Secondary structure model for an unusual SSU rRNA from the extremely thermophilic bacterium strain AZ3 B.1.

The SSU rRNA gene of the extremely thermophilic bacterium strain AZ3 B.1, encodes an rRNA containing four large inserts. A secondary structure model has been constructed which predicts that the inserts form large stem loop structures with a common sequence motif at the base of the helices. To date, these structures have only been detected in related, thermophilic organisms.

Pseudopseudohypoparathyroidism and pheochromocytoma. Association or coincidence?

We saw a patient who had a pheochromocytoma producing hypertension along with clear evidence of pseudopseudohypoparathyroidism (PPHP). Although PPHP does not have the biochemical features of hypocalcemia and elevated parathyroid hormone levels as seen in pseudohypoparathyroidism, it seems from this case to share the potential for multiple endocrine neoplasia seen in a number of metabolic disorders in which pheochromocytoma may be a prominent manifestation.

Relaxation therapy for hypertension. Comparison of effects with concomitant placebo, diuretic, and beta-blocker.

We compared the effects of relaxation therapy in hypertensive patients taking placebo, a beta-blocker (atenolol, 100 mg/d), or a diuretic (chlorthalidone, 50 mg/d), and we also compared the effects of relaxation therapy with the effects of the latter two drugs alone. Blood pressures were measured not only in the relaxation therapists' office and at a hypertension clinic, but also in the patient's environment by means of 24-hour ambulatory blood pressure recordings. The effect of relaxation therapy, while statistically significant, was modest. There was no generalization of effect to ambulatory blood pressure. Atenolol was significantly more effective than relaxation in reducing both systolic and diastolic pressure. Chlorthalidone was significantly more effective than relaxation in reducing systolic but not diastolic pressure in the hypertension clinic only. The long-term effects of relaxation were independent of concomitant drug use, but within the actual relaxation sessions blood pressure dropped further during chlorthalidone than during placebo or atenolol treatment.

Dose-related efficacy of irbesartan for hypertension: an integrated analysis.

Results of eight multicenter, randomized, placebo-controlled, double-blind, parallel-group studies were pooled to assess the efficacy of the angiotensin II-receptor blocker irbesartan over the dose range of 1 to 900 mg. A total of 2955 adults with a seated diastolic blood pressure of 95 to 110 mm Hg were randomized to treatment with oral irbesartan once daily or placebo for 6 to 8 weeks. Office blood pressure was measured at trough (24+/-3 hours after the last dose) and peak (3+/-1 hours after the last dose) by mercury sphygmomanometry. Demographic characteristics (mean blood pressure; 151/101 mm Hg; mean age, 54 years; 63% male; and 82% white) were similar across all dose groups. After the groups were pooled, antihypertensive efficacy was assessed by therapeutic response (trough seated diastolic blood pressure <90 mm Hg or a reduction from baseline of > or = 10 mm Hg) and by modeling of the maximum reductions in trough and peak seated diastolic and systolic blood pressure. Antihypertensive effects increased with increasing doses and reached a plateau at > or = 300 mg. Irbesartan 150 mg provided placebo-subtracted reductions in trough seated systolic and diastolic blood pressure of approximately 8 and approximately 5 mm Hg, respectively, with 56% of patients displaying a favorable response. In conclusion, irbesartan provides clinically significant blood pressure lowering, with a clear relationship between (log) dose and antihypertensive effect.

Beta-blockade disappearance rate predicts beta-adrenergic hypersensitivity.

