Different antihypertensive effect of beta-blocking drugs in low and normal-high renin hypertension.

The treatment response to beta-adrenoceptor blocking drugs was compared in two groups of patients with primary (essential) hypertension and different renin levels. Each group consisted of 25 patients and was equally distributed regarding age, severity and stage of hypertension. In the first group (group 1), the mean upright plasma renin activity was 0.8 ng ml-1h-1 (range 0.3 to 1.5) and the patients were considered to have low renin hypertension. In the other group (group 2) the patients had a mean plasma renin activity of 2.1 ng ml-1h-1 (range 1.1 to 5.1) and were considered to have normal to high renin hypertension. In both groups the patients were initially treated with beta-blocking drugs; in group 1 with a beta-blocker corresponding to an average dose of 311 mg propranolol a day for at least eight weeks and in group 2 with propranolol 320 mg a day in a fixed dose for eight weeks. The hypotensive response differed significantly between the two groups (p less than 0.001). In group 1 the pretreatment blood pressure was 197/117 mm Hg supine and 198/120 mm Hg standing. During treatment blood pressure decreased only 5/3 mm Hg supine and 9/5 mm Hg standing. The pretreatment blood pressure in group 2 was 187/114 mm Hg supine and 186/117 mm Hg standing. Beta-blocking therapy reduced blood pressure 36/23 and 34/18 mm Hg, respectively (both p less than 0.001). Pulse rates fell significantly in the two groups, both in the lying and standing positions. In 17 patients with low renin hypertension (group 1), a volume-depleting drug was added (spironolactone, 14 patients; thiazides, 3 patients) and this achieved a marked fall in blood pressure levels of 38/16 mm Hg supine and 37/19 mm Hg standing (both p less than 0.001). These results suggest the following: (1) Most patients with normal to high plasma renin activity respond well to moderate doses of propranolol. (2) Propranolol given in the same doses is almost without antihypertensive effect in patients with low renin hypertension. (3) A volume factor may be operating in patients with low renin hypertension since a hypotensive effect is demonstrated after the addition of volume-depleting drugs. (4) Determination of plasma renin activity with adequate methods can predict the treatment response to hypotensive agents.     

Sulfur amino acid metabolism in juvenile-onset nonketotic and ketotic diabetic patients

Sulfur amino acid metabolism was studied in non-fasting nonketotic and ketotic juvenile-onset diabetic children and the results were compared to age-matched healthy children on an ordinary diet. An increased excretion of total sulfur and inorganic sulfate was found in diabetic children, probably a result of a decreased protein-serum synthesis and/or increased endogenous protein catabolism, although as a result of hyperglycemia a decreased tubular reabsorption may also have contributed. All diabetics showed a normal excretion of methionine. For cyst(e)ine and taurine an increased excretion was seen in ketotic diabetics, probably also a consequence of an increased endogenous protein degradation. As a sign of the latter, an increased output of 3-methylhistidine was also observed, a confirmation of earlier reports. The increased output of mercaptolactate and mercaptoacetate found in ketotic patients, was probably also a result of enhanced endogenous protein degradation. An increased urinary excretion of N-acetylcysteine was seen in diabetic children, which may reflect an enhanced availability to acetyl coenzyme A.     

The excretion of sulfur compounds in the urine of newborn infants

The excretion of sulfur-containing compounds was determined on the third and sixth day of life in male infants and the results were compared with those previously obtained on fed and fasting men. The output of total sulfur and inorganic sulfate was very low on the third day of life but had increased by the sixth day to levels found in the fasting men, whereas the excretion of mercaptolactate in the newborns decreased from the third to the sixth day of life. These results may be explained by the initial fasting state of neonates followed by an anabolic phase. Neonates excreted acid-labile ester sulfate and mercaptoacetate at levels similar to those found in adults, but the neonatal urine also contained sulfate esters (probably steroid sulfates) that required more drastic acid conditions for hydrolysis. Raised concentrations of sulfurcontaining amino acids (methionine, cystathionine, cyst(e)ine and taurine) were found in neonatal urine in confirmation of earlier reports. The excretion of thiosulfate could only be determined in newborns on the sixth day and was low in comparison with that of adults. High urinary thiocyanate concentrations were found in newborns fed by tobacco-smoking mothers, whereas the excretion of thiocayanate was low in other newborns. The possible medical hazards from the exposure of neonates to thiocyanate are emphasized.     

