Low elevation of Svalbard glaciers drives high mass loss variability.

Compared to other Arctic ice masses, Svalbard glaciers are low-elevated with flat interior accumulation areas, resulting in a marked peak in their current hypsometry (area-elevation distribution) at  ~450 m above sea level. Since summer melt consistently exceeds winter snowfall, these low-lying glaciers can only survive by refreezing a considerable fraction of surface melt and rain in the porous firn layer covering their accumulation zones. We use a high-resolution climate model to show that modest atmospheric warming in the mid-1980s forced the firn zone to retreat upward by  ~100 m to coincide with the hypsometry peak. This led to a rapid areal reduction of firn cover available for refreezing, and strongly increased runoff from dark, bare ice areas, amplifying mass loss from all elevations. As the firn line fluctuates around the hypsometry peak in the current climate, Svalbard glaciers will continue to lose mass and show high sensitivity to temperature perturbations.

A tipping point in refreezing accelerates mass loss of Greenland's glaciers and ice caps.

Melting of the Greenland ice sheet (GrIS) and its peripheral glaciers and ice caps (GICs) contributes about 43% to contemporary sea level rise. While patterns of GrIS mass loss are well studied, the spatial and temporal evolution of GICs mass loss and the acting processes have remained unclear. Here we use a novel, 1 km surface mass balance product, evaluated against in situ and remote sensing data, to identify 1997 (±5 years) as a tipping point for GICs mass balance. That year marks the onset of a rapid deterioration in the capacity of the GICs firn to refreeze meltwater. Consequently, GICs runoff increases 65% faster than meltwater production, tripling the post-1997 mass loss to 36±16 Gt-1, or ∼14% of the Greenland total. In sharp contrast, the extensive inland firn of the GrIS retains most of its refreezing capacity for now, buffering 22% of the increased meltwater production. This underlines the very different response of the GICs and GrIS to atmospheric warming.

Brief Communication: Upper air relaxation in RACMO2 significantly improves modelled interannual surface mass balance variability in Antarctica.

The regional climate model (RCM) RACMO2 has been a powerful tool for improving surface mass balance (SMB) estimates from GCMs or reanalyses. However, new yearly SMB observations for West Antarctica show that the modelled interannual variability in SMB is poorly simulated by RACMO2, in contrast to ERA-Interim, which resolves this variability well. In an attempt to remedy RACMO2 performance, we included additional upper air relaxation (UAR) in RACMO2. With UAR, the correlation to observations is similar for RACMO2 and ERA-Interim. The spatial SMB patterns and ice sheet integrated SMB modelled using UAR remain very similar to the estimates of RACMO2 without UAR. We only observe an upstream smoothing of precipitation in regions with very steep topography like the Antarctic Peninsula. We conclude that UAR is a useful improvement for RCM simulations, although results in regions with steep topography should be treated with care.

Phase II trial of irofulven (6-hydroxymethylacylfulvene) for patients with advanced renal cell carcinoma.

The aim of this study was to determine the antitumor activity of irofulven (6-hydroxymethylacylfulvene) in patients with advanced renal cell carcinoma (RCC). Eligible patients had advanced renal cell carcinoma with bidimensionally measurable disease, a Karnofsky performance status of at least 70, life expectancy of greater than three months, no prior treatment with chemotherapy, and no evidence of brain metastases. Irofulven was administered at a dose of 11 mg/m2 by 5-min intravenous infusion, on 5 consecutive days. Cycles were repeated every 28 days. Thirteen patients were enrolled in this study and 12 were evaluable for response. Of the twelve evaluable patients, no major responses were achieved. Eight patients had stable disease as best response. Toxicity included myelosuppression and gastrointestinal side effects. At the dose and schedule used in this trial, irofulven did not produce clinical response in RCC.

Randomized multicenter phase II trial of subcutaneous recombinant human interleukin-12 versus interferon-alpha 2a for patients with advanced renal cell carcinoma.