We determined whether the beta-blockade disappearance rate would determine the degree of subsequent transient beta-adrenoceptor hyperresponsiveness after abrupt withdrawal of a beta-adrenoceptor drug. In a single-blind randomized study, 10 healthy men took a placebo for 1 week and then took nadolol one time a day (t1/2, 18 to 24 hours) or propranolol three times a day (t1/2, 4 to 6 hours) in doses that were increased weekly for 4 weeks to reach 240 mg per day. beta-Receptor responsiveness was assessed before and repeatedly after abrupt drug withdrawal by infusion of isoproterenol and epinephrine and by ergometer exercise. In the 13 days after drug discontinuation, peak beta-receptor sensitivity correlated (p less than 0.05) with the disappearance rate of beta-blockade as assessed by heart rate responses to isoproterenol (r = 0.68) and to submaximal exercise (r = 0.62) and by diastolic blood pressure responses to isoproterenol (r = 0.86) and epinephrine (r = 0.86). Plasma catecholamine levels and renin activity showed no overshoot. beta-Blockers with long plasma t1/2 values may prevent beta-blocker withdrawal syndromes by means of "self-tapering."

Nadolol, propranolol, and thyroid hormones: evidence for a membrane-stabilizing action of propranolol.

Ten normal subjects participated in a placebo-controlled, randomized, parallel study to determine the effects on thyroid hormones of chronic (4 wk) propranolol or nadolol, including observation for 2 wk after their discontinuation. Subjects took placebo for 1 wk, then propranolol or nadolol doses increased weekly to 240 mg/day by 3 wk. After 1 wk of placebo, after 2 wk of the highest dose of propranolol or nadolol, and 2, 4, 6, 9, and 13 days after their discontinuation, thyroid hormone levels were measured by radioimmunoassay and heart rate responses to exercise were assessed. Both drugs induced equal and high degrees of exercise tachycardia inhibition. Propranolol decreased 3,3'5-triiodothyronine (T3) levels, increased 3-3'-5'-triiodothyronine (rT3) levels, tended to increase thyroxine levels, but did not increase thyroid-stimulating hormone levels. After discontinuation of propranolol, rT3 levels slowly (day 6) returned to values after placebo, suggesting delayed recovery of 5'-deiodination. There was no evidence of any rebound in T3 levels after withdrawal of propranolol. Nadolol induced no significant changes in the thyroid hormones measured. The data agree with the known effects of propranolol on thyroid hormones in normal man and show that nadolol does not have these effects when given chronically at an equivalent beta-blocking dose. The likely explanation is that the membrane-stabilizing activity of propranolol alters thyroid physiology by interfering with 5'-deiodinase.

Nonselective beta-blockade enhances pressor responsiveness to epinephrine, norepinephrine, and angiotensin II in normal man.

Nonselective beta-blockers increase peripheral vascular resistance and, sometimes, blood pressure (BP); increased responsiveness to circulating pressor agents could be one of the underlying mechanisms. Heart rate (HR) and BP responses to graded intravenous infusions of epinephrine, norepinephrine, and angiotensin II were recorded after placebo and then after 4 wk of beta-blocker treatment (nadolol or propranolol, 240 mg/day) in 10 healthy young men. Adequacy of beta-blockade was demonstrated by a mean 31% decrease in HR response to bicycle exercise, with no differences between the two beta-blockers. Under placebo conditions epinephrine lowered diastolic BP and raised HR; these effects were reversed during treatment with beta-blockers. beta-Blockade potentiated BP responses to norepinephrine and angiotensin II: Thirty-five percent less norepinephrine and 52% less angiotensin II were required to increase mean BP by 15 mm Hg. A final study 2 wk after beta-blocker cessation revealed the absence of lasting effect. These results confirm the concept of unopposed alpha-constriction for epinephrine and also demonstrate increased BP responses to norepinephrine and angiotensin II during chronic beta-blockade.

Hemodynamic interaction of nonselective vs. beta-1-selective beta-blockade with hydralazine in normal humans.

To assess the effects of nonselective vs. beta 1-selective beta-blockade on the hyperdynamic circulation induced by hydralazine, eight healthy volunteers received placebo, propranolol, 20 and 40 mg, and atenolol, 25 and 50 mg, on 5 separate days, followed by hydralazine (range 75 to 150 mg). Hydralazine decreased afterload (end-systolic wall stress) and increased venous return and left ventricular performance (by M-mode echocardiography). Both beta-blockers blunted the increases in heart rate, cardiac output, and venous return similarly, although heart rate and cardiac output were not completely normalized. Atenolol did not affect the hydralazine-induced decrease in afterload, whereas propranolol significantly opposed this change (P less than 0.03). The hyperdynamic circulation seen with hydralazine is mostly beta mediated, primarily beta 1. When given with hydralazine the two beta-blocker types differ primarily in their effects on afterload.

