Antihypertensive therapy in type 2 diabetes: implications of the appropriate blood pressure control in diabetes (ABCD) trial.

As the population ages, the incidence of type 2 diabetes will increase as will the incidence of concomitant vascular complications. Hypertension substantially increases the risk of cardiovascular disease in patients with diabetes. Results from the recent Appropriate Blood Pressure Control in Diabetes (ABCD) trial demonstrated an advantage of an angiotensin-converting enzyme (ACE) inhibitor (enalapril) over a long-acting calcium antagonist (nisoldipine) with regard to the incidence of cardiovascular events over a 5-year follow-up period in hypertensive persons with type 2 diabetes. This trial was a prospective, randomized, blinded study comparing the effects of moderate blood pressure control (target diastolic pressure 80-89 mm Hg) with those of intensive control (target diastolic pressure 75 mm Hg) on the incidence and progression of diabetic vascular complications. The study also compared nisoldipine with enalapril as first-line antihypertensive therapy in terms of prevention and progression of complications of diabetes. In 470 hypertensive patients, the incidence of fatal and nonfatal myocardial infarctions was significantly (p = 0.001) higher among those receiving nisoldipine (n = 25) compared with those receiving enalapril (n = 5). Comparison with previous studies suggests that the difference observed between nisoldipine and enalapril resulted from a beneficial effect of enalapril rather than a deleterious effect from nisoldipine. Since these findings in the ABCD trial are based on a secondary endpoint, they require confirmation. Nevertheless, they suggest that ACE inhibitors should be the initial antihypertensive medication used in patients with type 2 diabetes and hypertension.

The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension.

BACKGROUND: It has recently been reported that the use of calcium-channel blockers for hypertension may be associated with an increased risk of cardiovascular complications. Because this issue remains controversial, we studied the incidence of such complications in patients with non-insulin-dependent diabetes mellitus and hypertension who were randomly assigned to treatment with either the calcium-channel blocker nisoldipine or the angiotensin-converting-enzyme inhibitor enalapril as part of a larger study. METHODS: The Appropriate Blood Pressure Control in Diabetes (ABCD) Trial is a prospective, randomized, blinded trial comparing the effects of moderate control of blood pressure (target diastolic pressure, 80 to 89 mm Hg) with those of intensive control of blood pressure (diastolic pressure, 75 mm Hg) on the incidence and progression of complications of diabetes. The study also compared nisoldipine with enalapril as a first-line antihypertensive agent in terms of the prevention and progression of complications of diabetes. In the current study, we analyzed data on a secondary end point (the incidence of myocardial infarction) in the subgroup of patients in the ABCD Trial who had hypertension. RESULTS: Analysis of the 470 patients in the trial who had hypertension (base-line diastolic blood pressure, > or = 90 mm Hg) showed similar control of blood pressure, blood glucose and lipid concentrations, and smoking behavior in the nisoldipine group (237 patients) and the enalapril group (233 patients) throughout five years of follow-up. Using a multiple logistic-regression model with adjustment for cardiac risk factors, we found that nisoldipine was associated with a higher incidence of fatal and nonfatal myocardial infarctions (a total of 24) than enalapril (total, 4) (risk ratio, 9.5; 95 percent confidence interval, 2.7 to 33.8). CONCLUSIONS: In this population of patients with diabetes and hypertension, we found a significantly higher incidence of fatal and nonfatal myocardial infarction among those assigned to therapy with the calcium-channel blocker nisoldipine than among those assigned to receive enalapril. Since our findings are based on a secondary end point, they will require confirmation.

Upregulation of endothelial and neuronal constitutive nitric oxide synthase in pregnant rats.