Recombinant human interleukin-12 (rHuIL-12) is a pleiotropic cytokine with anticancer activity against renal cell carcinoma (RCC) in preclinical models and in a phase I trial. A randomized phase II study of rHuIL-12 compared with interferon-alpha (IFN-alpha) evaluated clinical response for patients with previously untreated, advanced RCC. Patients were randomly assigned 2:1 to receive either rHuIL-12 or IFN-alpha2a. rHuIL-12 was administered by subcutaneous (s.c.) injection on days 1, 8, and 15 of each 28-day cycle. The dose of IL-12 was escalated during cycle 1 to a maintenance dose of 1.25 microg/kg. IFN was administered at 9 million units by s.c. injection three times per week. Serum concentrations of IL-12, IFN-gamma, IL-10, and neopterin were obtained in 10 patients treated with rHuIL-12 after the first full dose of 1.25 microg/kg given on day 15 (dose 3) of cycle 1 and again after multiple doses on day 15 (dose 6) of cycle 2. Thirty patients were treated with rHuIL-12, and 16 patients were treated with IFN-alpha. Two (7%) of 30 patients treated with rHuIL-12 achieved a partial response, and the trial was closed to accrual based on the low response proportion. IL-12 was absorbed rapidly after s.c. drug administration, with the peak serum concentration appearing at approximately 12 h in both cycles. Serum IL-12 concentrations remained stable on multiple dosing. Levels of IFN-gamma, IL-10, and neopterin increased with rHuIL-12 and were maintained in cycle 2. rHuIL-12 is a novel cytokine with unique pharmacologic and pharmacodynamic features under study for the treatment of malignancy and other medical conditions. The low response proportion associated with rHuIL-12 single-agent therapy against metastatic RCC was disappointing, given the preclinical data. Further study of rHuIL-12 for other medical conditions is underway. For RCC, the study of new cytokines is of the highest priority.

Novel investigative approaches for advanced renal cell carcinoma.

Metastatic renal cell carcinoma remains one of the most treatment-resistant malignancies in humans. As such, long-term survival is limited to a minority of patients. Interferon-alpha and interleukin-2 induced major responses in some patients with renal cell carcinoma, and in so doing generated a great deal of interest and hope. However, clinical benefit is limited to relatively few patients. Here, we briefly discuss the management of metastatic renal cell carcinoma, and then elaborate on several novel treatment approaches in development, including retinoids, monoclonal antibodies, and antiangiogenesis strategies.

Effect of cytokine therapy on survival for patients with advanced renal cell carcinoma.

PURPOSE: To evaluate the relationship between treatment with cytokine therapy and survival, investigate the effect of nephrectomy on survival, and identify long-term survivors among a cohort of 670 patients with advanced renal cell carcinoma (RCC). PATIENTS AND METHODS: A total of 670 patients with advanced RCC treated on 24 clinical trials of systemic chemotherapy or cytokine therapy were the subjects of this retrospective analysis. Treatment was categorized as cytokine (containing interferon alfa and/or interleukin-2) in 396 patients (59%) and as chemotherapy (cytotoxic or hormonal therapy) in 274 (41%). Among the 670 patients, those with survival times of greater than 5 years were identified as long-term survivors. RESULTS: Patients treated with cytokine therapy had a longer survival time than did those treated with chemotherapy, regardless of the year of treatment or risk category based on pretreatment features. The median survival times for favorable-, intermediate-, and poor-risk patients were 27, 12, and 6 months for those treated with cytokines and 15, 7, and 3 months for those treated with chemotherapy, respectively. The magnitude of difference in median survival was greater in the favorable- and intermediate-risk groups. The median survival time was less than 6 months in the poor-risk group for both treatment programs. Median survival time was 14 months among patients with prior nephrectomy plus time from diagnosis to treatment greater than 1 year versus 8 months among those with time from diagnosis to treatment less than 1 year, regardless of pretreatment nephrectomy status. Thirty patients (4.5%) among the 670 patients were identified as long-term survivors; 12 were free of disease after nephrectomy and treatment with interferon alfa, interleukin-2, or surgical resection of metastasis. CONCLUSION: The low proportion of patients with advanced RCC who achieve long-term survival emphasizes the need for clinical investigation to identify more effective therapy.

A mammalian severin replaces gelsolin in transformed epithelial cells.

