Tumour oxygenation is increased by hyperthermia at mild temperatures. 1996.

The effects of hyperthermia on the oxygenation status in R3230 AC tumours of Fischer rats were measured using a polarographic oxygen electrode system. The median pO(2) in about 10 mm diameter tumours grown s.c. in the leg of rats was 3.7 +/- 0.3 mm Hg and it significantly increased upon heating at modest temperatures. For example, the tumour pO(2) measured within 10-15 min after heating for 30 min at 42.5 degrees C was about three-fold greater than that in the control tumours. About 62% of pO(2) values measured in control tumours were <5 mm Hg. After heating at 42.5 degrees C for 30 min, 37% of pO(2) values were <5 mm Hg. Such an increase in tumour oxygenation or reoxygenation of hypoxic cells appeared to result from an increase in tumour blood flow caused by the mild temperature hyperthermia. The presence of hypoxic cells in tumours is believed to be a major factor in limiting the effectiveness of radiotherapy, certain chemotherapy drugs and phototherapy. Hyperthermia at mild temperatures easily achievable with the use of presently available clinical hyperthermia devices may be an effective means to overcome the hypoxic protection in the treatment of human tumours.

Therapeutic end points for the treatment of atrioventricular node reentrant tachycardia by catheter-guided radiofrequency current.

OBJECTIVES: The purpose of this prospective study was to test the hypothesis that the elimination of inducible repetitive atrioventricular (AV) node reentry despite the persistence of slow AV pathway conduction is a valid end point for radiofrequency catheter ablation procedures in patients with supraventricular tachycardia due to AV node reentry. BACKGROUND: Although modification of AV node physiology by radiofrequency current can eliminate AV node reentrant tachycardia, therapeutic end points that are definitive of a satisfactory result in patients undergoing modification of the slow AV pathway have not been established. Applications of radiofrequency current at selected sites may eliminate all evidence of slow pathway conduction or sufficiently modify the refractory properties of the slow pathway to preclude sustained arrhythmias. Accordingly, total abolition of dual AV node physiology may not be necessary to prevent arrhythmia recurrence. METHODS: Radiofrequency catheter ablation of the slow AV pathway was attempted in 59 patients with typical AV node reentry. Tissue ablation was performed with a continuous wave of 500-kHz radiofrequency current. Twenty-five to 35 W was applied for 60 s at the site selected for tissue destruction. RESULTS: Dual AV node physiology was eliminated completely in 35 patients (59%), persisted without inducible AV node reentry in 13 patients (22%) and persisted with inducible single AV reentrant beats in 11 patients (19%). In patients with persistent dual AV node physiology, the maximal difference between the effective refractory period of the fast and slow pathways was reduced from 104 +/- 62 ms before the procedure to 37 +/- 37 ms after AV conduction had been modified (p < 0.001). During a mean follow-up interval of 15 months (range 4 to 28), only one patient (2%) had a recurrence of the tachycardia. CONCLUSIONS: Results demonstrate that when complete elimination of dual AV node physiology is difficult, modification of slow pathway conduction to the extent that repetitive AV node reentry cannot be induced is a definitive end point that portends a good prognosis.

Long-term effectiveness of surgical treatment of ectopic atrial tachycardia.

OBJECTIVES: The purpose of this study was to determine the long-term clinical outcome of patients with ectopic atrial tachycardias treated surgically. BACKGROUND: Ectopic atrial tachycardia is an uncommon arrhythmia that can be symptomatic and is associated with the development of a cardiomyopathy. Management strategies are not well defined because of the paucity of data on the long-term effectiveness of pharmacologic and nonpharmacologic therapies. METHODS: The long-term clinical impact of medical and surgical therapy was determined in 15 consecutive patients with ectopic atrial tachycardia. All 15 patients were initially treated with antiarrhythmic drugs (mean 5.7 +/- 2.2 drugs/patient). An effective drug regimen was identified in only 5 (33%) of the 15 patients; the remaining 10 patients were treated surgically. In each, individualized surgical procedures were guided by computer-assisted intraoperative mapping, with atrial plaques comprising up to 156 electrodes. Focal ablation was performed in four patients and atrial isolation procedures in six. RESULTS: The 10 patients treated surgically were followed up a mean of 4 +/- 3.2 years. Ectopic atrial tachycardia recurred in one patient. A permanent pacemaker was implanted in two patients, one of whom also required reoperation for constrictive pericarditis. There were no operative deaths. Ectopic atrial tachycardia recurred in three (60%) of the five patients discharged on antiarrhythmic drug therapy during a mean follow-up interval of 6.4 +/- 4.3 years. There was one nonarrhythmic death. CONCLUSIONS: Map-guided surgery demonstrated long-term efficacy in abolishing symptoms in 9 of the 10 patients with ectopic atrial tachycardia. Results demonstrate that surgery is effective for patients with ectopic atrial tachycardias who are not easily treated with antiarrhythmic drugs.