The role of cardiac beta-1 receptors in the hemodynamic response to a beta-2 agonist.

The role of beta 1-receptors in the hemodynamic response to beta 2-stimulation was assessed in seven healthy subjects by infusion of the selective beta 2-agonist terbutaline both with and without selective beta 1-blockade by atenolol (50 mg). Infusion of terbutaline increased heart rate (+28 bpm) and indices of left ventricular (LV) performance associated with a marked decrease in LV end-systolic wall stress. The LV end-diastolic dimension remained unchanged despite the tachycardia, suggesting that venous return had increased. Systolic blood pressure increased, whereas total peripheral resistance and diastolic blood pressure decreased. Atenolol pretreatment caused the hemodynamic changes expected of beta 1-blockade but did not blunt the effects of terbutaline on heart rate, peripheral resistance, or venous return. Increases after terbutaline in LV performance and systolic blood pressure were significantly blunted by atenolol. Stimulation of beta 1-receptors therefore appears to play no role in the chronotropic and only a moderate role in the inotropic response after infusion of a beta 2-agonist. Alternative mechanisms for the cardiac changes with terbutaline include (1) withdrawal of vagal tone, (2) decrease in afterload, and (3) stimulation of cardiac beta 2-receptors.

Epinephrine and left ventricular function in humans: effects of beta-1 vs nonselective beta-blockade.

Changes in cardiac performance in response to epinephrine administered by graded infusion were assessed by M-mode echocardiography in normotensive healthy subjects after pretreatment with placebo, the beta 1-selective blocker atenolol, or the nonselective beta-blocker propranolol. Epinephrine alone increased heart rate and left ventricular end diastolic dimension and decreased left ventricular end systolic dimension. Left ventricular performance as assessed by fractional shortening and systolic blood pressure/end-systolic volume (P/V) ratio was also increased. Atenolol pretreatment did not significantly affect the increase in heart rate by epinephrine. However, atenolol did prevent the effects of epinephrine on left ventricular dimensions and left ventricular performance at the lower infusion rates and significantly blunted these effects at the highest infusion rate. After propranolol, epinephrine significantly decreased left ventricular end diastolic dimension despite decreasing heart rate and left ventricular emptying (associated with a high afterload). P/V ratio remained unchanged. These results indicate that beta 2-receptors may play a major role in the increase in heart rate caused by epinephrine. In contrast, epinephrine's positive inotropic effect appears to be mediated primarily via beta 1-receptors and, at higher concentrations, possibly also through beta 2-receptors. The pattern of changes in left ventricular end diastolic dimension suggests that epinephrine increases venous return via both beta 1- and beta 2-receptor stimulation and that alpha-receptor stimulation (epinephrine after propranolol) may actually decrease venous return.

Vasodilators and regression of left ventricular hypertrophy. Hydralazine versus prazosin in hypertensive humans.

Long-term treatment of hypertensive rats with arterial vasodilators may further increase left ventricular hypertrophy. Since left ventricular hypertrophy may be an important determinant of outcome in hypertension, the long-term effects of arterial vasodilation with hydralazine on left ventricular mass and function were compared with those of an alternative third-line drug, the alpha1 blocker prazosin, in patients still hypertensive despite combined diuretic and beta blocker therapy. A single-blind, randomized, two-group parallel design was employed. Both treatments induced a sustained antihypertensive effect, with hydralazine showing more effect on supine blood pressure, and prazosin having more effect on standing pressure. Heart rate, cardiac output, and volume status showed only minor changes. Plasma norepinephrine showed a sustained increase when measured in both the supine and standing positions, but the increases were similar for the two treatments. Supine and standing plasma renin activity increased only during long-term treatment with hydralazine. Prazosin induced a progressive decrease in left ventricular mass over time (-34 +/- 15 g/m2 at 12 months), but hydralazine did not (-9 +/- 10 g/m2 after 12 months). Stepwise regression indicated that a decrease in systolic blood pressure was associated with a decrease in left ventricular mass with both treatments, but an increase in plasma norepinephrine was associated with an increase in left ventricular mass only with hydralazine, suggesting that increased sympathetic activity may affect left ventricular mass via cardiac alpha1 receptors. Thus, if regression of left ventricular hypertrophy is a worthwhile therapeutic goal, hydralazine and analogous arterial vasodilators are not drugs of choice.