Body fat and adipose tissue cellularity in infants: A longitudinal study

Body fat, fat cell size, and fat cell number were determined in a longitudinal study on 16 normal-weight infants during the age period 1–18 mo. The methods used included whole-body counting of ⁴⁰K for determination of body fat and adipose tissue biopsies. A new method of calculation of body fat in infants is presented. No sex differences were found. Body fat expressed as per cent of body weight increased from 16.2% to 28.1%. From 1 to 12 mo of age the expansion of body fat was explained by an increase in fat cell size, while in the age period 12–18 mo it was mainly due to an increase in fat cell number. At 18 mo the fat cell size was the same as in 8-yr-old girls and 22-yr-old women (normal-weight females previously studied). The fat cell number at 18 mo, however, was far below the number at 8 yr of age, as well as the still higher number of the 22-yr-old women.     

The effects of short-term fasting on the excretion of sulfur compounds in healthy subjects

The urinary excretion of sulfur-containing compounds was studied before, on the third, and on the seventh day of fasting in 10 healthy subjects. The excretion of total sulfur, inorganic sulfate, ester sulfate, “non-sulfate sulfur”, methionine, cystathionine, cysteine, N-acetylcysteine, taurine, thiosulfate and thiocyanate was decreased during fasting, whereas the excretion of mercaptoacetate was unaltered and that of mercaptolactate increased. The excretion of inorganic sulfate, taurine and thiocyanate was also decreased when calculated relative to that of total sulfur, suggesting that these compounds are derived mainly from dietary sulfur amino acids. The output of ester sulfate, methionine, cystathionine, cysteine and thiosulfate was unaltered in relation to that of total sulfur, indicating that these compounds are derived from both dietary and endogenous sulfur amino acids, liberated during protein catabolism. By contrast, the excretion of mercaptolactate and mercaptoacetate was increased relative to that of total sulfur, suggesting that these compounds are derived mainly from endogenous sulfur amino acids formed by the enchanced protein catabolism seen during fasting.     

Audibility of an artificial third heart sound in relation to its frequency, amplitude, delay from the second heart sound and the experience of the observer

The possibility of detecting synthetic third heart sounds was studied. A special unit was used that added a sound to a previously recorded phonocardiogram. The sound could be changed in frequency, amplitude and delay from the second heart sound. Four groups of observers--cardiologists, residents, nurses and students--listened to 32 random examples. Detection rate increased with experience of the observer (p less than 0.0001) as well as with amplitude (p less than 0.0001), frequency (p less than 0.0001) and delay of the sound (p less than 0.05). The sensitivity was highest among the cardiologists, but the specificity was not different between the groups. Data from this study indicate that the audibility of the third heart sound depends on several important factors. The sound should usually be audible, but variability of results were considerable even among experienced cardiologists. A quantified phonocardiographic recording should be used for validation.     