Relation between sodium intake, renal function, and the regulation of arterial pressure.

The long-term regulation of arterial pressure requires the maintenance of a balance between sodium and water intake and sodium and water excretion. Normal salt and water balance leads to stable body fluid volumes and the maintenance of normal renal function is critical to establishing extracellular fluid volume homeostasis. This review focuses on the role of the kidney in the long-term control of salt and water balance with particular emphasis on the relations between sodium intake, the renin-angiotensin-aldosterone system, renal sympathetic nerve activity, and the regulation of arterial pressure via renal sodium and water excretion. The accumulation of evidence in recent years demonstrates that low level elevation of renin release, circulating angiotensin II or aldosterone, or activation of renal sympathetic outflow may alter renal function such that normal natriuretic and diuretic responses to arterial pressure are significantly impeded. Under these circumstances, the maintenance of normal sodium and water excretion requires a significant elevation of arterial pressure. Thus, compromised renal function leads to elevation of arterial pressure to maintain adequate sodium and water balance during periods of increased sodium intake. The resultant chronic elevation of arterial pressure then becomes a compromise that is used by the kidneys to maintain normal extracellular body fluid volumes.

Chronic renal neuroadrenergic hypertension is associated with increased renal norepinephrine sensitivity and volume contraction.

Individuals with essential hypertension have been characterized by increased renal sympathetic vascular tone with decreased plasma volume and normal cardiac output compared with normotensive individuals. We used a servo-controlled intrarenal infusion system to evaluate the hemodynamic, renal excretory, and plasma hormonal responses to 28-day, low-level elevations in the intrarenal adrenergic neurotransmitter norepinephrine. In uninephrectomized dogs (n = 6), servo-controlled norepinephrine infusion increased mean arterial pressure from 95.6 +/- 3.1 to 115.7 +/- 4.9 mm Hg on day 1 without concomitant reductions in renal blood flow. Arterial hypertension was sustained and renal vascular resistance increased during the 28 days of servo-controlled norepinephrine infusion despite significant decreases in the daily dose of intrarenal norepinephrine (1.49 +/- 0.23 to 0.47 +/- 0.25 mg/d) necessary to maintain renal blood flow constant. Arterial pressure returned to control values with the cessation of servo-controlled norepinephrine, whereas renal blood flow and renal vascular resistance remained slightly decreased and increased, respectively. Cumulative sodium balance exhibited a net 177 +/- 37 mmol sodium loss over the 28 days of norepinephrine infusion, indicating that the hypertension did not result from sodium retention or expansion of extracellular fluid volume. Intrarenal norepinephrine did not change plasma epinephrine, norepinephrine, or vasopressin concentrations. Atrial natriuretic factor, however, increased at 7 and 14 days of servo-controlled norepinephrine, and plasma renin activity increased on day 14 of norepinephrine infusion. We conclude that low-level elevation of intrarenal adrenergic neurotransmitter produces sustained arterial hypertension that is independent of expansion in extracellular fluid volume, increases in circulating catecholamines or plasma renin activity, or reductions in renal blood flow. This hypertension may be associated with increased renal vascular sensitivity to norepinephrine and/or other renal vasoactive factors.

Renal neurogenic mediation of intracerebroventricular angiotensin II hypertension in rats raised on high sodium chloride diet.

