THE REPORT by Lynch et al1in this issue of the Archives indicates that maintained, moderately intense exercise is associated with a decreased incidence of diabetes mellitus in subsequent years in Finnish men. The study can be criticized on the grounds that the subjects were not randomly assigned to exercise or no exercise (ie, they may have constituted different populations before the study was started). However, I believe the conclusion of Lynch et al1 is likely to be correct. There are many reports that increased exercise in populations is associated with a lower prevalence of non—insulindependent diabetes mellitus and that physical exercise improves glucose tolerance in normal subjects, as well as in patients with diabetes mellitus.2 Can you get your patients in the United States to increase their level of physical activity substantially? I often do not succeed. Here are some favts that might be discussed with an

UNLABELLED This study tested the capability of a single 42-microgram dose of inhaled salmeterol xinafoate, a long-acting beta 2-agonist, to protect against bronchoconstrictive effects of exposure to 0.75 ppm sulfur dioxide (SO2) during exercise, for up to 24 h. Ten SO2-responsive adult volunteers with stable asthma were studied under 4 conditions of drug pretreatment/exposure, administered in random order, double-blind: salmeterol/SO2, placebo/SO2, salmeterol/clean air, and placebo/clean air. Each subject underwent 10-min exposure/exercise challenges in a chamber 1, 12, 18, and 24 h after pretreatment. Exercise ventilation rates averaged 29 L/min. Response was measured as the decrement in FEV1 between preexposure and postexposure (lowest value within 30 min). After salmeterol, mean decrement post-SO2 was 7% at 1 h and 12% at 12 h. At 18 and 24 h after salmeterol, and at all times after placebo, mean decrements were 25 to 30%. After 18 and 24 h, salmeterol still improved base-line FEV1 relative to placebo, although improvement was not statistically significant at 24 h. Acute symptom increases accompanied FEV1 decrements. CONCLUSION In our asthmatic subjects, pretreatment with salmeterol imparted clinically and statistically significant (p < 0.01) protection against bronchoconstriction induced by SO2/exercise for at least 12 h, and maintained an improvement in lung function for as much as 18 h.

Hemodynamic and hormonal responses to bolus intravenous injections of synthetic porcine endothelin (pET) were examined in anesthetized dogs. There were no significant changes in mean blood pressure (MBP), right atrial pressure (RAP), or plasma atrial natriuretic factor (ANF) concentration in response to 40 pmol/kg of the peptide. However, responses to 400 pmol/kg of the peptide were significant: MBP rose from 114 +/- 6 mmHg (mean +/- SE) to 139 +/- 7 mmHg (p less than 0.01), RAP rose from 5.4 +/- 0.9 mmHg to 7.8 +/- 1.1 mmHg (p less than 0.01), and ANF increased from 45 +/- 10 pg/ml to 277 +/- 33 pg/ml (p less than 0.01). Peak value of RAP was observed 2.6 +/- 0.4 min, while peak of ANF was 11.4 +/- 0.9 min after peptide injection. There was a strongly positive correlation (r = 0.93, p less than 0.01) between the increase in RAP and the increase in ANF in dogs given 400 pmol/kg of pET. These results indicate that exogenously administered pET to anesthetized dogs alters hemodynamics and induces ANP release, and are compatible with a postulate that the ANF release is caused by elevated RAP.

• The purpose of this study was to Identify the best of three methods of treating hypertensive outpatients in order to minimize dietary sodium levels and thereby decrease the need for antihypertensive drugs. Forty-eight outpatients with hypertension were randomly assigned to three treatment programs: (1) advice; (2) an intensive educational program; and (3) small-group management plus feedback. This last program had a problem-solving format in which patients shared ideas and provided mutual support for dietary change. Only these group management patients were told the results of their sodium determinations. In a one-year study, group management plus the feedback to patients of Information on the sodium content of their urine was more effective in decreasing dietary sodium intake than advice or an intensive educational effort. (Arch Intern Med1984;144:1415-1417)

