Effect of variation in dietary NaCl intake on the intrarenal distribution of plasma flow in the rat.

The effect of dietary variation in sodium chloride intake on the intrarenal distribution of plasma flow was investigated in rats using the antiglomerular basement membrane antibody technique. Rats were placed on a liquid diet containing either 9.86 (n = 9) or 0 (n = 9) mEq NaCl/daily portion for 2 wk. Labeled antibody was injected and the diets were reversed. After an additional 2 wk period, antibody labeled with a different radionuclide was injected and the animals were sacrificed. Fractional plasma flow distribution was then calculated for each dietary period. No change in flow to any cortical region could be detected. In six additional awake rats on identical dietary regimen, total plasma flow was estimated by the clearance of hippuran-(131)I. No change in this parameter occurred with changes in NaCl intake. We conclude, therefore, that no change in either total renal plasma flow or intracortical distribution of plasma flow occurs with wide variations in dietary sodium chloride intake in the rat. The implications of this constancy of regional plasma flow are discussed with reference to presumed concomitant alterations in the intrarenal distribution of nephron filtration rate.

Mercuric chloride inhibition of vasopressin release from the isolated neurointermediate lobe of the rat pituitary.

The effects of HgCl2 and ouabain on vasopressin release and Ca2+ uptake and distribution was examined in the neurointermediate lobe of the rat pituitary. HgCl2 (0.5 mM) inhibited vasopressin release by approx. 90% in both basal and potassium depolarized states. With 0.1 mM HgCl2 vasopressin release was inhibited by 50% in the depolarized state, but release was not effected in basal state. On the other hand, ouabain (0.5 mM) caused a 3-fold stimulation of vasopressin release in the depolarized state. Both HgCl2 (0.5 mM) and ouabain (0.5 mM) increased net 45Ca+2 uptake by about 80% in groups of neurointermediate lobes. Following 45Ca+2 uptake, HgCl2 (0.5 mM), which is absorbed by the neurointermediate lobe, produced an increase in cytosolic 45Ca+2 content and a decrease in mitochondrial 45Ca+2 content compared to control. In comparison, ouabain (0.5 mM), which does not penetrate the neurointermediate lobe, gave no change in cytosolic 45Ca+2, but an increase in mitochondrial 45Ca+2. These results suggest that HgCl2 inhibits vasopressin release from the neurointermediate lobe of the rat pituitary at a point distal to Ca+2 uptake by the gland.

Beta-adrenergic blocking agents in the treatment of hypertension. Choices based on pharmacological properties and patient characteristics.

Drugs that block beta-adrenergic receptors have become one of the most widely used classes of drugs to treat hypertension. This review puts the use of beta-blockers as monotherapy for hypertension in perspective and provides reasons for choosing among the several beta-blockers available. The major reasons for discriminating within this class of drugs are related to differences in concomitant clinical conditions, differences in patient responses, and intrinsic differences among the beta-blockers. These differences relate to special properties such as beta-agonist activity (intrinsic sympathomimetic activity), beta 1-selectivity, and concomitant alpha-blockade, as well as differences in side effect profiles, excretion characteristics, and length of action of the various drugs.

End-stage renal disease in specific ethnic and racial groups: risk factors and benefits of antihypertensive therapy.

