Defect in the sodium-modulated tissue responsiveness to angiotensin II in essential hypertension.

In normal subjects, dietary sodium intake modulates renovascular, adrenal, and pressor responses to infused angiotensin II (AII). To examine the hypothesis that this modulation is abnormal in some patients with essential hypertension, we studied 18 hypertensives and 9 normal subjects twice--during dietary sodium restriction and during loading. Paraaminohippurate (PAH) clearance was used to assess renal plasma flow. AII was infused in graded doses (0.3-3.0 ng/kg per min). Plasma aldosterone, cortisol, renin activity, AII, sodium, potassium, and PAH clearance were measured at the onset and end of each AII dose. During dietary sodium repletion, eight of the subjects with essential hypertension showed a normal renovascular response (greater than 125 ml/min per 1.73 m2) to AII infusion (3 ng/kg per min). The decrement in renal blood flow in these normal responders (NR) was 168 +/- 10, which was comparable to the range in normotensive subjects (206 +/- 25 ml/min per 1.73 m2). All of the remaining hypertensive patients, designated abnormal responders (AbR), had lower (less than 125) renal blood flow responses to the same dose of infused AII (mean decrement: 84 +/- 11 ml/min per 1.73 m2) compared with the NR and normotensive subjects. Renal blood flow responses to all AII doses were statistically greater on a high-vs.-low salt diet in the NR (P less than 0.001, chi-square) and normotensives (P = 0.004, chi-square) but sodium intake had no effect on this response in the AbR. Basal renal blood flow in NR increased significantly (P less than 0.001, paired t test) with dietary sodium repletion, from 491 +/- 36 (low salt) to 602 +/- 40 ml/min per 1.73 m2 (high salt), but was almost identical in the AbR on differing dietary sodium intakes (429 +/- 24 vs. 425 +/- 26 ml/min per 1.73 m2). The adrenal responses to sodium intake and infused AII also differed in the two subgroups. In the NR, the adrenal response to AII was significantly greater (P = 0.011, Wilcoxon signed rank test) after sodium restriction. In contrast, there was no significant difference in the aldosterone response to AII infusion between the low and high sodium diets in the AbR. Thus, a substantial subgroup of essential hypertensives has an abnormality in responsiveness to AII in two systems central to volume homeostasis: the kidney and adrenal. They fail to modulate their renal blood flow and aldosterone responses to AII with changes in dietary sodium intake. Moreover, basal renal blood flow does not increase appropriately with increased sodium intake. These abnormalities, which may be due to an increased local production of AII or a defect in the AII receptors in these three target tissues, could contribute to the elevated blood pressure.

Exaggerated growth hormone response to arginine infusion in Huntington's disease.

Growth hormone regulation was studied in 10 patients with Huntington's disease after intravenous administration of arginine. In 20 control subjects arginine infusion resulted in a rise of plasma growth hormone levels from a mean baseline value of 3.2+/-0.6 ng/ml to a peak level of 17.6+/-2.7 ng/ml at 60 min. Growth hormone rise in the majority of patients with Huntington's disease was clearly intact and significantly greater than normal in magnitude, increasing from the baseline level of 2.6+/-0.5 ng/ml to a peak level of 28.3+/-3.7 ng/ml at 60 min (P = less than 0.05). Carbohydrate tolerance of these patients was previously examined, and 4 with normal glucose tolerance and normal insulin responses to arginine infusion had growth hormone levels significantly higher than controls at 30 min. Six patients with impaired carbohydrate tolerance and exaggerated insulin responses to arginine had significantly higher growth hormone responses at 30 min and also at 60 min. Neuronal degeneration of several hypothalamic nuclei has been reported in Huntington's disease. The observations that growth hormone responds in an exaggerated fashion to stimulation by arginine infusion or falling glucose levels as previously described may be explained by intrahypothalamic dysfunction such as impairment of somatostatin secretion.

Renin suppression by saline is blunted in nonmodulating essential hypertension.