A persisting paradox in cytoskeletal regulation of cell motility is the loss of the actin filament fragmenting protein, gelsolin, in transformed epithelial cells that have gained the ability to migrate. Either actin filament severing does not occur during motility of carcinoma cells or a novel fragmentation protein is expressed during transformation. Using an antibody specific for severin, the Mr 40,000 actin filament severing protein from Dictyostelium discoideum amoebae, we have identified a mammalian form of severin in murine LL/2 carcinoma cells lacking gelsolin. Mammalian severin (M-severin) isolated from LL/2-derived Lewis lung carcinoma tumors severed F-actin in a calcium-dependent manner, mimicking the function of Dictyostelium severin. M-severin preferentially localized to the cleavage furrow of dividing LL/2 cells and to the actin-rich cortex of migratory LL/2 cells, known sites of active actin cytoskeleton rearrangement. The mammalian severing protein was fully expressed in transformed LL/2 epithelial cells but went undetected in normal mouse muscle, liver, spleen, or kidney. Normal mouse lung tissue contained minute amounts of M-severin, attributed to motile cells in pulmonary connective tissue. In striking contrast to M-severin, gelsolin was highly expressed in normal lung but disappeared in transformed LL/2 carcinoma cells. Based on prior observations of a functional role for actin filament fragmentation in cell migration, the simultaneous induction of M-severin and loss of gelsolin during epithelial transformation suggests that replacement of gelsolin by M-severin may function to achieve actin filament rearrangements necessary for active cell migration in invasive or metastatic carcinoma. Induction of M-severin in an invasive tumor was directly observed in human colon adenocarcinoma by cytoimmunohistochemistry with antibodies directed against severin isolated from both Dictyostelium amoebae and Lewis lung carcinoma cells. Because normal colon epithelium from the same patient did not express M-severin, it may serve as a sensitive marker for detection and staging of epithelial tumors.

Up-regulation of retinoic acid receptor beta expression in renal cancers in vivo correlates with response to 13-cis-retinoic acid and interferon-alpha-2a.

Retinoic acid receptor-beta (RAR-beta) mRNA is not expressed by retinoid-resistant renal cancer cell lines but is present in retinoid-sensitive SK-RC-06 renal cancer cells and increases following incubation with retinoic acid (RA), suggesting that the antitumor action of RA is mediated through RAR-beta (A. D. Hoffman et al., Clin. Cancer Res., 2: 1077-1082, 2996). To determine whether RAR-beta expression correlates in vivo with major clinical response to patients with renal cell carcinoma (RCC) who were treated with retinoid-based therapy, we used in situ hybridization to analyze RAR-beta expression in tumor specimens obtained from patients who were treated on a clinical trial with 13-cis-RA and IFN-alpha. Thirty-three tissue specimens were analyzed (23 pretreatment and 10 on-treatment). mRNA expression was based on staining intensity, with scores within tumor cells ranging from 0 to 2, where a score of 0 indicated absence of staining, a score of 1 indicated weak staining, and a score of 2 indicated strong staining. RAR-beta expression was present in 22 of 23 (96%) pretreatment and 9 of 10 (90%) on-treatment specimens. Pretreatment levels of expression did not associate with the site of biopsy and did not predict for major clinical response to RA plus IFN-alpha therapy (two-sided Fisher's exact test, P = 0.826). However, an increase in the intensity of RAR-beta mRNA expression was detected in four of five (80%) patients who achieved a major response but in none of the five patients with progressive disease in whom sequential biopsies were available (two-sided Fisher's exact test, P = 0.048). These data show that RAR-beta transcripts increase in tumor cells of RCC patients who clinically respond to retinoid-based therapy. Retinoids that potently induce RAR-beta expression should be evaluated in the treatment of advanced RCC.

Bilateral renal masses after local Bacillus Calmette-Guerin therapy for postcystectomy ureteral cancer.

Bacillus Calmette-Guerin was administered through the ileal conduit of a 63-year-old man with upper tract recurrence of transitional cell carcinoma. Subsequent computed tomography showed bilateral renal masses, which were granulomatous at pathologic examination. The bacilli likely reached the kidneys via proven ileoureteral reflux. Patients with reflux may benefit from antituberculous prophylaxis.