Guanadrel sulfate is structurally and pharmacologically similar to guanethidine but has different pharmacokinetic properties. The drug produces peripheral postganglionic sympathetic blockade as a consequence of interference with neuronal release of norepinephrine and displacement of norepinephrine from storage vesicles. Animal studies using large multiples of human antihypertensive doses suggest a low order of human toxicity. Clinical studies have failed to reveal any major effect on hematologic, hepatic or renal function. The effect on serum lipids and plasma renin is unknown. The drug is well absorbed after oral administration. Peak plasma levels in humans occur 1.5–2 hours after a administration. Protein binding is less than 20%. Data from animal studies and clinical trials demonstrating a lack of central nervous system side effects indicate that little if any drug enters the central nervous system. The drug is partially metabolized by the liver, but nearly 50% of an orally administered dose appears unchanged in the urine. The mean elimination half‐life is approximately 12 hours. The onset of antihypertensive action after oral administration of guanadrel to humans is 30–120 minutes (mean 77 minutes). The offset of drug action after a single oral dose ranges between 4–14 hours (mean 9 hours). The hypotensive response to guanadrel in hypertensive subjects is the result of a decline in systemic vascular resistance with an impairment of the normal sympathetic reflexes in the erect position. Guanadrel causes a reduction in renal blood flow and glomerular filtration rate in the erect position. Open label clinical trials of antihypertensive efficacy indicate that guanadrel is effective in 60 and 70% of patients in the supine and erect positions, respectively. In comparative clinical trials, guanadrel appears to be as effective as guanethidine or methyldopa in reducing blood pressure in persons with mild to moderately severe hypertension; mean doses ranged from 56–162 mg/day. In other studies, investigators have used doses of 5–600 mg daily. The maximum recommended dosage is 400 mg/day. Side effects reported with guanadrel administration are those that would be predicted for a postganglionic sympathetic inhibitor that does not enter the central nervous system. Sexual dysfunction, orthostatic dizziness and diarrhea occur with the drug but do not seem to be as frequent or as severe as with guanethidine administration. In a comparison of guanadrel to methyldopa, methyldopa caused more complaints of drowsiness, and drowsiness scores of methyldopa patients remained higher than those of guanadrel patients even after two years of therapy. The drug has received approval as a step 2 antihypertensive agent in the United States. The available data suggest that it will serve as a reasonable alternative to other step 2 antihypertensives.

In a two‐year study of 547 hypertensive patients receiving diuretics, the addition of guanadrel sulfate or methyldopa reduced elevated blood pressure to a similar degree and provided good control in 70% of the patients. Guanadrel‐treated patients experienced less frequent and less severe drowsiness than methyldopa‐treated patients. The frequency of morning orthostatic faintness was low and similar in both treatment groups. Guanadrel produced no tissue toxicity. Guanadrel sulfate, a postganglionic sympathetic inhibitor, is nearly free of central nervous system side effects and is recommended over methyldopa for step 2 therapy when diuretics alone fail to control mild or moderate hypertension.

We examined the role of dietary electrolytes and humoral factors in causing seasonal changes in blood pressure. Normal subjects had no seasonal difference in blood pressure, although urinary sodium and norepinephrine were significantly higher in winter than in summer. In patients with essential hypertension blood pressure, urinary sodium and norepinephrine excretion and plasma norepinephrine concentration were significantly higher in winter. Plasma renin activity, plasma and urinary aldosterone and urinary kallikrein excretion were not significantly different between the two seasons in both normal subjects and hypertensive patients. In conclusions, the blood pressure of patients with essential hypertension has a seasonal variation with higher pressures in the winter than in the summer. Increased sympathetic nervous activity and an increased load of sodium presented to the kidney for excretion may be contributing factors in the rise in blood pressure in winter in patients with essential hypertension.