Chronic elevation of sodium intake may affect the sensitivity of the central nervous system to intracerebroventricular (I.C.V.) angiotensin II (Ang II) infusion. Experiments were conducted to determine the influence of raising Sprague-Dawley rats from 2 to 3 weeks of age on low (5.0 mmol/L per kg food), normal (50 mmol/L per kg food), or high (250 mmol/L per kg food) NaCl diets on renal and cardiovascular responses to low-dose I.C.V. Ang II infusion. At 12 weeks of age, Sprague-Dawley rats were instrumented for chronic study, including brain lateral ventricular cannulation. Artificial cerebrospinal fluid was infused (0.25 microL/min I.C.V.) during control and recovery, whereas Ang II (20 ng/min) was infused for 5 days. During the experiment, respective sodium intakes were infused intravenously over 24 hours. In rats fed high sodium, control mean arterial pressure was 115+/-2 mm Hg and increased to 132+/-4 mm Hg by day 5 of I.C.V. Ang II infusion. This increase in arterial pressure was associated with significant (P<.05) decreases in sodium excretion, leading to the retention of 5.4+/-0.6 mmol/L total sodium over the 5 days of Ang II infusion. In rats raised on low and normal sodium intakes from weaning and in 10-week-old rats exposed to a high sodium diet for only 2 weeks, arterial pressure was not increased and sodium was not retained during I.C.V. Ang II infusion at 20 ng/min. In rats raised on the high sodium diet, bilateral renal denervation abolished the arterial hypertension and reduced the sodium retention over 5 days of I.C.V. Ang II infusion. Thus, chronic elevation of sodium intake increases the hypertensive response to low-dose I.C.V. Ang II infusion, which is dependent on intact renal nerves. We conclude that elevated postnatal NaCl intake enhances the pressor sensitivity of the brain to Ang II.

Renal nerves affect rate of achieving sodium balance in spontaneously hypertensive rats.

The spontaneously hypertensive rat (SHR) has an elevated efferent sympathetic nerve activity, suggesting that the renal handling of sodium and water may be altered. This study evaluated the renal neurogenic influence on the rate of achieving sodium balance in adult SHRs and Wistar-Kyoto (WKY) rats after either a step increase or step decrease in fixed sodium intake. Conscious, unrestrained rats with either innervated or denervated kidneys were initially placed on a low-sodium (0.3 mEq/d) or high-sodium (5.0 mEq/d) intake by intravenous infusion. Hourly urinary sodium excretion was determined 24 hours before and 72 hours after sodium intake had been increased from low to high or decreased from high to low. After either step change in fixed sodium intake, both innervated SHRs and innervated WKY rats achieved sodium balance within 24 hours. Similarly, the time course of achieving sodium balance was nearly identical between WKY rats with innervated and denervated kidneys after either switch in sodium intake. In SHRs receiving a step increase in sodium intake, both innervated and denervated kidneys increased urinary sodium excretion equally for 9 hours; however, at this time, innervated SHRs continued to increase sodium excretion rapidly, whereas denervated rats were delayed in a further response. Thus, innervated SHRs achieved sodium balance approximately 18 hours sooner than denervated SHRs. Differences in urinary sodium excretion did not result from concomitant changes in plasma renin activity or mean arterial pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal nerves and the development of Dahl salt-sensitive hypertension.

Several experimental forms of hypertension require intact renal innervation for the development or maintenance (or both) of the elevated arterial pressure. We determined the relationships between urinary sodium and water excretion and arterial pressure in Dahl salt-sensitive rats (DS) with innervated (n = 6) and denervated (n = 7) kidneys after switching from a low to a high sodium diet. Arterial pressure significantly increased in both groups within 48 hours after they began to eat an 8% sodium chloride diet. This hypertension increased to 188 +/- 9 and 190 +/- 7 mm Hg, respectively, in rats with innervated and denervated kidneys after 12 days. Mean arterial pressures were not significantly different between groups on any day. The rise in arterial pressure of DS placed on a high sodium intake was associated with an elevation of urine flow rate and urinary sodium excretions in rats with either innervated or denervated kidneys. Urine flow rates and urinary sodium excretions were greater in denervated than in innervated rats on Days 4 through 7 after beginning the high sodium diet. This diuresis and natriuresis in rats with denervated kidneys were associated with greater water and sodium intakes on Days 4 to 7 of the high sodium diet when compared with rats with innervated kidneys. These results demonstrate that, following exposure to a high sodium intake, DS have increased arterial pressure within 24 hours. The development of this arterial hypertension is not dependent on intact renal innervation. In conscious DS, the renal innervation does participate in the regulation of urinary sodium excretion by promoting renal sodium and water reabsorption.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in oxygenation status and blood flow in a rat tumor model by mild temperature hyperthermia.