Pregnancy is characterized by hemodynamic and body fluid alterations. Increased nitric oxide (NO) production has been suggested to play a role in the hemodynamic alterations of pregnancy and has also been reported to increase arginine vasopressin (AVP) release. We therefore hypothesized that gestation could increase both NO synthase (NOS) constitutive isoforms, neuronal NOS and endothelial NOS, and thereby contribute to the hyposmolality and peripheral arterial vasodilation of pregnancy, respectively. The present study was therefore undertaken to examine the constitutive NOS isoforms in aortas, mesenteric arteries, and hypothalami of pregnant rats on day 20 of gestation compared with age-matched nonpregnant rats. Plasma AVP was determined by radioimmunoassay and hypothalamic mRNA AVP by solution hybridization assay. Hypothalamic neuronal NOS was assessed by Northern blot and Western blot; endothelial NOS was assessed by Western blot in arteries and hypothalamus. The results demonstrated that 1) plasma AVP and hypothalamic AVP mRNA are increased in pregnant rats (n = 8), 2) neuronal NOS protein and mRNA are increased in hypothalamus of pregnant rats (n = 4), and 3) endothelial NOS expression, as assessed by Western blot analysis, is increased in both conductance (aorta) as well as resistance (mesenteric) arteries of pregnant rats (n = 4). We conclude that both of the constitutive NOS isoforms are increased in pregnant rats, suggesting that the peripheral arterial vasodilation and hyposmolality of pregnancy could be mediated by these isoforms.

Arginine vasopressin gene expression in rats with puromycin-induced nephrotic syndrome.

Nephrotic syndrome is characterized by water and sodium retention, which leads to edema formation. The nonosmotic stimulation of arginine vasopressin (AVP) release from the pituitary gland has been implicated to be one of the important factors of abnormal water retention in patients with nephrotic syndrome. It is not known, however, whether nephrotic syndrome is associated with stimulation of hypothalamic vasopressin gene expression. Puromycin aminonucleoside is known to cause altered glomerular permeability, which results in experimental nephrotic syndrome in rats. In the present study, therefore, AVP gene expression has been studied in the hypothalamus of rats with puromycin aminonucleoside-induced nephrotic syndrome (PNS). Nephrotic syndrome was induced by a single intravenous injection of puromycin aminonucleoside (50 mg/kg body weight). Nephrotic syndrome was confirmed by urinary protein excretion (control 20.8 +/- 3.5 mg/24 hr v PNS 273.9 +/- 41.4 mg/24 hr; P < 0.0001, n = 6) and serum albumin concentrations (control 4.52 +/- 0.07 g/dL v PNS 2.96 +/- 0.22 g/dL; P < 0.001, n = 6). In PNS rats, plasma AVP was significantly higher than in control rats (control 0.77 +/- 0.10 pg/mL v PNS 2.13 +/- 0.42 pg/mL; P < 0.005, n = 12), even though there were no differences in plasma osmolality (control 292.0 +/- 2.0 mOsm/kg H2O v PNS 290.3 +/- 2.5 mOsm/kg H2O; P = NS, n = 12) or serum sodium concentration (control 142.7 +/- 0.7 v PNS 142.1 +/- 1.1; PNS, n = 12).(ABSTRACT TRUNCATED AT 250 WORDS)

The ABCD (Appropriate Blood Pressure Control in Diabetes) trial. Rationale and design of a trial of hypertension control (moderate or intensive) in type II diabetes.

OBJECTIVE: The primary objective of the ABCD (Appropriate Blood Pressure Control in Diabetes) Trial is to determine the efficacy of intensive versus moderate antihypertensive control on the outcome of type II diabetic end-organ complications in normotensive and hypertensive populations. The secondary objective is to determine whether any differential effect on end-organ complications exists between an angiotensin converting enzyme inhibitor (enalapril) and a calcium channel blocker (nisoldipine). DESIGN: The ABCD Trial is a prospective, controlled, randomized, double-blind trial, with a planned follow-up of 5 years. SETTING: All patients are seen at the Colorado Prevention Center, site of the ABCD Trial, for follow-up visits. PATIENTS: Patients are type II diabetic males and females between the ages of 40 and 74 years with entry diastolic blood pressures > or = 80 mmHg. Patients were recruited from University of Colorado-affiliated hospitals, several health maintenance organizations, and mailing lists from the Colorado affiliate of the American Diabetes Association. INTERVENTIONS: Patients were randomized to intensive antihypertensive drug therapy or moderate antihypertensive drug therapy. Patients were also randomized to nisoldipine or enalapril, with open-label medications added if further blood pressure control was necessary. MAIN OUTCOME MEASURES: The primary outcome measure is glomerular filtration rate as assessed by 24-hour creatinine clearance. Secondary outcome measures are microalbumin urinary excretion, left ventricular hypertrophy, retinopathy, and neuropathy. Cardiovascular morbidity and mortality will also be evaluated. CONCLUSION: Given the data showing the impact of hypertension on diabetic complications, the ABCD Trial was designed to determine if intensive antihypertensive therapy will be more efficacious than moderate antihypertensive therapy on the outcome of these complications. Results from the ABCD Trial are expected to lend interpretable and clinically relevant findings with regards to the treatment of hypertension in type II diabetes.