Folic acid responsive postmenopausal homocysteinemia

Homocysteinemia is associated with juvenile arteriosclerosis, recurrent thromboembolic complications and osteoporosis. Plasma homocysteine, measured as homocysteine-cysteine mixed disulfide (MDS), has in other than homocysteinemics been reported to be higher in patients with coronary heart or cerebrovascular disease than in controls, and higher in men than in premenopausal women. Here, in groups of normal men and normal premenopausal and postmenopausal women, we measured plasma MDS in the fasting state and four hours after a methionine load (100 mg/kg body weight), before and after four weeks of folic acid therapy at 5 mg daily. In their fasting plasma, postmenopausal women (n = 5) had significantly (P less than 0.05) higher MDS concentrations than premenopausal women (n = 5) and younger men (n = 5). After the methionine load MDS concentrations in postmenopausal women rose markedly, reaching levels significantly higher than those in younger men (P less than 0.05), and with no overlap with values in premenopausal women (P less than 0.01), or in older men (n = 5, P less than 0.01). Folic acid therapy resulted in substantial reductions (n = 15, P less than 0.01) of MDS concentrations both before the methionine load (-31%) and after (-28%), though subjects had initially had normal concentrations of serum and erythrocyte folates. We speculate that moderate homocysteinemia might contribute to postmenopausal arteriosclerosis and osteoporosis. Should this prove to be the case, folic acid might be a useful prophylactic.     

Effect of metoprolol on indirect signs of the size and severity of acute myocardial infarction

In a double-blind randomized trial, 1,395 patients with suspected acute myocardial infarction (MI) were investigated to evaluate the possibility of limiting indirect signs of the size and severity of acute MI with the beta 1-selective adrenoceptor antagonist metoprolol. Metoprolol (15 mg) was given intravenously and followed by oral administration for 3 months (200 mg daily). Placebo was given in the same way. The size of the MI was estimated by heat-stable lactate dehydrogenase (LD[EC 1.1.1.27]) analyses and precordial electrocardiographic mapping. Lower maximal enzyme activities compared with placebo were seen in the metoprolol group (11.1 +/- 0.5 mukat X liter-1) when the patient was treated within 12 hours of the onset of pain (13.3 +/- 0.6 mukat X liter-1; n = 936; p = 0.009). When treatment was started later than 12 hours, no difference was found between the 2 groups. Enzyme analyses were performed in all but 20 patients (n = 1,375). Precordial mapping with 24 chest electrodes was performed in patients with anterior wall MI. The final total R-wave amplitude was higher and the final total Q-wave amplitude lower in the metoprolol group than in the placebo group. Patients treated with metoprolol less than or equal to 12 hours also showed a decreased need for furosemide, a shortened hospital stay, and a significantly reduced 1-year mortality compared with the placebo group, whereas no difference was observed among patients treated later on. After 3 months, however, there was a similar reduction in mortality among patients in whom therapy was started less than or equal to 12 hours and greater than 12 hours after the onset of pain. The results support the hypothesis that intravenous metoprolol followed by oral treatment early in the course of suspected myocardial infarction can limit infarct size and improve long-term prognosis.     

Increased plasma catecholamines in high renin hypertension

Plasma Catecholamines, indexes of sympathetic nervous tonicity, were measured simultaneously with renin both supine and after standing plus furosemide In patients with primary hypertension and normotensive volunteers. Seventy percent of hypertensive patients with high renin levels had increased Catecholamines compared with a 14 percent incidence in the combined group with low and normal renin (P < 0.001). Basal Catecholamines were related directly to renin in the hypertensive patients and to blood pressure in the normal (P < 0.05), but not in the high and low renin subgroups, and inversely to percent increase of catecholamines after standing plus furosemide in hypertensive and normotensive patients (P < 0.01). Sympathetic nervous hypertonicity may be responsible for the elevation of blood pressure and for the activation of the renin-angiotensin system in patients with high renin hypertension.     

Initial vector rates in differentiation between supraventricular extrasystoles with aberration and ventricular extrasystoles.

A computer method was constructed for analysing vector rates. Initial vector rates of QRS of ventricular extrasystoles (VES) and of aberrant supraventricular extrasystoles were compared. Bundle branch block (BBB) was used as a model for aberration. Spontaneous VES during heart catheterization and VES found by His-bundle recording represented the VES group. The VES were found to contain a longer average "activation time," i.e. the duration from the onset to the spatial amplitude maximum, than the BBB. The maximum amplitudes were similar. A method for calculating initial vector rate distribution was also developed. This showed a significantly higher proportion of fast rate components in BBB than in VES. The calculation of vector rate distribution gave advantages over the calculation of the mean initial vector rate, when considering electrocardiographic abnormalities such as preexcitation QRS or post-infarction Q waves. With a simple discriminatory analysis using initial vector rate distribution values, a 95% precision was obtained in differentiating between VES and BBB. It is concluded that a QRS from a supraventricular impulse focus with aberration has faster initial vector rates than a QRS from a ventricular focus and that this difference is useful in distinguishing between them.     