PURPOSE: Experiments were conducted to elucidate the relationship between the changes in oxygen partial pressure (pO2) and blood flow in heated tumors with an ultimate goal of using mild temperature hyperthermia (MTH) to increase tumor oxygenation. METHODS AND MATERIALS: The blood flow and pO2 in the R3230 adenocarcinoma grown (subcutaneously) in the right hind limbs of Fischer rats were measured immediately or 24 h after heating at 40.5 degrees-43.5 degrees C for 30 or 60 min. The blood flow was measured with the radioactive microsphere method and the tumor pO2 was measured polarographically using an Eppendorf pO2 histograph. RESULTS: The tumor PO2 significantly increased immediately and 24 h after heating for 30 min at 40.5 degrees-43.5 degrees C or for 60 min at 40.5 degrees and 41.5 degrees C. On the other hand, in tumors heated at 42.5 degrees C for 60 min, the tumor pO2 immediately after heating was similar to the control value whereas that 24 h after heating was about threefold greater than the control tumor pO2. Heating at 43.5 degrees C for 60 min resulted in a significant decline in pO2 immediately after and 24 h after heating. The increase in tumor pO2 immediately after heating appeared to be due to an increase in tumor blood flow. However, the changes in tumor pO2 and tumor blood flow 24 h after heating, particularly after high thermal doses (e.g., 60 min heating at 42.5 degrees or 43.5 degrees C), were not correlated. CONCLUSION: Heating at mild temperatures (i.e., 40.5 degrees-42.5 degrees C for 30-60 min), caused thermal dose-dependent increases in pO2 in the R3230 AC tumors of Fischer rats during 0-24 h after heating. Such an increase in tumor oxygenation after MTH appeared to be due to an increase in tumor blood flow.

Vascular thermal adaptation in tumors and normal tissue in rats.

PURPOSE: The vascular thermal adaptation in the R3230 adenocarcinoma, skin and muscle in the legs of Fischer rats was studied. METHODS AND MATERIALS: The legs of Fischer rats bearing the R3230 AC adenocarcinoma (subcutaneously) were heated once or twice with a water bath, and the blood flow in the tumor, skin and muscle of the legs was measured with the radioactive microsphere method. RESULTS: The blood flow in control R3230 AC tumors was 23.9 ml/100 g/min. The tumor blood flow increased about 1.5 times in 30 min and then markedly decreased upon heating at 44.5 degrees C for 90 min. In the tumors preheated 16 h earlier at 42.5 degrees C for 60 min, reheating at 44.5 degrees C increased the tumor blood flow by 2.5-fold in 30 min. Contrary to the decline in blood flow following an initial increase during the 44.5 degrees C heating without preheating, the tumor blood flow remained elevated throughout the 90 min reheating at 44.5 degrees C. These results indicated that thermal adaptation or thermotolerance developed in the tumor vasculatures after the preheating at 42.5 degrees C for 60 min. The magnitude of vascular thermal adaptation in the tumors 24 h and 48 h after the preheating, as judged from the changes in blood flow, were smaller than that 16 h after the preheating. Heating at 42.5 degrees C for 60 min induced vascular thermal adaptation also in the skin and muscle, which peaked in 48 h and 24 h, respectively, after the heating. CONCLUSION: Heating at 42.5 degrees C for 1 h induced vascular thermal adaptation in the R3230 AC tumor, skin, and muscle of rats that peaked 16-48 h after the heating. When the tumor blood vessels were thermally adapted, the tumor blood flow increased upon heating at temperatures that would otherwise reduce the tumor blood flow. Such an increase in tumor blood flow may hinder raising the tumor temperature while it may increase tumor oxygenation.

Pathophysiological changes after local heating of rat liver.

Changes in blood flow in rat liver by local heating of the left lateral lobe were studied. A small portion of the left lateral lobe was heated by capacitive application of 8 MHz RF with a 2 cm diameter electrode on the ventral surface and a 7 cm diameter electrode on the dorsal surface of upper body of rats. A circular area with diameter of about 1 cm in the left lateral lobe could be heated to relatively homogeneous temperatures. The temperature in the remaining part of the left lateral lobe as well as in the rest of liver tissue also increased to varying degrees during the local heating of the left lateral lobe. When heated at 39 degrees or 41 degrees C for 45 min, the arterial blood flow, as measured with the radioactive microsphere method, in the heated area, and that in the rest of the left lateral lobe as well as in the whole liver initially increased during the first 30 min and then started to decline. During a 45 min heating at 43 degrees C, the arterial blood flow in the heated area slightly increased for 15 min and then significantly decreased thereafter. The arterial blood flow in the rest of the liver tissue also increased during the first 15 min of a 43 degrees C heating and began to decline. Histological examination of liver heated at 43 degrees C for 30 min showed wedge-shaped infarctions early on, which appeared to be organized into scar tissue by 7 days after heating. The concentrations of glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), and lactate dehydrogenase (LDH) in the serum significantly increased 2 hr after heating the small portion of the left lateral lobe at 43 degrees C for 30 min and began to decrease thereafter although the serum level of GOT and GPT was still greater than the control value 24 hr after heating.

