the control of essential hypertension.

In a multicenter, randomized, double-blind trial, the authors compared the antihypertensive efficacy of once-daily treatment with the new angiotensin II type 1 receptor blocker (ARB) olmesartan (20 mg) with recommended starting doses of losartan (50 mg), valsartan (80 mg), and irbesartan (150 mg) in 588 patients with a cuff diastolic blood pressure (DBP) of greater than or equal to 100 and less than or equal to 115 mm Hg and a mean daytime DBP of greater than or equal to 90 mm Hg and less than 120 mm Hg, as measured by ambulatory blood pressure monitoring. Cuff and ambulatory blood pressures were monitored at baseline and after 8 weeks of treatment. All groups were predominantly white and approximately 62% male, and their mean age was approximately 52 years. In all groups, mean baseline DBP and systolic blood pressure (SBP) were approximately 104 and 157 mm Hg, respectively. The reduction of sitting cuff DBP with olmesartan (11.5 mm Hg), the primary efficacy variable of this study, was significantly greater than with losartan, valsartan, and irbesartan (8.2, 7.9, and 9.9 mm Hg, respectively). Reductions of cuff SBP with the four ARBs ranged from 8.4-11.3 mm Hg and were not significantly different. The reduction in mean 24-hour DBP with olmesartan (8.5 mm Hg) was significantly greater than reductions with losartan and valsartan (6.2 and 5.6 mm Hg, respectively) and showed a trend toward significance when compared to the reduction in DBP with irbesartan (7.4 mm Hg; p=0.087). The reduction in mean 24-hour SBP with olmesartan (12.5 mm Hg) was significantly greater than the reductions with losartan and valsartan (9.0 and 8.1 mm Hg, respectively) and equivalent to the reduction with irbesartan (11.3 mm Hg). All drugs were well tolerated. The authors conclude that olmesartan, at its starting dose, is more effective than the starting doses of the other ARBs tested in reducing cuff DBP in patients with essential hypertension.

Analysis of Variance↗

PubMedDate not supplied

Mechanism of angiotensin I converting enzyme inhibition by SQ20,881 (less than Glu-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro) in vivo. Further evidence for extrapulmonary conversion.

The mechanism by which the angiotensin I (AI) converting enzyme inhibitor SQ20,881 (less than Glu-Trp-Pro-Arg-Pro-Glu-Ile-Pro-Pro) blocks the pressor response to exogenous AI was studied in vivo in the intact anesthetized dog. When administered as a single dose 250 times that of injected AI (250 nmoles/kg) into either the pulmonary or systemic circulation, SQ20,881 produced inhibition of pulmonary conversion of exogenous AI to AII that lasted for more than 6 hours as judged by the absence of immunoreactive or labeled AII in the pulmonary venous effluent. In contrast, the pressor response to exogenous AI began to reappear within 1 hour of SQ20,881 administration. Six hours following SQ20,881, the pressor response to AI had nearly returned to normal, still in the absence of demonstrable intrapulmonary conversion and without release of detectable amounts of AII into the pulmonary venous effluent. These experiments demonstrated that AI has a pressor effect in the presence of SQ20,881 that is independent of pulmonary conversion. Studies with (Des-Asp) AII and (Des-Asp, Arg) AII showed that the delayed pressor response to AI following SQ20,881 administration could not be accounted for by circulating peptide metabolites of AI or AII. A competitive inhibitor of AII, (D-Asp, Ile) AII completely blocked the returning pressor response, suggesting that extrapulmonary generation of AII was responsible. The data strongly suggest that the systemic vascular bed taken as a whole contains large amounts of AI converting enzyme that is capable of rapid generation of AII without releasing the peptide into circulation. The extrapulmonary enzyme is more resistant to long-lasting blockade by SQ20,881 than pulmonary converting enzyme. The physiological role of extrapulmonary conversion systemic and local circulatory homeotasis remains to be assessed.

Angiotensin I↗

PubMedDate not supplied

Nomenclature for experimental renovascular hypertension. Report of the Nomenclature Committee of the Council for High Blood Pressure Research of the American Heart Association.

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Hypertension, Renal↗