Enhancement of vascular action of arginine vasopressin by diminished extracellular sodium concentration.

The present study was undertaken to examine the effects of diminished extracellular sodium concentration on the vascular action of arginine vasopressin (AVP) in cultured rat vascular smooth muscle cells (VSMC). The preincubation of cells with the 110 mM extracellular Na+ ([Na+]e) solution supplemented with 30 mM choline chloride for 60 minutes enhanced the effect of AVP- (1 x 10(-8) M) induced VSMC contraction. The treatment of 110 mM [Na+]e solution also enhanced the cellular contractile response to the protein kinase C (PKC) activators, phorbol 12-myristate 13-acetate and 1-oleoyl-2-acetyl-glycerol. Furthermore, preincubation with the 110 mM [Na+]e solution also potentiated the effect of 1 x 10(-8) M AVP, but not 1 x 10(-6) M, to increase the cytosolic-free Ca2+ ([Ca2+]i) concentration. The 110 mM [Na+]e media decreased the basal intracellular Na+ concentration and increased intracellular 45Ca2+ accumulation, basal [Ca2+]i and AVP-produced 45Ca2+ efflux. These effects of 110 mM [Na+]e solution to enhance the vascular action of AVP were abolished by using Ca(2+)-free 110 mM [Na+]e solution during the preincubation period. The preincubation with the 110 mM [Na+]e solution did not change either the Kd and Bmax of AVP V1 receptor of VSMC or the AVP-induced production of inositol 1,4,5-trisphosphate. The present in vitro results therefore indicate that the diminished extracellular fluid sodium concentration within a range observed in clinical hyponatremic states enhances the vascular action of AVP.(ABSTRACT TRUNCATED AT 250 WORDS)

Divergent effects of acute and chronic ethanol exposure on contraction and Ca2+ mobilization in cultured vascular smooth muscle cells.

In cultured rat vascular smooth muscle cells (VSMC), acute preincubation of 100 mmol/L ethanol for 30 min attenuated the number of contracting cells in response to (10(-7) mol/L) arginine vasopressin (AVP) (P < .01). In contrast, VSMC cultured chronically for 3 days in medium supplemented with 100 mmol/L ethanol enhanced (10(-7) mol/L) AVP-induced shape change (P < .01). Specific 3H-AVP binding to VSMC after acute or chronic exposure to 100 mmol/L ethanol did not differ from those of control experiments. Acute ethanol pretreatment attenuated basal, 10(-7) mol/L AVP-, 65 mmol/L K(+)-stimulated Ca2+ uptake, in a dose-dependent manner. In contrast, 100 mmol/L ethanol for 4 days enhanced the (P < .001) AVP- 10(-7) mol/L and (P < .01) 65 mmol/L K(+)-stimulated 45Ca2+ uptake. Acute ethanol exposure inhibited and chronic ethanol administration enhanced Ca2+ uptake stimulated by 6 x 10(-7) mol/L Bay K 8644, an activator of voltage-sensitive Ca2+ channels. Nifedipine, a blocker of these Ca2+ channels, diminished AVP-stimulated (P < .02) and K(+)-induced (P < .001) Ca2+ uptake more potently in VSMC pretreated for 4 days with 100 mmol/L ethanol than in control cells. Acute ethanol preexposure for 30 min attenuated AVP-stimulated inositol trisphosphate (IP3) formation (P < .05) and the rise in cytosolic free Ca2+ ([Ca2+]i) (P < .01). In contrast, chronic ethanol-treated VSMC enhanced IP3 formation (P < .05) and the rise in [Ca2+]i (P < .01) in response to AVP.(ABSTRACT TRUNCATED AT 250 WORDS)

Vasopressin gene expression in rats with experimental cirrhosis.