Increase in tumor blood flow by pentoxifylline.

PURPOSE: The effect of pentoxifylline (PTX) on the blood flow in experimental rodent tumors was investigated. METHODS AND MATERIALS: When the R3230 AC adenocarcinoma implanted in the leg of Fischer 344 rats grew to about 1 g, the effect of PTX on the blood flow in the tumor and in the skin and muscle was determined with the microsphere method using 85Sr labelled 25 microns diameter microspheres. The SCK mammary carcinoma was induced subcutaneously in the leg or foot of A/J mice and the effect of PTX on the tumors was investigated: the blood perfusion in the leg tumors (7 mm in diameter) was determined with the 86Rb uptake method and that in the foot tumors (5 mm diameter) was determined with the laser Doppler flow (LDF) method. RESULTS: The blood flow in the R3230 AC adenocarcinoma significantly increased when measured 30 min after an IP injection of 50 mg/kg PTX while the blood flow in the normal skin and muscle remained unchanged. The 86Rb uptake in the SCK tumor slightly increased 30 min after an IP injection of 50 mg/kg PTX. The LDF in the SCK tumors grown in the foot began to increase 5-10 min after an injection of 25 mg/kg PTX reaching 1.5-2.0 times in 20-30 min and it returned to the original level at 60 min. CONCLUSION: The results in the present study together with our previous observation that PTX increases the tumor pO2 in rodent tumors strongly suggest that PTX may be useful for increasing the radiosensitivity of human tumors.

Relationship between sodium balance and renal innervation during hypertension development in the spontaneously hypertensive rat.

INTRODUCTION: The spontaneously hypertensive rat (SHR) has been shown to possess elevated efferent sympathetic nerve activity, and renal denervation delays the development of hypertension in this genetic strain. Evidence that the renal sympathetic nerves have direct effects on tubular function suggests that one of the mechanisms for increasing arterial pressure in the SHR might involve neurally mediated sodium retention. AIMS AND METHODS: The present study examined the relationships between renal sympathetic tone, daily sodium balance and the development of hypertension in SHR over a 4-week period. Conscious, unrestrained, 7-week-old SHR with innervated or denervated kidneys were placed on a fixed sodium intake by intravenous infusion (5.72 mumol/day per 100 g body weight). Urinary sodium excretion was determined once a day for 28 consecutive days; systolic blood pressure (SBP) and body weight were monitored twice a week. RESULTS: Renal denervation delayed the onset of and retarded the development of hypertension. Despite the difference in SBP, daily sodium balance was equal in the innervated and the denervated SHR. The positive sodium balances exhibited by both groups are attributed to the rapid growth observed during the time course of the experiment. The growth rate was also similar in the two groups. CONCLUSION: The present data indicate that, although the renal nerves may mediate enhanced transient tubular sodium reabsorption, sodium retention does not contribute directly to the development of hypertension in the SHR. Rather, it appears that the elevation of arterial pressure might occur as a requirement to excrete excess sodium and thus maintain a daily sodium balance.

Prospective detection of vulnerability to sustained ventricular tachycardia in patients awaiting cardiac transplantation.