Cardiovascular effects of indapamide in hypertensive patients with or without renal failure. A dose-response curve.

Fifteen patients with mild-to-moderate hypertension (10 with normal and five with decreased renal function) were studied after treatment with placebo and low (1 mg), intermediate (2.5 mg), and high (5.0 mg per day) doses of indapamide, each for four weeks. Six patients--five with normal renal function--were classified as nonresponders (decrease in diastolic blood pressure less than 5 mm Hg). The remaining nine patients had dose-related decreases in blood pressure. Patients with or without renal failure showed similar decreases in blood pressure. Blood pressure reduction was associated with a significant decrease in cardiac index in the responders at the highest dose, related to a decrease in left ventricular end-diastolic dimension and stroke volume, whereas heart rate did not increase. This apparent decrease in venous return was associated with a significant decrease in body weight but not plasma volume in the responders. Indapamide did not change plasma norepinephrine levels, but decreased pressor responsiveness to exogenous norepinephrine. Responders had lower initial plasma renin activity and a smaller absolute increase in plasma renin activity while receiving indapamide, whereas angiotensin II pressor responsiveness was decreased more. The results presented indicate that the blood pressure lowering effect of indapamide in the present patient population is observed with or without renal failure and is associated with a decrease in pressor reactivity. In nonresponders, compensatory mechanisms (e.g., renin) may negate the antihypertensive effect of indapamide.

Reproducibility of nurse-measured, exercise and ambulatory blood pressure and echocardiographic left ventricular mass in borderline hypertension.

OBJECTIVE: To compare the short-term reproducibility of four diagnostic tests: resting blood pressure, exercise blood pressure, non-invasive daytime ambulatory blood pressure and echocardiographic left ventricular mass. DESIGN: Blinded, prospective test-retest (reliability) study. SETTING: Hypertension research units in two teaching hospitals. PARTICIPANTS: Six normal volunteers and 22 patients with untreated borderline to mild hypertension, mean age 44 years. MAIN OUTCOME MEASURES: The intraclass correlation coefficient (RI) and standard deviation of the difference (SDD) between visits. MAIN RESULTS: The mean blood pressures and left ventricular mass did not differ between visits. Concordance between visits reached RI = 0.86 systolic/0.66 diastolic for ambulatory blood pressure and RI = 0.85 systolic/0.64 diastolic for nurse-measured random-zero sphygmomanometer resting blood pressure. The respective variabilities were SDD = 9/8 and 8/8 mmHg. Submaximal exercise systolic blood pressure (SBP) and echo left ventricular mass showed excellent reliability. Echo left ventricular mass and resting SBP or ambulatory SBP were significantly more reproducible than resting diastolic blood pressure (DBP) or ambulatory DBP. CONCLUSIONS: Despite averaging many readings within each day, clinically important between-visit variations in ambulatory blood pressure remained. The between-visit variability of daytime ambulatory blood pressure was similar to that of resting blood pressure when carefully measured by a research nurse. The echo left ventricular mass appears to be more reproducible over the short term than the current diagnostic standard for hypertension, the resting DBP.

24-hour blood pressure control by once-daily administration of irbesartan assessed by ambulatory blood pressure monitoring. Irbesartan Multicenter Investigators' Group.