本態性高血圧症の成因を解明する目的で,本症患者の血圧,各種内分泌性血圧調節因子の季節的変動について検討した.境界域型,固定型高血圧症患者の安静臥床時,立位時収縮期および拡張期血圧は1979年8月(夏期,月間平均気温29.1°C)に比し1980年2月(冬期,同4.8°C)において有意な高値を示し,安静,立位時血漿ノルエピネフリン濃度, 24時間尿ノルエピネフリン(UNE),ナトリウム排泄量(UNa)も冬期で有意に増加していた.一方健常者ではUNE, UNaともに夏期に比し冬期に有意な高値を示したが,血圧には両季節間で有意な変動を認めなかつた.安静,立位時血漿レニン活性,アルドステロン濃度, 24時間尿アルドステロン,カリクレイン排泄量は,健常者,高血圧症患者において有意な季節的変動を示さなかつた.高血圧症患者の個々の血圧の季節間変動値と, PNE, UNE, UNaおのおのの両季節間差との間には有意な相関を認めなかつた.本症患者でみられた冬期の血圧上昇の機序には,冬期の交感神経系機能の亢進,おそらく食塩摂取量の増加およびこれら昇圧系因子に対する血圧の反応性の増大などの諸要因が考えられる.また以上の結果は本症の病因,病態に交感神経,食塩摂取の因子が関与していることを示唆する.

Sex histories and serum samples were obtained from 27 hypertensive men before and after 3 months of therapy with either 100 mg of hydrochlorothiazide or 0.25 mg of reserpine daily. Sera were analyzed for testosterone, dihydrotestosterone, estradiol, luteinizing hormone and prolactin. Both drugs effectively lowered blood pressure. The incidence of impaired sexual performance was low and insignificantly different in the two treatment groups. There were no significant changes in serum hormone concentrations as a result of drug therapy.

5 alpha-dihydrocortisol has been reported to amplify the mineralocorticoid activity of aldosterone. In this study 5 alpha-dihydrocortisol was administered to unilaterally nephrectomized rats treated with 11-deoxcorticosterone acetate (DOCA) and sodium chloride to examine its potentiating effect on the elevation of blood pressure in these animals. Subcutaneous administration of DOCA at two dose levels (40 microgram and 100 microgram/100 g of body weight 3 times a week) resulted in a significant rise in blood pressure when compared with controls given no DOCA. However, concomitaut injection of 5 alpha-dihydrocortisol (300 microgram/100 g of body weight 3 times a week) with both doses of DOCA did not accelerate the development or potentiate the severity of the hypertension in a 4 week period. Furthermore, administration of 5 alpha-dihydrocortisol did not cause a further decrease in plasma renin activity or a greater increase in urinary kallikrein excretion than those observed after DOCA alone. Thus, 5 alpha-dihydrocortisol does not potentiate DOCA in the production of low renin hypertension in unilaterally nephrectomized salt-loaded rats.

Compliance was compared in 52 previously noncompliant hypertensive patients randomly assigned for eight weeks to either a nurse-operated hypertension clinic (control) or a patient-operated hypertension group] (experimental). Control patients listened to audiotapes on hypertension and its management and met individually with a nurse who adjusted their drug regimens. Experimental patients were trained to take their own blood pressure (BP) and select their own drugs in a group program emphasizing informed self-help. After the eight-week training period and at two- and six-month follow-up visits, both groups had significantly lower BPs. Compared with control patients, experimental patients had lower diastolic BPs, better pill counts, and better attendance (all P < .05). This study suggests that training noncompliant patients in groups to manage their own hypertension may achieve better results than traditional management programs.