Impaired ability to excrete a water load occurs in a substantial number of patients with advanced cirrhosis and in animals with experimental cirrhosis. The nonosmotic stimulation of arginine vasopressin release from the pituitary has been implicated as an important factor in the abnormal water excretion in patients and animals with cirrhosis. In this study, arginine vasopressin hypothalamic gene expression was studied in cirrhotic rats. Cirrhosis was induced by a combination of phenobarbital treatment in drinking water and weekly intragastric administration of carbon tetrachloride for 13 to 15 wk. Severe cirrhosis was confirmed by morphological analysis and the presence of ascites. Plasma arginine vasopressin was also significantly higher in rats with cirrhosis (control = 1.77 +/- 0.16 and cirrhotic rats = 4.14 +/- 0.62 pg/ml, n = 9, p < 0.002). Hypothalamic arginine vasopressin messenger RNA was also significantly higher in cirrhotic rats (control = 762.1 +/- 132.3 and cirrhotic rats = 1,834.2 +/- 271.9 pg/hypothalamus, n = 9, p < 0.005). Pituitary arginine vasopressin content was significantly lowered in cirrhotic rats (control = 3.69 +/- 0.98 and cirrhotic rats = 1.57 +/- 0.09 micrograms/pituitary, n = 9, p < 0.05). No difference was seen in hypothalamic arginine vasopressin content between the two groups (control = 4.64 +/- 0.34 and cirrhotic rats = 4.23 +/- 0.33 ng/hypothalamus, n = 9, NS). Oxytocin messenger RNA in the hypothalamus was also not significantly different between the two groups (control = 8.61 +/- 0.68 and cirrhotic rats = 9.33 +/- 0.65 unit of density, n = 9, NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Short-term hypothyroidism and vasopressin gene expression in the rat.

Hypothyroidism is associated with abnormalities in renal water handling, which include a delay in excretion of an acute water load, decreased urinary concentrating ability, and increased urine volume. In the present study, we investigated the role of vasopressin in aminotriazole-induced hypothyroidism by measuring vasopressin concentration in the plasma and pituitary along with vasopressin mRNA levels in the hypothalamus. After 5 weeks of aminotriazole treatment, L-thyroxine levels were significantly lower in the experimental animals (122 +/- 8 v 26 +/- 1 nmol/L [9.5 +/- 0.6 v 2.0 +/- 0.1 micrograms/dL]; P less than 0.001). Serum sodium (148 +/- 0.5 v 144 +/- 1.2 mmol/L [mEq/L]; P less than 0.01), and plasma osmolality (311 +/- 2.5 v 304 +/- 1.8 mmol/kg [mOsm/kg] H2O; P less than 0.05) were also lower in the experimental animals. There were no differences in plasma (1.9 +/- 0.4 v 1.5 +/- 0.2 pg/mL) or pituitary (1.5 +/- 0.4 v 1.5 +/- 0.2 microgram/pituitary) vasopressin levels. In addition, steady-state vasopressin mRNA levels were not different between the two groups (1,286 +/- 210 v 1,093 +/- 138 pg/hypothalamus). One week of L-thyroxine replacement resulted in significant increases in serum thyroxine levels without changes in the other variables measured. These results indicate that short-term hypothyroidism, which has been shown to exert substantial effects on renal function, causes only a modest central alteration in the plasma vasopressin-osmolality relationship, which occurs in the absence of detectable changes in vasopressin synthesis.

Arginine vasopressin gene expression in chronic cardiac failure in rats.

Arginine vasopressin (AVP) is known to be increased in patients and experimental animals with chronic cardiac failure (CCF). The importance of an increase in biosynthesis of AVP in the hypothalamus has, however, not heretofore been investigated and is the purpose of the present study. CCF secondary to infarction of myocardial tissue was induced by ligation of the left anterior descending coronary artery and sham operated animals served as controls. Four weeks later hypothalamic AVP mRNA was determined by solution hybridization using sense and anti-sense strand RNA. The blood pressure was lower in CCF than sham animals (131.2 +/- 3.1 vs. 112.8 +/- 4.0 mm Hg, P less than 0.05) and the total heart, and right and left ventricle weights were significantly higher in CCF rats. Plasma AVP was higher in CCF (sham 6.78 +/- 0.30; CCF 11.46 +/- 0.64 pg/ml, P less than 0.001) and plasma atrial natriuretic peptide was also higher in CCF than sham animals (205 +/- 36 vs. 554 +/- 56 pg/ml, P less than 0.001). The AVP mRNA in hypothalamus was significantly higher in CCF than sham animals (55.5 +/- 3.7 vs. 95.9 +/- 4.0 pg/micrograms total RNA, P less than 0.001). There was no difference in beta-actin mRNA in the hypothalamus of sham and CCF rats, indicating that the AVP-mRNA increase was specific in CCF. These results therefore demonstrate that increased AVP biosynthesis in the hypothalamus, in addition to release of the hormone from the posterior pituitary, may occur in CCF.