This prospective study tested the hypothesis that abnormal signal-averaged electrocardiograms (ECGs) and inducible ventricular arrhythmias identify patients awaiting cardiac transplantation who are prone to sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). Thirty-seven patients with advanced symptoms of heart failure and a mean left ventricular ejection fraction of 20 +/- 7 were studied. In response to programmed ventricular stimulation using up to 3 extrastimuli, sustained monomorphic VT was induced in 8 (22%) and polymorphic VT or VF was induced in 5 patients (13%). Patients with inducible arrhythmias underwent drug therapy guided by results of programmed ventricular stimulation or implantation of a defibrillator. Patients in whom ventricular arrhythmias could not be induced were not treated for arrhythmias. The signal-averaged ECG was abnormal and sustained VT or VF was induced in 10 patients (27%). Follow-up ranged from 1 to 33 months (mean 12). Four patients (11%) died suddenly and 4 (11%) had nonfatal sustained VT or VF. The positive predictive value for sudden death or nonfatal VT/VF was 27% for the signal-averaged ECG, 38% for programmed ventricular stimulation, and 50% if both tests were abnormal. The negative predictive values for these tests were 87, 88 and 88%, respectively. The actuarial incidence of arrhythmic events was significantly higher in patients with inducible ventricular arrhythmias (p = 0.017) and in patients in whom both the results of signal-averaged electrocardiographic analysis and the response to programmed ventricular stimulation were abnormal (p = 0.002). This study demonstrates that results of signal-averaged electrocardiographic analysis and the response to programmed ventricular stimulation improve risk stratification for sudden cardiac death in patients awaiting cardiac transplantation.

Phase II trial of oral 1,25-dihydroxyvitamin D (calcitriol) in hormone refractory prostate cancer.

Epidemiologic and experimental data support a role for 1,25-dihydroxyvitamin D(3) in the growth regulation of prostate cancer. We conducted a phase II clinical trial evaluating calcitriol (1,25(OH)(2)D(3)) in patients with hormone refractory prostate cancer. We enrolled 14 patients in this study. 1,25(OH)(2)D(3) was initiated at a daily oral dose of 0.5 µg and escalated to 1.5 µg daily. No objective responses were observed. However, in two patients decreases of 25% and 45% in prostate specific antigen levels were seen. Hypercalcemia was the predominant toxicity. We conclude that 1,25(OH)(2)D(3) given in this manner is inactive in advanced prostate cancer. Dose escalation of oral 1,25(OH)(2)D(3) is limited by hypercalcemia.

Motor activity and transit in the autonomically denervated jejunum.

The role of extrinsic (autonomic) innervation in postprandial contractile activity of the small intestine is unknown. Using a canine model, we investigated the effects of complete extrinsic denervation on the parameters of fasting and postprandial jejunal contractions and their relationship to intestinal transit. Individual contractions were recorded using strain gauge transducers. Spatial and temporal parameters of contractions were analyzed by computer methods. Bolus injection of 14C-polyethylene glycol was used to calculate intestinal transit rates. Statistical comparisons of control and denervated animals were made by nonparametric tests. Extrinsic denervation did not abolish fasting or fed motor activity, but the following effects were observed: (1) the frequency of migrating motor complexes (MMCs) increased; (2) the onset of fed motor activity was delayed, and the duration of fed activity was shortened; (3) frequency, mean amplitude, and mean area of postprandial contractions were decreased; (4) fewer contractions propagated distally, and mean propagation distance was shortened; and (5) intestinal transit was slower for solids, but not for liquids. In the small intestine, extrinsic nerves modulate motor activity, which is under primary control of the intrinsic (enteric) nervous system.

The effect of compression duration on hemodynamics during mechanical high-impulse CPR.

OBJECTIVE: To determine whether shorter compression durations combined with fixed increased compression velocity during mechanical high-impulse CPR (HI-CPR) improve resuscitation hemodynamics, compared with mechanical standard CPR (SCPR). METHODS: A porcine model of ventricular fibrillation was used, with each animal serving as its own control. Twelve anesthetized swine (20-25 kg each) were instrumented for hemodynamic monitoring. Ventricular fibrillation was induced and followed, after 3 minutes, by mechanical SCPR (50% duty cycle) for 10 minutes. Mechanical HI-CPR was then applied, with compression durations varied randomly at 2-minute intervals for 20% (COM20), 30% (COM30), and 40% (COM40) of the CPR cycle. A 2-minute mechanical SCPR control phase completed the experiment. RESULTS: Hemodynamic measurements were significantly better for COM20 and COM30 vs SCPR, including, respectively: mean arterial pressure (MAP), 45 +/- 8 and 43 +/- 7 vs 36 +/- 7 torr; coronary perfusion pressure (CPP), 21 +/- 6 and 21 +/- 8 vs 16 +/- 6 torr; and end-tidal CO2 (ETCO2), 7 +/- 2 and 6.6 +/- 2 vs 5 +/- 1.4 torr. MAP, CPP, and ETCO2 during COM40 were not significantly different from those during SCPR, and there was no difference between COM20 and COM30 for any hemodynamic parameter. Aortic flow velocity was significantly better in COM20, COM30, and COM40 vs SCPR: 2.3 +/- 0.7, 2.1 +/- 0.9, and 1.95 +/- 0.9 vs 1.3 +/- 0.5 cm/sec, respectively. CONCLUSION: In a swine model of mechanical HI-CPR, shorter compression durations combined with fixed increased compression velocity significantly improve resuscitation hemodynamics, compared with those afforded by mechanical SCPR.