During the past few years, it has become apparent that there are factors that place a person at greater risk for the development and progression of renal failure. This has been documented since the early 1980s by the United States Renal Data System that has collected data confirming that end-stage renal disease occurs at a greater rate in certain subpopulations of Americans. It is evident from an examination of the data that African Americans and American Indians have an incidence of end-stage renal disease that is not proportional to their percentage of the total population. In fact, African Americans and American Indians are reported to have at least a 4-fold greater incidence of end-stage renal disease than white Americans. There have been 5 factors identified: hypertension, glucose intolerance, insulin resistance, salt sensitivity, and hyperlipidemia, which may play a greater role in these subpopulations. In addition, as with other populations, lifestyle issues may serve to alter these primary risk factors or may act as direct modulators of renal disease progression. There is also a possibility that interactions between risk factors frequently occur that may modify the development or progression of the disease. This article reviews these risk factors and emphasizes the interaction between hypertension and the other factors. In addition, the effects of antihypertensive agents on risk factors and on renal outcome are emphasized. Where possible, issues specific to African Americans and American Indians are underscored; however, one must accept that the database on these populations is only now developing. This review should help the clinician make appropriate choices when prescribing antihypertensive therapy for patients who may be at risk of developing progressive renal failure.

Labetalol. Current research and therapeutic status.

Labetalol hydrochloride is the prototype drug of a new class of antihypertensive agents that competitively and peripherally blocks both beta- and alpha-adrenergic receptors. It possesses approximately one fourth of the beta-blocking activity of propranolol hydrochloride and one half of the alpha-blocking activity of phentolamine. In humans, the effective beta- to alpha-blocking activity is approximately 7:1. It has been used successfully in oral form to treat patients with mild, moderate, and severe hypertension and in intravenous form to manage hypertensive emergencies. Prominent side effects include orthostatic hypotension and gastrointestinal disturbances. Overall, the drug appears to offer several advantages over pure beta-blocking drugs in some patients and should expand the armamentarium of the practicing physician in the management of the difficult hypertensive patient.

Renal failure and hyperkalemia associated with ketorolac tromethamine.

Three patients who were treated with ketorolac tromethamine (Toradol), an injectable nonsteroidal anti-inflammatory drug for pain management, developed acute renal failure or hyperkalemia or both. These complications were reversible in two cases after discontinuing the drug. Clinical conditions preexisted in each patient that rendered them susceptible to the renal complications of nonsteroidal anti-inflammatory use. It is well known that caution should be observed while using nonsteroidal anti-inflammatory drugs in patients whose renal function may be preserved through prostaglandin-mediated vasodilatory effects. The same cautions apply to ketorolac. Since its major marketed use is as an analgesic and its potent effect on prostaglandin synthesis may not be well recognized, those cautions must be emphasized.

Intravenous dilevalol. Effects of the R-R optical isomer of labetalol in patients with severe hypertension.

Dilevalol hydrochloride, the R-R optical isomer of labetalol hydrochloride, was administered intravenously to subjects with severe hypertension. Twelve subjects with supine diastolic blood pressure of more than 115 mm Hg (mean, 124 +/- 2 mm Hg) were studied. Initial doses of 25 mg of dilevalol administered as a slowly given bolus reduced blood pressure by 14/16 mm Hg. With subsequent additional boluses to a total dose of up to 600 mg, supine diastolic blood pressure was reduced to less than 95 mm Hg in ten of 12 subjects studied (mean reduction, 28 mm Hg). Side effects were minimal and upright blood pressure at the time of reduction of blood pressure to goal was not significantly different from supine blood pressure. Plasma renin activity decreased in 11 of 11 subjects studied. Plasma epinephrine concentrations did not change significantly, whereas plasma norepinephrine concentrations increased 2 1/2-fold, probably reflecting the effect of beta 2-agonism on norepinephrine release. Dilevalol appears to be a safe and effective way of lowering blood pressure short term when intravenous antihypertensive therapy is indicated.

Dilevalol in severe hypertension. A multicenter trial of bolus intravenous dosing.