A phase II study of pyrazoloacridine in patients with advanced renal cell carcinoma.

The aim of this study was to determine the antitumor activity of pyrazoloacridine in patients with renal cell carcinoma. Eligible patients had advanced renal cell carcinoma with bidimensionally measurable disease, a Karnofsky performance status of at least 70, life expectancy of greater than three months, no prior treatment with chemotherapy, and no evidence of brain metastases. Patients were treated intravenously with 750 mg/m2 every three weeks. Twelve patients were enrolled in this study and all were evaluable for response and toxicity. Of the twelve patients, no major responses were achieved. Toxicity was mild, with three patients requiring a 20% dose reduction. At the dose and schedule used in this trial, pyrazoloacridine is inactive in renal cell carcinoma.

Renal cell carcinoma.

Renal cell carcinoma (RCC) is characterized by (a) lack of early warning signs, which results in a high proportion of patients with metastases at the time of diagnosis; (b) protean clinical manifestations; and (c) resistance to radiotherapy and chemotherapy. The estimates of new diagnoses and deaths from kidney cancer in the United States during 1996 are 30,600 and 12,000, respectively. RCC occurs nearly twice as often in men as in women. The age at diagnosis is generally older than 40 years; the median age is in the midsixties. The incidence of RCC has been rising steadily. Between 1974 and 1990, there was a 38% increase in the number of patients who had a diagnosis of RCC. This increase was accompanied by a significant improvement in 5-year survival. Both trends are likely the result of improved diagnostic capability. Newer radiographic techniques, including ultrasonography, computed tomography, and magnetic resonance imaging, are detecting kidney tumors more frequently and at a lower disease stage, when tumors can be resected for cure. Surgical treatment is the only curative therapy for localized RCC. Radical nephrectomy remains the mainstay of surgical management, but techniques are being modified. These modifications include partial nephrectomy and resection of vena caval thrombi. In highly selected cases, surgical resection of locally recurrent RCC or of disease at a solitary metastatic site is associated with long-term survival. Metastatic RCC is highly resistant to the many systemic therapies that have been extensively investigated. A minority of patients achieve complete or partial response to interferon, interleukin-2, or both. Response can be dramatic but is rarely durable. Because most patients do not achieve response, these agents are not considered effective treatments for RCC, but the response in some patients indicates the need for continued research on their use. Identification of new agents with better antitumor activity against metastases remains a high priority in clinical investigation of therapy for this refractory disease.

A phase II study of 13-cis-retinoic acid in patients with advanced renal cell carcinoma.

The aim of this study was to determine the antitumor activity of 13-cis-retinoic acid as a single agent in patients with advanced renal cell carcinoma. Eligible patients had advanced renal cell carcinoma with bi-dimensionally measurable disease, a Karnofsky performance status of at least 70, life expectancy of greater than three months, no evidence of brain metastases, and treatment with no more than one chemotherapy regimen. Patients were treated with one mg/kg/day of 13-cis-retinoic acid orally. Twenty-six patients were enrolled in this study and 25 were evaluable for response and toxicity. Of the twenty-five evaluable patients, no major responses were achieved. Toxicity was mild, with no patient requiring a dose reduction. At the dose administered in this trial, 13-cis-retinoic acid is inactive as a single agent in renal cell carcinoma.

Clinical, hemodynamic and sympathetic neural correlates of heart rate variability in congestive heart failure.