We have reported that 50% of subjects with normal renin essential hypertension have both delayed suppression of the renin-angiotensin-aldosterone axis following sodium infusion and a delayed rate of excretion of an acute salt load. In another study we have also described a subset of patients with essential hypertension (called nonmodulators) who have several abnormalities, including a pressor response to salt loading. To evaluate whether the abnormalities described in these different groups of patients actually occur in the same patient, we assessed the renin-angiotensin-aldosterone axis response to short-term saline loading in 38 hypertensive patients. Their ability to modulate was determined by their renal vascular response to infused angiotensin II on a high salt diet (200 mEq Na). In response to a 3-hour infusion of saline, 75 mEq/hr, the reduction in plasma renin activity at both 60 and 120 minutes was significantly greater (p less than 0.008) in patients with normal modulation than in the nonmodulators. Plasma aldosterone levels were also significantly lower (p less than 0.001) in those with intact modulation. Thus, nonmodulating essential hypertensive patients have abnormalities in several systems that influence sodium homeostasis, including altered adrenal and renal vascular response to angiotensin II, altered renal blood flow response to salt loading, and a delayed suppression of the renin-angiotensin-aldosterone system with short-term saline infusion.

Contribution of prostaglandins to the antihypertensive action of captopril in essential hypertension.

To determine whether prostaglandins contribute to the depressor response to the converting enzyme inhibitor, captopril, we measured the plasma prostaglandin levels by radioimmunoassy before and after captopril administration, and then examined the effect of prostaglandin synthetase inhibition on captopril's antihypertensive effect. When a single oral captopril dose (25-100 mg) was given to 31 sodium-restricted patients with essential hypertension, the levels of the stable transformation product of prostacyclin remained unmeasurable and that of thromboxane A2 did not change, while the metabolite of PGE2 (PGE-M) increased by 53% (34 +/- 4pg/ml pre-captopril, 52 +/- 5 pg/ml after; p less than 0.001). As expected, blood pressure (BP) and angiotension II (AII levels fell, and kinin levels rose (all changes p less than 0.001). We then blocked prostaglandin synthesis in 18 of these subjects for 24 hours with either indomethacin (n = 10) or aspirin (n = 8) before repeating the captopril dose, to assess the importance of these PGE-M increments. The PGE-M responses to captopril were effectively blocked in nine of 10 subjects receiving indomethacin and four of eight receiving aspirin. In these 13 patients, the depressor response to captopril was significantly blunted (-20 +/- 3mm Hg pre-synthetase inhibition vs - 13 +/- 2 mm Hg post; p less than 0.05). When these agents did not block the PGE-M response to captopril, the BP response was also unchanged (-15 +/- 4mm Hg pre, -18 +/- 5mm Hg post). Neither indomethacin nor aspirin changed the AII or kinin responses to captopril. We conclude that the prostaglandins may be important mediators of captopril's antihypertensive effect in the sodium-restricted state.

Absence of sleep-related growth hormone elevations in myotonic dystrophy.

There is evidence that in myotonic dystrophy, the endocrine and central nervous systems are affected. To study a possible relationship between both defects, we investigated nocturnal sleep patterns and associated growth hormone secretion in two men and three women with myotonic dystrophy. In three patients who were clinically the most severely affected by myotonic dystrophy, plasma growth hormone elevations related to the slow-wave phase of sleep were absent. The two least severely affected patients had plasma growth hormone increases of low magnitude and brief duration (from 0.4 ng per milliliter to 13.0 ng per milliliter). These data suggest a failure of integration at a subcortical level of the slow-wave phase of sleep with the hypothalamic-pituitary mechanisms of growth hormone secretion. Thalamic neuronal lesions occurring in myotonic dystrophy could be responsible for such failure.

Improvement of growth hormone response to stimulation in primary aldosteronism with correction of potassium deficiency.