Dilevalol, the R-R optical isomer of labetalol, a nonselective beta-antagonist with vasodilation from selective beta 2 agonism, was administered in sequential multiple bolus intravenous injections of 10 to 100 mg in total doses ranging from 35 to 585 mg (mean dose, 414 mg) to 101 patients with supine diastolic blood pressures above 120 mm Hg. Mean blood pressure was reduced from 200 (+/- 3)/129 (+/- 1) mm Hg to 149 (+/- 2)/101 (+/- 1) mm Hg, a mean reduction of 51/28 mm Hg. The therapeutic goal was established as a reduction in supine diastolic blood pressure to less than 100 mm Hg or a reduction of at least 30 mm Hg. This was achieved in 62 (61%) of 101 patients, with an additional 7 patients having a final supine diastolic blood pressure of 100 mm Hg. Treatment with dilevalol was less successful in black male patients than in the group at large. There was a tendency for older patients to respond better than younger patients. Prior recent treatment of patients with beta-adrenergic antagonists decreased the effectiveness of the drug. Significant orthostatic hypotension was not noted. Sixty-four patients were transferred to oral dilevalol treatment in combination with a diuretic, and blood pressure in this group averaged 160/100 mm Hg after 1 month of therapy. Dilevalol appears to be a safe and effective drug that can be used intravenously successfully in the majority of patients with severe hypertension and provides an alternative to therapy with other agents. It also is a useful agent for oral treatment of these patients after successful intravenous therapy.

Intravenous nicardipine for the treatment of severe hypertension. A double-blind, placebo-controlled multicenter trial.

A placebo-controlled, double-blind multicenter trial was conducted in 123 patients with severe hypertension to examine the efficacy and safety of intravenously administered nicardipine hydrochloride in controlling blood pressure. Seventy-three patients were initially randomized to receive nicardipine treatment. This group had an initial blood pressure of 213 +/- 3/126 +/- 2 mm Hg. Sixty-seven patients achieved the therapeutic goal (diastolic blood pressure less than or equal to 95 mm Hg; systolic blood pressure less than or equal to 160 mm Hg). Fifty patients were randomized to receive placebo solution. Blood pressure in these patients was 216 +/- 3/125 +/- 2 mm Hg. No patient in this group achieved the therapeutic goal during the "blinded" portion of the study. Forty-four of 49 patients who did not respond to placebo administration responded to subsequent treatment with nicardipine. Patients with end-organ damage were included in the study. These included patients with left ventricular hypertrophy, retinopathy, and renal insufficiency. Patients with and without end-organ damage responded equally well to nicardipine treatment. Serious adverse experiences were infrequent, the most common adverse reaction being headache in 24% of the patients studied.

Chemiluminescence and superoxide anion production by leukocytes from diabetic patients.

Stimulated neutrophils exhibit a burst of oxidative metabolism which results in the formation of superoxide anion and other oxygen species that participate in bacterial killing. Chemiluminescence is also produced and is a sensitive measure of oxidative metabolism and correlates well with antimicrobial activity. Since infection is an important cause of morbidity and mortality in diabetic patients we examined chemiluminescence and superoxide production by leukocytes from diabetics in the resting state and in response to a soluble (phorbol myristate acetate) and to a particulate stimulus (opsonized zymosan). No significant difference in the resting chemiluminescence was observed. However, the resting superoxide anion production by patients' leukocytes was significantly higher in autologous serum; when patients' leukocytes were placed in normal serum, a significant reduction in the resting superoxide anion production was observed. Using phorbol myristate acetate as a stimulus, leukocytes from diabetic patients had a markedly reduced chemiluminescence response [controls 388 +/- 48, n = 22, patient 220 +/- 37, peak cpm X 10(3)/10(6)P leukocytes, n = 22, (P less than 0.01)] and reduced superoxide anion response [controls 30.1 +/- 3.8, n = 16, patients 13.3 +/- 2.6 nmol/15 min/10(6)P leukocytes, n = 16 (P less than 0.001)]. Significantly reduced chemiluminescence response (P less than 0.05) and superoxide production (P less than 0.05) by leukocytes from diabetic patients were also observed using opsonized zymosan as a stimulus. No significant effects on chemiluminescence or superoxide response to phorbol myristate acetate were observed with cross-incubation studies in which patients' leukocytes were placed in normal serum or control leukocytes in patient serum. In vitro addition of insulin (25 microU; 100 microU/ml) had no significant effect on patient cell response; similarly increasing the glucose concentration from 100 mg/dl to 200 mg/dl and 400 mg/dl had no significant effect on control cell response. Glucagon in a lower concentration (200 pg/ml) had no significant effect; only at a higher concentration (400 pg/ml), it caused an inhibition of the phorbol stimulated chemiluminescence and superoxide response of control leukocytes. These results show an impaired oxidative burst by leukocytes from diabetic patients which may contribute to impaired bacterial killing and may explain, in part, the morbidity and mortality in diabetic patients suffering from infection.