Early intervention with a beta-blocking drug after acute myocardial infarction

Several controlled studies with long-term administration of beta blockers in postinfarction patients have demonstrated a reduction in cardiac events and mortality. During acute myocardial infarction (AMI), conventional treatment is directed mainly at such complications as pump failure and arrhythmias. Another approach attempts to influence the natural evolution of impending myocardial necrosis by interrupting the process in its reversible phase. In a double-blind trial with metoprolol in suspected or definite AMI, 1,395 patients were studied, 698 of whom received metoprolol and 697 placebo. The 3-month mortality was 36% lower in the metoprolol group (p = 0.024). A reduction in severe ventricular arrhythmias (ventricular fibrillation and tachycardia) was also seen. Chest pain was reduced and there was less need of analgesic drugs in the metoprolol group. Intervention within 12 hours resulted in a limitation of infarct size, a decreased need for furosemide and a shortened hospital stay. A significant reduction in mortality was maintained after 2 years of follow-up despite the same treatment in both groups between 3 and 24 months. Early institution of metoprolol in AMI has resulted in reduced mortality and morbidity.     

Cardiac effects of treatment with quinidine and digoxin, alone and in combination

Systolic time intervals (QS2-I and LVET-I) and echocardiographically determined ejection fraction and velocity of circumferential fiber shortening were recorded in 10 healthy volunteers as measures of inotropic effect during maintenance treatment with 4 consecutive drug regimens: (1) quinidine, 1,200 mg/day; (2) digoxin, average dose 0.31 mg/day; (3) the combination of (1) and (2); and (4) digoxin alone (average dose 0.65 mg/day) to provide the same steady-state serum concentration of digoxin as during the period with combination of digoxin and quinidine. The steady-state serum concentration of digoxin during the low-dose regimen increased from 0.72 +/- 0.15 (mean +/- standard deviation [SD]) to 1.63 +/- 0.28 nmol/liter when quinidine was added. With the high dose of digoxin alone, the serum digoxin level reached 1.68 +/- 0.50 nmol/liter. Skeletal muscle digoxin concentrations during these periods were 27.7 +/- 8.3, 48.7 +/- 16.2, and 51.6 +/- 23.6 nmol/kg of dry weight, respectively. The skeletal muscle to serum concentration ratio of digoxin decreased significantly during quinidine treatment. Systolic time intervals were significantly prolonged by quinidine alone and shortened by digoxin alone, the latter effect being dose-dependent. Subtracting the effect of quinidine itself, the induced increase in digoxin level caused a significant increase in inotropic effect. When these corrected values were compared with those attained during the period with the same steady-state digoxin concentration but in the absence of quinidine, no significant differences were found. Echocardiographically measured ejection fraction and velocity of circumferential fiber shortening showed trends for similar drug effects, as did the systolic time intervals. This study, performed under steady-state conditions, demonstrates that the quinidine-induced increase in steady-state serum digoxin concentration will, with due consideration to quinidine's own pharmacodynamic properties, be accompanied by increased cardiac effects. This indicates that quinidine is not interfering with active receptor sites in the heart for digoxin.     