OBJECTIVES: To compare 24 h ambulatory blood pressure and trough office blood pressure lowerings after 8 weeks of therapy with 75 mg irbesartan once a day, 150 mg irbesartan once a day , and 75 mg irbesartan twice a day versus placebo; and to assess safety and tolerability of irbesartan therapy. DESIGN: Multicenter, double-blind, randomized, placebo-controlled trial. SETTING: Sixteen centers in Italy. PATIENTS: Caucasian patients (n = 215) aged > or = 18 years with seated diastolic blood pressure 95-110 mmHg and ambulatory diastolic blood pressure (ADBP) > or = 85 mmHg. PRIMARY OUTCOME: Mean 24 h ADBP after 8 weeks of irbesartan therapy. RESULTS: Mean changes (value before treatment minus value after treatment) in ADBP for placebo, 75 mg irbesartan once a day, 150 mg irbesartan once a day, and 75 mg irbesartan twice a day were -0.2, -5.4, -7.2, and -7.2 mmHg, respectively; respective changes in ambulatory systolic blood pressure were +1.6, -8.3, -10.5, and -9.7 mmHg. All irbesartan regimens reduced trough office seated diastolic blood pressure and seated systolic blood pressure after 2 and 8 weeks of treatment (all P < 0.01, versus placebo except for seated systolic blood pressure in patients in the 75 mg irbesartan once a day group). Trough: peak ratios were > or = 55% with 150 mg irbesartan once a day. Percentages of patients whose blood pressures were normalized with 150 mg irbesartan once a day (45%) and 75 mg irbesartan twice a day (47%) were greater than those with placebo (14%, P < 0.01) and with 75 mg irbesartan once a day (19%, NS, versus placebo). Adverse events with irbesartan were similar to those with placebo. CONCLUSIONS: All irbesartan regimens significantly reduced mean 24 h ADBP and ambulatory systolic blood pressure, and were well tolerated. Administration of 150 mg irbesartan once a day provided significant reduction of blood pressure for 24 h, equivalent to that obtained with the same daily dose divided into two separate administrations.

Effects and tolerability of irbesartan versus enalapril in patients with severe hypertension. Irbesartan Multicenter Investigators.

In this double-blind, randomized study, an antihypertensive regimen based on irbesartan, an angiotensin II receptor antagonist, reduced systolic and diastolic blood pressure by 40/30 mm Hg at week 12 in patients with severe hypertension; this reduction was at least equivalent to that of a regimen using enalapril up to 40 mg. The irbesartan-based regimen had a better tolerability profile with fewer adverse events (55% vs 64%) and significantly less cough (2.5% vs 13.1%, p = 0.007).

Who wants to eliminate heart disease?

Twenty-seven physicians and nine pharmacists at one University teaching hospital identified their preferred way of dying after attaining average life expectancy. Respondents' ranking of modes of dying showed high agreement (for physicians, W = 0.65, p < 10(-16)). Disease category, rapidity of death, and their interaction (ANOVA, all p < 0.0001) influenced choice. "Rapidly fatal cardiac death" was overwhelmingly preferred. Cancer and slowly fatal central nervous system disorders were rated last. Eliminating cardiovascular disease would necessarily increase the likelihood of other modes of death. If these respondents represent "informed consumers", then reducing cardiac death at normal life expectancy may be contrary to Western society's preferences.

Falls among older people: relationship to medication use and orthostatic hypotension.