Antihypertensive effectiveness of intravenous labetalol in accelerated hypertension.

Labetalol, an antihypertensive agent that blocks both beta- and alpha-adrenergic receptors, was administered intravenously to 19 patients with accelerated hypertension who required rapid lowering of blood pressure. Systolic blood pressure was lowered from 209 +/- 4 to 143 +/- 2 mm Hg; diastolic blood pressure was reduced from 140 +/- 2 to 93 +/- 2 mm Hg. Side-effects were minimal and included nausea, epigastric burning, rhinorrhea, and premature ventricular contractions. One patient became hypotensive and required treatment. Overall, the study demonstrates labetalol to be a safe and effective agent for the emergency lowering of blood pressure, with demonstrated results comparable to other parenteral agents.

Renal function effects of dilevalol, a nonselective beta-adrenergic blocking drug with beta-2 agonist activity.

The effects of dilevalol, a new beta-adrenergic blocking agent with beta-agonism, on renal function were determined in two groups of patients. Patients in group 1, all with normal renal function, received either dilevalol or atenolol. Patients in group II, all with impaired renal function, received either dilevalol or metoprolol. Parameters of renal function determined before and after chronic oral treatment included glomerular filtration rate (GFR), effective renal plasma flow, filtration fraction, mean arterial pressure (MAP), renal blood flow, and renal vascular resistance. Dilevalol lowered MAP by 14 mm Hg (P less than 0.005) in group I and 25 mm Hg (P less than 0.01) in group II but had no effect on other parameters of renal function, at either peak or trough drug levels. Atenolol and metoprolol also lowered MAP by 11 mm Hg (P less than 0.01) and 15 mm Hg (P less than 0.05), respectively. Atenolol reduced GFR by 23% at peak drug level, an effect that was partially ameliorated at trough drug level. The effect of atenolol on GFR appeared to vary as a function of baseline renal function in that greater reductions were seen in groups of patients with increasing baseline GFR. Metoprolol significantly decreased renal vascular resistance by 17% (P less than 0.05). These data suggest that dilevalol effectively lowers blood pressure in hypertensive patients with normal or compromised renal function with no negative impact on parameters of renal function.

Plasma clonidine concentration and pharmacologic effect.

Analysis of sequential plasma samples in 14 hypertensive subjects receiving their usual oral dose of clonidine (0.1 to 0.6 mg twice daily) indicated that clonidine plasma concentration increased for the first 2 hr and then decreased and stabilized over the next 12 hr. Percent fall in diastolic blood pressure, but not side effects, correlated well with plasma concentration. Our study indicates a potential role for plasma clonidine determination in the treatment of patients with hypertension. It also demonstrates that clonidine can probably be given at 12-hr intervals and be effective.

Effects of labetalol and methyldopa on renal function.

Renal function studies were performed in subjects with mild hypertension treated with labetalol (n = 5) and moderate to moderately severe hypertension treated in a random double-blind fashion with either labetalol (n = 6) or methyldopa (n = 6). Drugs were given in doses sufficient to reduce standing diastolic blood pressure to less than 90 mm Hg. This was achieved in all subjects without significant side effects. Inulin clearance, para-aminohippurate clearance, filtration fraction, free-water clearance, and maximal concentrating ability was assessed before and after 15 days of drug. No alterations in any parameter were noted with labetalol. Inulin clearance fell by 13% (p less than 0.05), and filtration fraction fell from 0.23 to 0.18 (p less than 0.02), but other parameters of renal function did not change with methyldopa.