Heart rate (HR) variability has long been recognized as a sign of cardiac health. In the presence of heart disease, HR variability decreases, an observation that has been associated with poor prognosis in a number of recent studies. HR variability is particularly altered in congestive heart failure (CHF), a condition associated with a number of typical functional hemodynamic and neurohumoral alterations. The relation of measurements of HR variability to these abnormalities in patients with heart failure has not been carefully examined. Twenty-three patients (19 men, 4 women, mean age 49 years) with New York Heart Association class II to IV CHF were studied prospectively without cardiac medications; radionuclide ventriculography, right-sided heart catheterization, peroneal microneurography, plasma norepinephrine and 24- to 48-hour ambulatory electrocardiography were performed. Average RR interval and its standard deviation, and HR power spectrum (0 to 0.5, 0.05 to 0.15 and 0.2 to 0.5 Hz) were derived from the ambulatory electrocardiographic recordings and compared with left ventricular ejection fraction, thermodilution cardiac output, pulmonary arterial wedge pressure, New York Heart Association class, age, muscle sympathetic nerve activity (peroneal nerve) and norepinephrine level by linear regression. None of the measures of HR variability were significantly related to age, left ventricular ejection fraction, cardiac output or functional classification, whereas the 0.05 to 0.15 and 0.20 to 0.50 Hz components were weakly but significantly related to cardiac output (r = 0.49 and 0.42, p = 0.02 and 0.045, respectively). In contrast, a generally stronger and negative relation was demonstrated between spectral and nonspectral measurements of HR variability, and indicators of sympathoexcitation, muscle sympathetic nerve activity and plasma norepinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of heart failure on baroreflex control of sympathetic neural activity.

Baroreflex control of heart rate, vascular resistance and norepinephrine is impaired in patients with heart failure, but recent animal studies demonstrate preserved baroreflex control of sympathetic nerve activity in this disorder. Studies were therefore performed to compare baroreflex control of efferent sympathetic nerve activity to muscle in 10 normal subjects (age mean +/- SEM 21 +/- 1 years) and in 11 patients with moderate to severe heart failure (age 48 +/- 5 years, New York Heart Association class II to IV, left ventricular ejection fraction 19 +/- 2%, pulmonary capillary wedge pressure 27 +/- 2 mm Hg, cardiac index 2.04 +/- 0.22 liters/min/m2). Baroreflex activation was produced by intravenous infusion of phenylephrine (0.5 to 2.0 micrograms/kg/min) and deactivation by infusion of nitroprusside (0.4 to 2.5 micrograms/kg/min). During phenylephrine infusion, comparable increases in mean arterial pressure were produced in normal subjects (89 +/- 2 to 99 +/- 3 mm Hg, p less than 0.01) and in patients with heart failure (90 +/- 2 to 99 +/- 3 mm Hg, p less than 0.01). The patients with heart failure exhibited significantly attenuated (p less than 0.01 for normal vs heart failure) decreases in heart rate (93 +/- 5 to 90 +/- 6 beats/min, p = not significant [NS]) compared with normal subjects (67 +/- 3 to 58 +/- 4 beats/min, p less than 0.01) and tended to demonstrate attenuated sympathoinhibitory responses to this pressor stimulus. More strikingly, patients with heart failure demonstrated significant impairment of baroreflex responses during nitroprusside-induced baroreceptor deactivation. In normal subjects, nitroprusside produced a decrease in mean arterial (90 +/- 2 to 80 +/- 3 mm Hg, p less than 0.001) and right atrial (4 +/- 1 to 2 +/- 1 mm Hg, p less than 0.01) pressures with a resultant reflex increase in heart rate (68 +/- 3 to 81 +/- 4 beats/min, p less than 0.001) and muscle sympathetic nerve activity (326 +/- 74 to 746 +/- 147 U/min, p less than 0.01). In patients with heart failure (n = 10), nitroprusside produced comparable (p = NS for normal vs heart failure) decreases in mean arterial (89 +/- 2 to 77 +/- 2 mm Hg, p less than 0.001) and right atrial (6 +/- 1 to 1 +/- 1 mm Hg, p less than 0.001) pressures, but did not significantly alter heart rate (91 +/- 6 to 97 +/- 4 beats/min, p = NS) or sympathetic nerve activity (936 +/- 155 to 1179 +/- 275 U/min, p = NS).(ABSTRACT TRUNCATED AT 400 WORDS)

Sympathetic responses of patients with congestive heart failure to cold pressor stimulus.