Attenuation of hypermetabolism in the remnant kidney by dietary phosphate restriction in the rat.

In vivo energy metabolism in remnant and normal kidney nephrons and the effect of dietary phosphate restriction on energy metabolism were studied. Tissue concentrations of ATP did not differ between remnant and normal kidneys; however, the tissue concentration of inorganic phosphate (Pi) was higher in remnant kidneys (1.17 +/- 0.10 vs. 0.82 +/- 0.09 mumol/g, P less than 0.05) as assessed by 31P-nuclear magnetic resonance (NMR). Intracellular pH was also higher in remnant kidneys (7.48 +/- 0.04 vs. 7.20 +/- 0.05, P less than 0.01), as was oxygen consumption (QO2) when normalized for rate of net tubular sodium reabsorption (Tna; 0.032 +/- 0.005 vs. 0.018 +/- 0.002 mumol.min-1.g-1, P less than 0.01). Compared with glycine supplemented controls, dietary phosphate restriction induced by the phosphate binder diaminodihydroacetoacetate, a maneuver which independently of protein restriction has been shown to ameliorate the progression of chronic renal failure, resulted in no major change in tissue levels of ATP, intracellular pH, or TNa+ but decreased Pi (0.62 +/- 0.07 vs. 1.40 +/- 0.11 mumol/g, P less than 0.01) and QO2 (4.0 +/- 0.4 vs. 7.7 +/- 1.0 mumol.min-1.g-1, P less than 0.01) in remnant kidneys. For the amount of sodium reabsorption performed, remnant kidneys are hypermetabolic, and this hypermetabolism is attenuated by dietary phosphate restriction. These data suggest that hypermetabolism may be involved in the tubulointerstitial mechanisms operant in the progression of chronic renal failure that occurs in the rat remnant kidney, and that attenuation of this abnormality may be the mechanism by which dietary phosphate restriction ameliorates this process.

Anti-calmodulin agents affect osmotic and angiotensin II-induced vasopressin release.

Calcium ions and particularly calcium influx play a crucial part in initiating the intracellular events that result in arginine vasopressin (AVP) release to both osmotic and nonosmotic stimuli. Calmodulin appears to modulate the effects of calcium on synaptic transmission and hormone release in other systems. This study tested the effects of three distinct classes of anti-calmodulin agents on the release of AVP to either a rise in osmolality of 20 mosmol/kg water or to 1 X 10(-5) angiotensin II (ANG II) in cultured hypothalamo-neurohypophysical complexes. Micromolar concentrations of R 24571, the active naphthalenesulfonamides, W 7 and W 13, and trifluoperazine (TFP) inhibited AVP release to osmotic stimulation. In contrast, W 5, a severalfold less active anti-calmodulin agent, had no effect on osmotically stimulated AVP release. The active naphthalenesulfonamides, but not R 24571 or TFP, blocked release of AVP to ANG II. In contrast, neither R 24571 nor TFP inhibited AVP release to ANG II stimulation. Collectively, the data demonstrated a dissociation between inhibition of AVP release and the anti-calmodulin properties of the drugs, thereby suggesting that nonspecific actions masked the calmodulin-blocking effects of the drugs or that the inhibition occurred by some alternative mechanism(s).

Improvement of renal preservation by verapamil with 24-hour cold perfusion in the isolated rat kidney.