Effects of medroxalol on renal function and the renin-angiotensin-aldosterone axis.

Ten subjects with hypertension received medroxalol, which blocks both alpha- and beta-adrenergic receptors, has intrinsic sympathomimetic beta 2-agonist properties and is a direct vasodilator. Renal function tests consisting of inulin clearance and p-amino hippuric acid (PAH) clearance, plasma renin activity (PRA) in recumbent and upright postures, and aldosterone excretion rate were performed. After intravenous medroxalol, inulin clearance and PAH clearance rose, renal vascular resistance fell, recumbent PRA was unchanged, and the rise in PRA with upright posture was blunted. After 1 mo on oral medroxalol, blood pressure was controlled while inulin clearance, PAH clearance, and renal vascular resistance were unchanged. The rise in PRA with upright posture remained blunted. Urinary aldosterone excretion was unchanged after 1 mo on medroxalol.

Effect of diet composition on metabolic adaptations to hypocaloric nutrition: comparison of high carbohydrate and high fat isocaloric diets.

The metabolic consequences of two hypocaloric diets were assessed in 10 obese men. The study, performed on a metabolic ward, compared the response of these men to two cholesterol-free liquid formula diets of differing composition (10 kcal/kg per day, 70% carbohydrate, 20% protein, 10% fat versus 70% fat, 20% protein, 10% carbohydrate) but identical in calories. These were administered for 14 days in a random order and each diet was preceded by a 7-day control weight maintenance diet (30 kcal/kg per day, 40% carbohydrate, 20% protein, 40% fat). The low calorie diets were well tolerated by the men and effected similar losses of nonaqueous body weight. Fasting glucose and insulin decreased significantly in these men after they ingested either weight loss diet for 14 days, but the change in each parameter was greater for high fat as compared to high carbohydrate (15% versus 7% and 67% versus 35%, respectively, P less than 0.01). In contrast, fasting glucagon concentration decreased in these subjects to a greater extent in response to the high carbohydrate diet (35% versus 16%, P less than 0.01). This adaptive response thus resulted in a 50% fall in insulin:glucagon molar ratio for high fat and no change for high carbohydrate weight loss. Despite these hormonal alterations no change in glucose tolerance was observed. Fasting serum triglyceride and cholesterol levels declined in these subjects to a greater extent following the high fat compared to the high carbohydrate regimen (45% versus 28%, P less than 0.01 and 8% versus 3%, not significant, respectively). These changes reflected decrements in very low density lipoproteins alone. Despite similar increments in free fatty acid levels, (350% versus 270%, not significant) serum ketone body (beta-hydroxybutyrate and acetoacetate) concentrations increased 7-fold on the high fat diet compared to the high carbohydrate diet, P less than 0.001. The hyperketonemia of these men in response to the high fat, low calorie diet suggested the occurrence of a shift in hepatic free fatty acid metabolism toward ketogenesis rather than triglyceride synthesis. The associated decrease in the insulin: glucagon molar ratio raised the question of a possible role for these hormones in the adaptation.

Endocrine and metabolic alterations with food and water deprivation.