OBJECTIVE: To assess the risk of falls attributable to medication use and orthostatic hypotension. DESIGN: Prospective cohort study. SETTING: Two self-care, apartment-style residential facilities in the Toronto area. PARTICIPANTS: A total of 100 consecutive older volunteers (mean age = 83, range 62-96) who were independent in activities of daily living and able to stand unaided. MEASUREMENTS: Prescription medications used by each subject were documented at baseline. Blood pressure measurements were performed supine, immediately after standing, and after 5 minutes. Subjects reported falls weekly, by postcard, for a period of 1 year; nonreporters were contacted by telephone. RESULTS: Fifty-nine percent of subjects fell at least once during the 1-year follow-up. Antidepressant use was associated with an increase in the risk of experiencing one or more falls (RR = 1.6, P = .02). The use of other drug classes examined, including diuretics and sedative-hypnotics, was not associated with an increased risk of falling. Orthostatic hypotension was not predictive of falls. Surprisingly, there was an increase in the diastolic blood pressure of fallers, after 5 minutes, that was not seen in the nonfallers (3.3 vs -0.2 mm Hg, P = .05). Possible explanations for this previously unreported observation are explored. CONCLUSION: Patients using antidepressants should be followed closely because the risk of falls is increased. Previously reported relationships between benzodiazepines and diuretics and falls are not supported by the present findings. Clinical detection of orthostatic hypotension is unlikely to be useful in predicting future risk of falling.

The effect of caffeine on daytime ambulatory blood pressure.

Caffeine produces an acute increase in blood pressure in the research laboratory, but its effect on the ambulatory blood pressure during normal daily activities is unknown. In 25 normotensive, caffeine-naive subjects, daily administration of 400 mg caffeine produced a small increase (+3/+3 mm Hg, P less than .001) in ambulatory daytime blood pressure on the first day, with values returning to baseline by the third day. The initial rise in blood pressure was associated with a fall in heart rate (-3 beats/min, P less than .02). Readings taken the morning following the first day of caffeine ingestion did not show any persistent effect of caffeine on blood pressure. A 400 mg dose of caffeine causes a small increase in daytime ambulatory blood pressure, but tolerance develops with daily caffeine consumption. Infrequent ingestion of caffeine may cause a transient rise in blood pressure which is unlikely to be harmful to an individual but might influence the diagnosis of hypertension in a patient with a borderline elevated blood pressure.

White coat phenomenon in patients receiving antihypertensive therapy.

The occurrence of the white coat phenomenon in hypertensive patients receiving drug therapy was determined in a consecutive series of 71 patients undergoing ambulatory blood pressure (ABP) recordings because of suspected differences between office and ambulatory values. Overall mean (+/- SEM) office blood pressure (BP) was 166 +/- 2/95 +/- 1 v awake ABP 139 +/- 2/86 +/- 1 mm Hg. The white coat phenomenon [(office BP - ABP) greater than or equal to 20/10 mm Hg] was present in 52 of 71 patients: office BP 170 +/- 3/96 +/- 2 v ABP 135 +/- 2/83 +/- 1 mm Hg. A marked white coat effect [(office BP - ABP) greater than or equal to 40/20 mm Hg] was seen in 22 patients with office BP being 178 +/- 4/98 +/- 3 v ABP 131 +/- 3/79 +/- 2 mm Hg. The frequent occurrence of white coat phenomenon in these patients suggests that office BP readings may not always represent usual ABP in patients receiving chronic antihypertensive therapy.

Reproducibility of ambulatory blood pressure and assessing treatment withdrawal in hypertension trial.

Ambulatory blood pressure monitoring (ABPM), like casual blood pressure (BP), is imperfectly reproducible between visits. The reproducibility of ABPM is less than the reproducibility predicted from a simple model of random variation of BP. This suggests either increased technical error in the technique, an element of increased biologic variability, or both. In addition, ABP shows a between-day variation (add about 6 to 7 mm Hg diastolic, similar in magnitude to what is observed with casual BP) which cannot be obviated by the average of many within-day measurements. The reliability of ABPM, although conventionally judged excellent at about RI = 0.75, is insufficient to avoid misclassification errors and regression to the mean when BP cutpoints are employed. About 40% of patients apparently failing treatment withdrawal at a threshold of +2 SD, or about 95 mm Hg diastolic ABP, will be false-positive failures when categorized by a single ABP. Despite the inconvenience, obtaining an average of two or more ABP measurements on different days may be cost-saving to a clinical trial because of the improved reproducibility; other costs may exceed $1000 per entrant.