There is substantial evidence that increased cellular calcium may activate processes that lead to cellular injury and death, and calcium entry blockers (CEB) have been shown to protect against renal ischemic injury. This approach has been used experimentally to enhance kidney preservation during both warm and cold ischemia. In the present study, the effect of the CEB verapamil on kidney function after 24 hr of hypothermic (4-7 degrees C) perfusion was examined and compared with simple cold storage with Eurocollins' solution (4 hr), 4 or 24 hr cold perfusion, without the addition of verapamil. The cold perfusion media consisted of 3% albumin in phosphate-free Krebs-Henseleit saline supplemented with 5 mM glucose. Cold perfusion was performed at 40 mmHg perfusion pressure with either 0 (C) or 5 microM verapamil (V) added to the cold perfusion media. Renal functional parameters of plasma flow (RPF), inulin clearance (Cin), fractional (FRNa+) and net sodium reabsorption (TNa+) were assessed during 60 min of reperfusion at 37 degrees C using 6.7% albumin in Krebs-Henseleit saline supplemented with glucose, inulin, and 20 amino acids. There was no increase in RPF with V (33 +/- 1 vs. 32 +/- 2 ml/min/g,NS) but Cin was significantly higher (271 +/- 30 vs. 168 +/- 20 microliter/min/g P less than 0.01) with V. Preservation of tubular function by V was demonstrated by an increase in FRNa+ (84 +/- 5 vs. 57 +/- 8%, P less than .01), TNa+ (32 +/- 6 vs. 15 +/- 3 mumol/min/g, P less than .01) and renal adenosine triphosphate (ATP) concentration (8.0 +/- 5 vs. 4.7 +/- 1.0 mumol/g dry tissue, P less than .01). Thus, V appears not only to enhance kidney preservation with warm and cold ischemia but also improves renal function, as assessed by glomerular filtration rate (GFR) tubular function, and tissue ATP concentration with 24-hr cold perfusion.

Phosphate depletion arrests progression of chronic renal failure independent of protein intake.

Following 5/6 nephrectomy, 18 rats were fed a normal diet. After 30 days, serum creatinine (SCr), urine protein excretion and urine volume were increased compared to pre-nephrectomy (0.27 +/- 0.1 vs. 1.62 +/- 0.6 mg/deciliter, 17.0 +/- 10.3 vs. 257.6 +/- 13.4 mg/24 hr, and 16.6 +/- 4.4 vs. 39.2 +/- 11.7 ml/24 hr, respectively, all P less than 0.001). At this time, when serum phosphorus (SPi) and serum calcium (SCa2+) were normal, the rats were separated into two groups, matched and paired by body weight and SCr, and housed separately in metabolic cages. Animals of one group ingested a normal diet supplemented with dihydroxyaluminum aminoacetate (DHAAA), 15 g%, to induce phosphate depletion (PD). The second group ingested the same diet supplemented with 7.5% glycine and was the phosphate replete (PR) group. All rats were pair fed throughout the study to maintain similar caloric, protein, carbohydrate, vitamin, and mineral intakes. At six weeks after separation, SPi was decreased in PD vs. PR group (2.85 +/- 0.8 vs. 6.71 +/- 1.2 mg/deciliter, P less than 0.001) and SCa2+ was increased in the PD group (11.98 +/- 0.7 vs. 10.03 +/- 0.7 mg/deciliter, P less than 0.001). Urine urea nitrogen, body weight, and sodium, potassium and solute excretion were similar between the groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Protective effect of intrarenal calcium membrane blockers before or after renal ischemia. Functional, morphological, and mitochondrial studies.