Studies in patients with congestive heart failure (CHF) demonstrate blunting of sympathoexcitatory responses to baroreflex perturbation. Whereas experimental and limited clinical evidence suggests impairment of baroreflex mechanisms as the etiology of these attenuated responses, an alternative mechanism would be an inability of patients with CHF to increase sympathetic neural outflow above markedly elevated baseline levels. Hemodynamic and sympathetic neural responses (peroneal microneurography) were therefore compared of normal subjects (n = 10) and patients with CHF (n = 10) during the non-baroreflex sympathoexcitatory stimulus of the cold pressor test. The cold pressor stimulus produced increases in arterial pressure and heart rate in both groups. During hand immersion in ice water, normal subjects demonstrated significant increases in muscle sympathetic nerve activity expressed as burst frequency (20 +/- 2 to 28 +/- 3 bursts/min, p less than 0.01), total integrated nerve activity (224 +/- 41 to 342 +/- 62 U/min, p less than 0.05), and total activity corrected for accompanying changes in heart rate (375 +/- 81 to 538 +/- 118 U/100 heart beats, p less than 0.05). Similarly, despite elevated control levels of sympathetic activity, patients with CHF also demonstrated significant sympathoexcitatory responses to the cold pressor stimulus, with increases in muscle sympathetic nerve burst frequency (60 +/- 7 to 67 +/- 7 bursts/min, p less than 0.01) total integrated nerve activity (818 +/- 159 to 1,015 +/- 191 U, p less than 0.001), and total activity corrected for accompanying changes in heart rate (1,008 +/- 178 to 1,173 +/- 201 U/100 heart beats, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical and hemodynamic correlates of sympathetic nerve activity in normal humans and patients with heart failure: evidence from direct microneurographic recordings.

To characterize the neural excitatory state of heart failure, simultaneous measurements of efferent sympathetic nerve activity to muscle (by microneurography) and rest hemodynamics were obtained in 10 normal subjects (age 25 +/- 2 years, mean +/- SEM) and 29 patients with heart failure (age 49 +/- 2 years; New York Heart Association functional class II to IV; left ventricular ejection fraction 21 +/- 1%; cardiac index = 2.16 +/- 0.13 liters/min per m2; pulmonary capillary wedge pressure 23 +/- 2 mm Hg). Sympathetic nerve activity was significantly higher in the patients with heart failure (54.7 +/- 4.5 bursts/min) than in normal subjects (16.7 +/- 2.2 bursts/min, p less than 0.001). Multiple linear regression analyses indicated that sympathetic activity in these human subjects was most strongly and inversely correlated with left ventricular stroke work index (r = -0.86, p less than 0.0001) and stroke volume index (r = -0.85, p less than 0.0001). There was a strong positive correlation between sympathetic nerve activity and pulmonary artery diastolic (r = 0.82, p less than 0.0001) and mean (r = 0.81, p less than 0.0001) pressures. Similar correlations were seen when patients with heart failure were analyzed separately. There was no significant correlation between sympathetic nerve activity and mean arterial pressure, left ventricular ejection fraction (by radionuclide ventriculography), cardiac chamber size (by echocardiography) or arterial oxygen tension in the patients with heart failure. Direct measurements of sympathetic nerve activity correlated closely with plasma norepinephrine (r = 0.72, p less than 0.0001) in patients with heart failure. Thus, sympathetic nerve activity at rest parallels impairment of cardiac performance in patients with heart failure.

Pathophysiologic levels of atrial natriuretic factor do not alter reflex sympathetic control: direct evidence from microneurographic studies in humans.