Potassium depletion frequently occurs in primary aldosteronism and has been implicated as the cause of the impaired carbohydrate tolerance frequently associated with this syndrome. Glucose, insulin, and growth hormone regulation were studied in a 42-yr-old, male patient with an aldosterone-secreting adenoma when the patient was potassium-depleted and again after potassium repletion. Potassium repletion was documented by serial body potassium measurements, with an increase in body potassium from 2400 mEq to 2850 mEq after 400 mg spironolactone and 80 mEq supplemental potassium chloride were administered daily for 7 days. Potassium repletion resulted in improvement of the patient's glucose tolerance test, with a decrease in the peak glucose level from 184 mg/100ml to 130 mg/100ml and an increase in the peak insulin level from 46 muU/ml to 85 muU/ml. Intravenous administration of arginine resulted in a subnormal insulin response of 28 muU/ml in the base-line test and an increase to 59 muU/ml after potassium stores were repleted. Growth hormone response to arginine infusion was also initially minimal at 12.5 ng/ml, increasing markedly to 26 ng/ml after potassium replenishment. Insulin-induced hypoglycemia resulted in a depressed growth hormone response of 8 ng/ml when the patient was potassium-deficient, but a normal response of 30 ng/ml after potassium repletion. These observations demonstrate that impairment of both insulin and growth hormone responses to stimulation occur in primary aldosteronism with potassium depletion. These abnormalities may be reversed by potassium repletion.

Hyperosmolar nonketotic coma in the elderly diabetic.

The gravity of this syndrome of severe diabetic stupor without ketosis may not be recognized because patients are usually middle-aged or elderly with mild diabetes. A lack of urgency in treating these patients is probably the cause of the widely reported mortality of 40 to 70 per cent.

The relationship of conjunctival and arterial blood gas oxygen measurements.

Conjunctival oxymetry (CjO2) measures peripheral tissue oxygen at the conjunctival level. CjO2 changes can indicate pulmonary or circulatory conditions leading to shock. Literature review does not define 'normal' CjO2/ABG PaO2 ratios. We designed a study to measure these ratios. Twenty-two healthy patients undergoing cardiac catheterization had simultaneous PcjO2 and PaO2 measurements completed. The range of conjunctival oxygen measurements was from 34 to 68 mmHg with a mean of 50.5 mmHg. The PaO2 readings ranged from 65 to 93 mmHg with a mean of 77.1 mmHg. The average PcjO2/PaO2 ratio was 0.656 with a range of 0.47-0.93. Thus the PcjO2 is on average 66% of the arterial blood gas PaO2. This ratio of 0.66 can serve as a base for further clinical studies in which PcjO2 is looked at in patients with pulmonary or circulatory illnesses or injuries.

Massive myocardial necrosis in thrombotic thrombocytopenic purpura: a case report and review of the literature.

Thrombotic thrombocytopenic purpura (TTP) is an uncommon syndrome resulting from diffuse occlusion of small arterioles and capillaries by hyaline microthrombi. It is characterized by fever, thrombocytopenic purpura, microangiopathic hemolytic anemia, and neurologic and renal dysfunction. While cardiac pathology in TTP is commonly seen at autopsy, clinical cardiac dysfunction is rare and typically results from conduction system involvement. While 3% to 8% of patients with TTP report chest pain on admission, reports of fatal ventricular pump failure are extremely rare. We now report a case of TTP resulting in death from widespread myocardial necrosis. This patient presented with elevated cardiac enzymes and electrocardiographic disturbances that mimicked viral myocarditis, as well as a profound thrombocytopenia. Such a case may represent the extreme of a distribution of cardiac involvement in TTP or the consequence of an unidentified autoimmune process capable of precipitating severe myocardial TTP.

Diabetic retinopathy: update on therapeutic advances.

It is clear that real advances have occurred in the therapy of diabetic retinopathy. However, this complication of diabetes can and does lead to blindness in the older patient. The present treatment modalities offer a means of maintaining or, in some patients, improving the visual performance of the patient. Laser photocoagulation and vitrectomy are the major new therapies. The future will hopefully give us a better understanding of the cause of diabetic retinopathy so that it may be prevented and cured. However, in the interim, all patients with diabetes mellitus should be urged to see on ophthalmologist yearly in order to obtain the best available therapy.

Age, smoking inhalation, and pulmonary function.

This study examined the relative effects of age and smoking on pulmonary function. Smoking was measured by six smoking variables, taken singly and as a composite. Subjects were 1,516 male participants in the Normative Aging Study. A stepwise multiple regression with vital capacity (VC) and forced expiratory volume at one second (FEV1.0) as the criteria accounted for 24.4% and 28.3% of the variance, respectively. Two-way analyses of variance showed that the age decline in pulmonary function was substantially greater for high inhalers than it was for low inhalers or nonsmokers. Age and the inhalation index were also noticeably and independently related to a decline in pulmonary function.