Megestrol acetate in the treatment of hormone refractory prostate cancer.

This retrospective study evaluates the efficacy of megestrol acetate in patients with hormone refractory metastatic adenocarcinoma of the prostate. Data are presented from 14 patients with advanced prostatic adenocarcinoma who were treated with 160-320 mg of megestrol acetate daily. Each patient was either asymptomatic or had minimal cancer-related symptoms. Disease response was monitored by prostate-specific antigen levels. The response rate was 14%, with two patients having a partial response. No complete responses were observed. The median time to disease progression was 2 months. Our findings when considered together with results from previously published data demonstrate little activity of megestrol acetate in patients with hormone refractory prostate cancer. Therefore, we cannot recommend megestrol acetate as an effective second-line therapy.

Role of intrarenal ANG II in reflex neural stimulation of plasma renin activity and renal sodium reabsorption.

Renal sympathetic stimulation of plasma renin activity (PRA) and sodium reabsorption was examined in conscious dogs before and during intrarenal angiotensin II (ANG II)-type 1 receptor blockade with losartan (Dup-753) and converting enzyme inhibition. In uninephrectomized dogs, renal function and PRA responses to 14% blood volume depletion (BVD) were measured. BVD was utilized to activate renal sympathetic outflow in the absence of hypotension. In eight vehicle-treated dogs, 14% BVD increased PRA from 1.38 +/- 0.32 to 2.79 +/- 0.66 ng ANG I.ml-1 x h-1 and decreased urinary sodium excretion (UNaV) from 85.1 +/- 11.3 to 45.4 +/- 7.5 mueq/min. During losartan (n = 6) and captopril (n = 5) infusion, plasma renin responses were enhanced in response to 14% BVD (1.93 +/- 0.48 to 5.74 +/- 2.25 and 3.03 +/- 0.73 to 9.19 +/- 1.94 ng ANG I.ml-1 x h-1, respectively), whereas antinatriuretic responses were similar to vehicle-infused dogs. Thus, neurogenic antinatriuresis is not mediated by secondary generation of ANG II, since UNaV decreased similarly to control in all conditions of ANG II blockade. Tonic intrarenal and/or circulating ANG II synthesis of dogs on a normal sodium diet inhibit neurogenic stimulation of renin release, since PRA responses were enhanced after blockade of ANG II.

Neurogenic control of renal function in response to graded nonhypotensive hemorrhage in conscious dogs.

The reflex control of plasma renin activity (PRA) and urinary sodium excretion (UNaV) was evaluated in 13 dogs instrumented for chronic study and maintained on a normal sodium intake (40 meq/day). Graded blood volume depletion of 14 (BVD1) and 21% (BVD2) of the estimated total blood volume was used to activate renal sympathetic nerve activity (RSNA), and experiments were conducted before and after bilateral renal denervation (DNX). In dogs with innervated kidneys, nonhypotensive BVD1 increased RSNA 40.9 +/- 10.9% (P < 0.05) above control. Blood volume depletion increased PRA from 1.95 +/- 0.52 to 3.5 +/- 0.57 ng.ml-1 x h-1 and decreased UNaV from 58.2 +/- 10.1 to 35.5 +/- 4.3 mu eq/min without changing renal blood flow or glomerular filtration rate. BVD2 failed to further activate RSNA (52.0 +/- 16.7%) but did increase PRA to 4.85 +/- 0.83 ng.ml-1 x h-1 and decreased UNaV to 17.9 +/- 2.7 mu eq/min. Renal DNX (n = 13) abolished both the PRA and antinatriuretic responses to BVD1 and BVD2. Thus volume-invoked reflex activation of RSNA, but not altered renal hemodynamics, mediates, activation of PRA and antinatriuresis. This neurogenic control of renal function may be critical to the rapid regulation of extracellular fluid volume, via alterations in urinary excretion.