To determine if circulating levels of atrial natriuretic factor comparable with those seen in pathophysiologic states alter autonomic control of the circulation, direct recordings of hemodynamic variables and efferent sympathetic nerve activity to muscle (microneurography) were obtained during two separate protocols in a total of 21 normal men (age 25 +/- 1 years). In protocol 1, the responses of 10 men were compared during incremental mechanical unloading of cardiopulmonary baroreceptors with lower body negative pressure versus responses to comparable unloading during infusion of alpha-human atrial natriuretic factor. Lower body negative pressure decreased pulmonary artery diastolic and right atrial pressures, did not alter arterial pressure or heart rate and increased muscle sympathetic nerve activity from 205.2 +/- 36.3 to 438.7 +/- 100.2 units/min (p less than 0.01). Intravenous infusion of atrial natriuretic factor (25 ng/kg per min) increased plasma levels of the hormone from 24 +/- 4 to 322 +/- 34 pg/ml (p less than 0.01, n = 6), produced similar decreases in pulmonary artery diastolic and right atrial pressures, did not alter arterial pressure, increased heart rate and increased sympathetic nerve activity from 233.1 +/- 35.6 to 387.2 +/- 64.9 units/min (p less than 0.05). Thus, during similar hemodynamic perturbations produced by lower body negative pressure or infusion of atrial natriuretic factor at the dose used in this study, these subjects exhibited comparable sympathoexcitatory responses, with a 109 +/- 23% increase in sympathetic activity during lower body negative pressure and a 76 +/- 19% increase during atrial natriuretic factor infusion (p = NS). In protocol 2, the responses of 11 additional men were examined during lower body negative pressure performed before and again during infusion of atrial natriuretic factor (12.5 ng/kg per min). During baseline (prehormone) trials, lower body negative pressure (-14.5 +/- 1.6 mm Hg) decreased central venous pressure, did not change arterial pressure or heart rate and increased sympathetic nerve activity from 215 +/- 47.7 to 372.3 +/- 64.3 units/min (p less than 0.001). Infusion of atrial natriuretic factor increased plasma levels of the hormone from 39 +/- 8 to 313 +/- 18 pg/ml (p less than 0.01, n = 7); central venous pressure was held constant during hormone infusion by intravenous infusion of saline solution.(ABSTRACT TRUNCATED AT 400 WORDS)

Sympathoinhibitory responses to digitalis glycosides in heart failure patients. Direct evidence from sympathetic neural recordings.

Digitalis glycosides exert both excitatory and inhibitory autonomic actions in animals and produce vasoconstriction in normal humans but produce vasodilation in heart failure patients. To determine whether or not these contrasting vascular responses are due to differing autonomic actions of the drug, we compared the responses to intravenous administration of Cedilanid-D (0.02 mg/kg) in eight normal subjects (mean age, 23 +/- 1 years) and eight patients with moderate-to-severe heart failure (mean age, 52 +/- 5 years, NYHA Class III-IV). Hemodynamics and efferent sympathetic nerve activity to muscle (MSNA) were measured during 5-minute periods before (control) and 20 minutes after drug administration. In the heart failure patients, Cedilanid-D significantly increased systolic and pulse pressures, whereas mean arterial pressure was unchanged. There was a decrease in right atrial pressure and a tendency for a decrease in pulmonary artery diastolic pressure with a slowing of heart rate. Cardiac index increased by 24 +/- 7%. Short-term administration of digitalis in these heart failure patients produced a fall in forearm vascular resistance (from 37.6 +/- 8.2 to 31.8 +/- 8.1 units, p less than 0.05) and an early, profound, and sustained decrease in MSNA (from 831.0 +/- 118.4 to 474.4 +/- 103.6 units/100 heart beats, p less than 0.01). Digitalis glycosides produced different vascular and MSNA responses in the normal subjects. In the normal volunteers, the drug significantly increased systolic, mean, and pulse pressures and decreased central venous pressure and heart rate. Despite the significant increase in arterial pressure, there was no change in forearm vascular resistance (from 11.7 +/- 1.0 to 12.7 +/- 1.0 units, p = NS) or MSNA (from 494.8 +/- 88.5 to 369.1 +/- 60.5 units/100 heart beats, p = NS), suggesting a sympathoexcitatory response in normal subjects. To determine whether or not the digitalis-induced sympathoinhibition in the heart failure patients was simply due to an inotropic effect (stimulation of inhibitory cardiac mechanoreceptors), we studied the responses of seven additional patients with heart failure before and during administration of dobutamine (3.4 +/- 0.4 micrograms/kg/min). Dobutamine produced a 34 +/- 3% increase in cardiac index, no significant change in systemic arterial pressures, a decrease in pulmonary artery diastolic and right atrial pressures, and no change in heart rate or forearm vascular resistance (from 30.2 +/- 4.3 to 26.5 +/- 4.7 units, p = NS).(ABSTRACT TRUNCATED AT 400 WORDS)