The present study examined whether a pre- or postischemic infusion of verapamil (V) or a postischemic infusion of nifedipine (N), drugs which block calcium (Ca++) influx across plasma membranes, provides protection against ischemic acute renal failure (ARF) in dogs. Renal hemodynamics and excretory function were examined 1 h (initiation phase) and 24 h (maintenance phase) after a 40-min intrarenal infusion of norepinephrine (NE). In each case, the uninfused contralateral kidney served as control. Four groups were studied: (a) dogs receiving NE alone; (b) dogs receiving an intrarenal infusion of V for 30 min before NE (V + NE); (c) dogs in which intrarenal V was infused for 2 h, beginning immediately after completion of NE infusion (NE + V); and (d) dogs in which intrarenal N was infused for 2 h, beginning immediately after completion of NE infusion (NE + N). Glomerular filtration rate (GFR) in the NE kidneys, as assessed by inulin clearance, at 1 and 24 h averaged 2.4 +/- 1.1 and 5.0 +/- 2.0 ml/min, respectively, as compared with control kidney GFRs of 28.0 +/- 3.5 and 43.8 +/- 5.0 ml/min, respectively (both at least P less than 0.01). In the V + NE group, GFR at 1 and 24 h averaged 15.0 +/- 5.5 and 31.0 +/- 4.5 ml/min, respectively, both at least P less than 0.05 as compared with values from NE kidneys. GFRs in the NE + V group averaged 15.0 +/- 2.4 and 16.3 +/- 3.6 ml/min at 1 and 24 h, both at least P less than 0.02 as compared with values from NE kidneys. GFR in the NE + N group averaged 18.6 +/- 6.0 ml/min at 24 h (P less than 0.05 as compared with GFRs in the NE kidneys). In addition, function of cortical mitochondria (Mito) was examined at the end of the 40-min NE infusion and after 1 and 24 h of reperfusion in the NE alone and NE + V groups. Mito respiration, assessed by acceptor control ratios, was reduced at each period in the NE alone kidneys. After 24 h, these Mito had accumulated Ca++ and exhibited reduced Ca++ uptake and increased Ca++ release rates. Mito from NE + V kidneys respired normally, did not accumulate Ca++, and exhibited no alterations in Ca++ uptake or release. Light and electron microscopy also demonstrated morphological protection of V against tubular necrosis and cell injury. Mito from the NE + N kidneys also respired normally and did not accumulate significant amounts of Ca++. The results of the present studies therefore demonstrated that chemically dissimilar calcium entry blockers exert substantial functional, cellular, and morphological protection against experimental ischemic ARF. These findings are compatible with the hypothesis that increased cytosolic Ca++ is critically important in the maintenance of renal vasoconstriction and the development of cellular necrosis with subsequent tubular obstruction in NE-induced ischemic ARF. V or N may provide protection against renal injury by retarding any increase in cytosolic Ca++ in renal vasculature and epithelium.

Osmotic and nonosmotic control of vasopressin release.

While the existence of an osmotic control for vasopressin (AVP) release has been long recognized, development of a sensitive immunoassay has allowed for better understanding of factors affecting the threshold and sensitivity of AVP release. Individual variation, genetic, environmental, and species differences, and the nature of the solute providing the osmotic stimuli can significantly affect the release of the hormone by altering the threshold and/or the sensitivity of the osmoreceptor. In addition to the hypothalamic osmoreceptor, AVP secretion is also controlled by an anatomically separate pathway which is responsive to nonosmotic stimuli. It appears that both low-pressure (left atrial) and high-pressure (carotid and aortic) receptors via the parasympathetic pathways provide the major nonosmotic pathway for vasopressin release. Such pathways are activated in response to acute systemic hemodynamic changes, stress, and hypoxia. The precise interaction between osmotic and nonosmotic AVP release remains to be clarified. A model of osmotic and nonosmotic interactions, based on available electrophysiologic studies, is presented and its clinical implications are discussed.

1,25 dihydroxycholecalciferol effects in chronic dialysis. A double-blind controlled study.

1,25 dihydroxycholecalciferol [1,25(OH)2D3] was studied in a double-blind controlled fashion in patients on chronic dialysis. Serum calcium was unchanged in 16 patients on vitamin D3 (D3) (400 to 1200 IU/day). In 15 patients on 1,25(OH)2D3 (0.5 to 1.5 microgram/day), serum calcium increased from 9.05 +/- .15 to 10.25 +/- .20 mg/dl (p less than 0.001), returning to 9.37 +/- .16 mg/dl (p less than 0.001) in the post control period. Patients on D3 showed no reversible decrease in immunoreactive parathyroid hormone levels, but patients on 1,25(OH)2D3 did, from a control of 1077 +/- 258 to 595 +/- 213 microliter equivalents/ml (p less than 0.01), and returned to 1165 +/- 271 microliter equivalents/ml (p less than 0.005). Nine of 12 patients on D3 who underwent serial iliac-crest biopsies showed histologic deterioration, and six of seven who received 1,25(OH)2D3 were improved or unchanged (p less than 0.025). Bone mineral and calcium decreased in patients on D3 (p less than 0.05) but not in those on 1,25(OH)2D3. Hypercalcemia occurred in five of 15 patients. We conclude that 1,25(OH)2D3 has a calcemic effect in chronic dialysis patients, decreases levels of immunoreactive parathyroid hormone, and is associated with histologic improvement in bone disease. Thus, 1,25(OH)2D3 is a valuable adjunct to the management of renal osteodystrophy but requires monitoring of serum calcium to avoid hypercalcemia.