Two healthy men were evaluated before and after a 56-day raft voyage to determine endocrine and metabolic status immediately after and during the recovery phase after long-term caloric, protein, and water deprivation. Daily intake during the trip consisted of no protein, 300 ml water, and for the first 40 days, 300 kcal glucose. The subjects lost weight from 84.1 to 58.1 and 78.3 to 57.7 kg, respectively. Significant variations included: 1) decreased excretion and loss of diurnal pattern of 17-hydroxycorticoids with normal serum corticoid levels and variation; 2) decreased serum testosterone levels and concomitant low follicle stimulating hormone and low normal luteinizing hormone levels; 3) decreased urinary 17-ketosteroid levels; 4) low plasma insulin levels with normal serum glucose concentrations; 5) increased triglyceride content in the 1.006 less than d less than 1.063 lipoproteins during fasting with a marked increase in high density lipoprotein cholesterol upon refeeding. The percent content of the R-serine (C-I) apoprotein among the soluble apoproteins of very low density lipoproteins diminished markedly during the fast; 6) abnormal liver function immediately after fasting with increased abnormality after the 2 weeks of refeeding and return to normal by 6 weeks; 7) normal fat and xylose absorption, normal estradiol, estrone and prolactin levels, and renal function studies.

Antihypertensives and their impact on renal function.

Antihypertensive agents possess many properties that could cause alterations in renal function. These are: alterations in systemic hemodynamics, changes in the renin-angiotensin aldosterone system, direct intrarenal effects, and alterations in salt and water metabolism. This article reviews the antihypertensive agents in general usage and major points are made concerning potential deleterious effects of methyldopa and nonselective beta-adrenergic blocking drugs on renal function. In particular, recent data are shown concerning the effects of labetalol on renal function indicating the absence of decrements in glomerular filtration rate and renal plasma flow in patients with normal renal function and in patients with mild to moderate renal insufficiency. A possible decrease in these parameters in patients with severe renal insufficiency is presented and discussed.

Hematuria and red cell casts in typical diabetic nephropathy.

Hematuria and red cell casts are unusual urinary findings in patients with diabetic nephropathy. This glomerular disease is more typically characterized by the presence of moderate to severe proteinuria. Hematuria with red blood cell casts in patients with suspected diabetic nephropathy suggests the presence of a second, unrelated form of glomerulonephritis. The full clinical and renal pathologic findings in eight patients with otherwise typical diabetic nephropathy who also had significant hematuria and red cell casts in the urinary sediment are reported. Three of the patients had an immune-mediated form of glomerulonephritis identified. Careful histologic, electron microscopic, and immunofluorescent examination of the renal tissue from the remaining five patients demonstrated only diabetic nephropathy, without evidence of immune-mediated glomerulonephritis in any. Screening urinalysis in a population of 30 patients with diabetic nephropathy revealed hematuria in 30 percent and red cell casts in 13 percent. It is concluded that significant hematuria with red cell casts may be a clinical feature of diabetic nephropathy.

Therapeutic adherence in the elderly: transdermal clonidine compared to oral verapamil for hypertension.

This double-blind, double-dummy, randomized clinical trial, conducted in elderly patients with mild hypertension, compared adherence to treatment, efficacy, side effects, and quality of life during treatment with transdermal clonidine versus oral sustained-release verapamil (verapamil-SR). Blood pressure declined significantly--from 148/95 mm Hg at baseline to 139/84 after titration and 135/86 after maintenance--with transdermal clonidine (n = 29), and from 156/96 to 144/85 and 148/88, respectively, with verapamil-SR (n = 29). Adverse event rates and quality-of-life questionnaire responses were similar in the two treatment groups. Transdermal clonidine was worn as directed during more than 96% of patient-weeks of treatment. Compliance with the oral verapamil regimen was less consistent: Verapamil-SR was taken as directed during approximately 50% of patient-weeks of therapy, and individual compliance, assessed by tablet counts, varied from 50-120%. In all, 86% of subjects were satisfied or highly satisfied with the convenience of transdermal therapy; 87% reported that side effects were slightly or not bothersome; 65% indicated that transdermal patches were more convenient than oral therapy; and almost 60% preferred transdermal to oral therapy. In this study transdermal clonidine and oral verapamil were equally safe and effective. A substantial majority of patients preferred transdermal to oral therapy, and adherence to treatment was greater with transdermal therapy.