The mineralocorticoid activities and effects on blood pressure of synthetic 16 (βdihydroxy-5-androsten-17-one) and its isomer, 16-oxo-A (16-oxo-androstenediol, 3β, 17β- dihydroxy-5-androsten-16-one) were examined in rats. In study 1, three groups of 5 rats each were given subcutaneous injections of 0.2 ml of ethanolic solutions for 4 weeks. Their drinking water contained 1% NaCl. In group I, the control group, 20% ethanol was injected.Each rat at in group II was given a daily injection of 20% ethanol containing 400pg of 16β- OH-DHEA. Each rat in group III was given a daily injection of 400 μg of 16-oxo-A in 20% ethanol. Body weight and systolic blood pressure were monitored twice weekly. The urinary Na+/K+ ratio was determined on the 14th and 29th days. Serum Na+, K+, and hematocrit analyses were done on the 29th day. Plasma renin activity was assayed in samples obtained before and after furosemide administration on the 29th and 30th days, respectively. There were no significant differences in the mean values of any of the determinations listed above between groups II and III (treated) and group I (control) with one exception. The mean hematocrit of group II was slightly (4%) but significantly (P<0.01) less than that of the control group on the 29th day.In study 2, unilaterally nephrectomized salt loaded male Wistar rats were injected once a week with large doses of steroids in sesame oil for 2 month periods. Rats injected with 10 mg and with 30 mg of 11-desoxycorticosterone acetate per kg of body weight per week developed hyertension. Rats given 30 mg/kg BW/week of 16β-OH-DHEA or 16-oxo-A and control rats did not develop hypertension.Other investigators have postulated that 16β-OH-DHEA and possibly its 16-oxo isomer are direct causative factors in the pathogenesis of low renin hypertension in humans. In contrast, we have not been able to demonstrate any substantial minerolocorticoid activity or any effect on blood pressure for either of these steroids. We conclude that it is unlikely that 16β-OH-DHEA and 16-oxo-A are direct causative factors in the production of low renin essential hypertension. On the other hand, if 16β-OH-DHEA is excreted in abnormally large amounts in the urine of patients with low renin hypertension, it may be a maker of the disease even if it is not a direct causative factor.

Textbook of Endocrinology, edited by Robert H. Williams, MD, ed 5, 1,138 pp, 527 illus, $28, WB Saunders Co, 1974. The massive volume, edited by Alex Labhart and authored mainly by endocrinologists working in Zurich, is well organized and comprehensive in scope. Each major section in the book has a brief historical outline followed successively by a description of the embryology, gross anatomy, histology, biochemistry, pharmacology, physiology, and clinical aspects of the subjects. The diagrams and tables are well selected and the pictures illustrating clinical problems are outstanding. The detailed table of contents (23 pages long, with 72 items on separate lines on a typical page) makes it an easy book to use. The index and bibliographies are thorough. In addition to the discussion of general aspects of endocrinology and the usual hormone-secreting glands, there are separate sections on tissue hormones, growth and development, hormones of the thymus, and the

Dopamine-beta-hydroxylase (DBH), an enxyme catalyzing the final step in the synthesis of norepinephrine, is released with norepinephrine on stimulation of the sympathetic nervous system. In this study an enzymatic colorimetric method was used to assay serum DBH activity in 196 individuals of whom 169 were either the parents or children in 29 families. We examined the association of DBH with age and with hypertension and the faamilial pattern of distribution of serum DBH activity. Serum DBH activity was highest in te groups 10 to 14, 40 to 49, and over 60 years. There was no significant difference in serum DBH activity between normal subjects and individuals with hypertension in any age group. tfurthermore, there was no significant correlation of mean blood pressure with serum DBH activity with or without correction of DBH for age differences; Highly significant correlations of serum DBH activity were found in sibling-sibling pairs and in mean parent-child pairs. No significant correlations were found for father-mother pairs. These observations suggest that the contribution of heredity is more important that shared environment in determining the familial pattern of distribution of serum DBH activity. Serum DBH activity did not have a bimodal distribution in the population. Noevidence was found for a maternal influence or for sex linkage in the transmission of this trait. Our data, derived from this study restricted to families with only two generations, are not adequate to specify with confidence the mode of inheritance of DBH activity in the general population.