Hemodynamic effects of captopril in essential hypertension, renovascular hypertension and cardiac failure: correlations with short- and long-term effects on plasma renin

The hemodynamic effects of captopril were investigated in 22 patients with essential hypertension, 22 with hypertension and renal artery stenosis and 14 with refractory chronic heart failure. The effects of a first dose of captopril, 50 mg orally, were observed for 2 hours, and the effects of repeated doses, 450 mg/day in combination with mild dietary sodium restriction, for at least 4 weeks.Short-term captopril treatment caused similar reductions in blood pressure in the three patient groups, that is, 21 ± 3 mm Hg in essential hypertension, 29 ± 6 mm Hg in renovascular hypertension and 21 ± 2 mm Hg in heart failure (mean ± standard error of the mean) despite large differences in pretreatment plasma renin. Heart rate and cardiac output did not change in hypertensive patients, and cardiac filling pressures decreased. The changes in right atrial pressure, pulmonary artery pressure and pulmonary capillary wedge pressure in essential hypertension and in renovascular hypertension did not differ. Heart rate decreased and cardiac output increased in heart failure, whereas cardiac filling pressures decreased. Blood pressure responses to long-term captopril therapy in essential and in renovascular hypertension were similar and, as with short-term treatment, changes in blood pressure were largely determined by changes in peripheral resistance. Several measurements of extracellular fluid volume showed no evidence of fluid retention by the kidneys.Short-term but not long-term blood pressure responses were correlated with pretreatment plasma renin (percent change in mean arterial pressure, short-term, versus log renin, r = 0.47, p < 0.001, n = 14). Both short- and long-term responses of total peripheral resistance were correlated with plasma renin (percent change in resistance, short-term versus log renin, r = 0.64, p < 0.001, n = 40; percent change in resistance, long-term versus log renin, r = 0.56, p < 0.001, n = 31). The correlations were weak and probably not important for clinical practice. These data indicate that other factors besides circulating renin are important in captopril's hypotensive effect. The favorable hemodynamic effects of converting enzyme inhibition warrant further consideration of this principle of therapy in the clinical management of most forms of hypertension and also in the treatment of chronic heart failure.     

Beta-adrenergic receptor blocking drugs in hypertension. With special reference to their use as initial therapy

Beta-adrenergic receptor blocking agents have been receiving attention as first-line agents for the treatment of hypertension. However, a number of significant side effects of these drugs have been brought to light. The most important of these--increases in "atherogenic" lipid concentrations--may place treated persons at risk of coronary artery disease and myocardial infarction. Other side effects, including bronchospasm, heart failure, cold extremities, reduced insulin secretion and central nervous system effects, may preclude their use in many patients. However, because several major trials have shown that controlling blood pressure reduces the incidence of coronary heart disease and stroke, the use of antihypertensive therapy is likely to increase and to continue for longer periods. The physician must prescribe an agent with the fewest and most minor side effects. Alternatives to beta-blocking drugs, such as the alpha-receptor blocking agent prazosin, should be considered and evaluated because of the limiting side effect profile of beta blockers.     

Cardiac reflexes in normotensive and spontaneously hypertensive rats.

Characteristics of left atrial receptors were studied in normotensive control (Wistar) and spontenaously hypertensive rats. The left atrial pressure was chronically elevated in spontaneously hypertensive rats and at the end of the expiratory phase was 10.3 mm Hg as compared with 4.6 mm Hg in normotensive control rats. The thresholds of the receptor endings were twice as high in the hypertensive as in the normotensive rats (10.2 and 4.6 mm Hg, respectively). In other experiments the reflex inhibition of renal sympathetic outflow was studied during plasma infusion in baroreceptor denervated normotensive and hypertensive rats was was inhibited at a lower left atrial pressure in the former. These differences are attirubted to decreased distensibility of the left atrium in spotaneously hypertensive rats. The reflex splanchnic nerve inhibition with volume load also was recorded in awake rats. At a 10 percent increase in blood volume, splanchnic outflow was more significantly decreased in spotaneously hypertensive than in normotensive rats. The mechanism underlying such a hyperreactive volume receptor response is unknown, but a less distensible venous system, centrally or peripherally, might be a contributing factor.     

Risk factors for myocardial infarction and death due to ischemic heart disease and other causes

As part of a study of the male population in an industrial city in Sweden, one third of all male inhabitants of Göteborg born in 1913 were invited to an examination in 1963. Of those invited, 855 (88 percent) accepted. This report examines the incidence of nonfatal myocardial infarction and death from ischemic heart disease and other causes in this group of men during the ensuing 10 years.There were 61 deaths; autopsy was performed in 56 cases. Nineteen men died of ischemic heart disease and 18 of cancer; 12 men died violently. Thirty-one men survived an acute myocardial infarction. Cigarette smoking and registration with the Temperance Board at the time of the initial examination were more common in men who later had a nonfatal myocardial infarction or died of ischemic heart disease or other causes than in surviving subjects and men who did not have an infarction. Dyspnea was more common in men who died of ischemic heart disease but was less common in those who died of other causes than in the remaining subjects. Values for systolic blood pressure were higher and those for peak expiratory flow lower in men who died of ischemic heart disease. Serum cholesterol values were higher and those for serum triglycerides tended to be higher in men who died of ischemic heart disease than in other subjects. Heart size tended to be greater in those who had nonfatal or fatal ischemic heart disease. Obesity, the level of physical activity, fasting blood glucose levels, coffee consumption, hematocrit and erythrocyte sedimentation rate as determined at age 50 years had no predictive value for assessing the risk of nonfatal myocardial infarction, fatal ischemic heart disease or death from other causes before age 60. The results indicate that many so-called risk factors have a different relation to fatal than to nonfatal ischemic heart disease.     

Comparison of blood pressure, plasma lipid and cardiac performance responses to prazosin versus propranolol in thiazide-treated hypertensive patients

Twenty-seven patients with uncontrolled hypertension (diastolic blood pressure greater than or equal to 95 mm Hg) receiving thiazide diuretics were treated with the addition of either propranolol (n = 10) or prazosin (n = 17). Nine patients were successfully controlled with propranolol and 12 with prazosin. Six patients required both study drugs for optimal blood pressure control, 5 of whom had received prazosin as the initial study drug. Changes in serum lipid components and cardiac performances with the addition of the study drugs were monitored. A decrease in total cholesterol and an increase in high-density lipoprotein (HDL) cholesterol were seen when prazosin was added, and an increase in total cholesterol and a decrease in HDL cholesterol occurred after the addition of propranolol. Although in this small group of patients these changes did not reach statistical significance, they were similar to changes described in other studies in which these drugs were used as monotherapy for hypertension. The only lipid change of statistical significance was a small increase in the serum triglyceride concentration in patients receiving propranolol. The findings for total cholesterol and its fractions suggest that the effects of the study drugs may not be additive to those of thiazides and that thiazides had already effected a maximal lipid response. Both agents in combination with a thiazide diuretic were equally effective in decreasing diastolic blood pressure to the goal of less than or equal to 85 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)     

Non-specific aorto-arteritis in Singapore with special reference to hypertension.

Aorto-arteritis has recently emerged as a distinct disease entity with involvement of aorta and its major branches by a non-specific inflammation of unknown etiology. Though the distribution of this disease is worldwide, it is more prevalent in Japan, India, and South-east Asia. This paper describes a series of 48 cases seen in Singapore and emphasizes the protean nature of this disease. Though modes of clinical presentation were many, hypertension appeared to be the commonest as it occurred in 33 patients, giving an incidence of 69 per cent. This incidence was much higher than the 48 per cent reported among Europeans and 42 per cent reported among South Africans. It would therefore appear that hypertension was a far more common manifestation of aorto-arteritis among Asians. The commonest cause of hypertension in aorto-arteritis in this series was renovascular, with renal artery stenosis or occlusion occurring in 27 cases (85 per cent). The frequency of involvement of the renal artery is much greater than the 34 per cent reported by the Japanese. Therefore renovascular hypertension should be regarded as a predominant feature of aorto-arteritis in Singapore.