Urinary excretion of vasoactive substances in chronic renal failure

To investigate the pathophysiological role of vasoactive substances in the progression of chronic renal disease, we measured the 24-hour urinary excretion of prostaglandin 6-keto F1alpha, thromboxane B2, NOx, cGMP and ET-1 in 26 patients with chronic renal failure under conservative treatment and in 40 control subjects. Urinary 6-keto PgF1alpha, TxB2 and cyclic GMP were evaluated by RIA, and ET-1 was assayed by EIA. NOx were evaluated using a colorimetric assay as nitrate/nitrite. Urinary excretion of prostaglandin 6-keto F1alpha averaged 18.1 +/- 20.9 ng/g Ucreat in patients vs. 240.9 +/- 257.3 in controls (p < 0.0001), thromboxane B2 422 +/- 374 ng/g Ucreat in patients vs. 967 +/- 589 in controls (p < 2x 10(-5)), NOx 7.07 +/- 5.54 mg/g Ucreat in patients vs. 9.79 +/- 3.77 in controls (p < 0.01), cGMP 310 +/- 200 pg/g Ucreat in patients vs. 488 +/- 241 in controls (p < 0.001). In contrast, ET-1 urinary excretion was almost doubled in patients (13.45 +/- 5.84 ng/g of Ucreat) in comparison with controls (6.84 +/- 2.81 p < 1x10(-5)). While in control subjects significant correlations between urinary excretions of prostaglandin 6-keto F1alpha and thromboxane B2 (r = 0.69, p < 0.001) or NOx and ET-1 (r = 0.54, p < 0.001) were present, in patients only the relationship between urinary excretions of prostaglandin 6-keto F1alpha and thromboxane B2 (r = 0.53, p < 0.01) was retained. Our data suggest that in the normal kidney a balance between prostaglandin I2 and thromboxane A2, or nitric oxide and endothelin-1 is present, which contributes to hemodynamic regulation and protects this organ from ischemic damage. This balance is abolished in CRF, where a large increment of vasopressor agent endothelin is present, which, joined to a prevalent decrease of prostaglandin I2 synthesis, could contribute to the ischemic and fibrogenetic damage of the kidney, leading to progression of renal disease.     

The effects of halothane in hypoxic pulmonary vasoconstriction

Human and animal experiments have not consistently shown halothane to inhibit hypoxic pulmonary vasoconstriction (HPV). The authors used a canine lung lobe perfused in situ to more precisely characterize the effects of halothane on HPV. The pulmonary vasculature can be divided into inflow, middle, and outflow segments by sequentially occluding the lobar inflow and outflow of blood. The lobes were ventilated with four different gas mixtures (normoxia, hypoxia, normoxia/halothane, hypoxia/halothane) and measured inflow, outflow, and middle segment (Rm) resistances using this stop-flow technique. All values are shown as means +/- standard deviation. The authors found that hypoxia increased Rm from normoxia values of .006 +/- .005 cmH2O.ml-1.min-1 to .025 +/- .008 cmH2O.ml-1.min-1 (P less than 0.05). During hypoxia/halothane Rm returned to .005 +/- .004 cmH2O.ml-1.min-1. The relationship between pressure and flow (P-Q) for the lobes for each gas mixture was also determined. The slopes of the P-Q lines by linear regression were all similar. The zero-flow pressure intercepts of the P-Q lines for normoxia (3.2 +/- .9 cmH2O) and hypoxia (4.4 +/- 1.1 cmH2O) were significantly decreased after the administration of halothane (1.7 +/- 1.0 cmH2O and 2.6 +/- 1.0 cmH2O, respectively). Since the zero-flow intercept likely reflects the tone at alveolar vessel level, the authors conclude that halothane inhibits HPV by decreasing the tone in the middle vascular segment.     

The influence of hypoxia and hyperoxia on the kinetics of propofol emulsion

PURPOSE: To study the effect of hypoxia and hyperoxia on the pharmacokinetics of propofol emulsion, hepatic blood flow and arterial ketone body ratio in the rabbit. METHODS: Twenty four male rabbits were anesthetized with isoflurane (1.5-2%) in oxygen. After the surgical procedure, isoflurane administration was discontinued and intravenous propofol infusion (30 mg x kg(-1) x hr(-1)) was started. The infusion rate of propofol was maintained throughout the study. After an initial 90 min period of propofol infusion, rabbits were randomly allocated to one of three groups: hypoxia (F(I)O2 = 0.1), normoxia (F(I)O2 = 0.21), and hyperoxia (F(I)O2 = 1.0). Propofol infusion was continued under the allocated F(I)O2 for 60 min. Propofol concentrations in arterial blood, total body clearance of propofol, hepatic blood flow and arterial ketone body ratio were measured. RESULTS: The mean arterial propofol concentration at the end of infusion was higher in the hypoxia group (15.2 +/- 2.8 microg x mL(-1), mean +/- SD) than in the normoxia (7.4 +/- 1.7) and hyperoxia (8.0 +/- 1.9) groups (P < 0.05). Total body clearance of propofol, hepatic blood flow and arterial ketone body ratio were all reduced in the hypoxia group (P < 0.05). Total ketone body concentration in arterial blood increased in the hyperoxia group (P < 0.01). CONCLUSION: Hypoxia produced an accumulation of propofol in blood and reduced propofol clearance. These changes could result from decreased hepatic blood flow and low cellular energy charge in the liver. Hyperoxia, on the other hand, increased total ketone body in arterial blood.     

Effects of Alfentanil on the Ventilatory Response to Sustained Hypoxia

Background: The ventilatory response to acute hypoxia is biphasic, with an initial rapid increase followed by a slower decline. In humans, there is evidence that the magnitude of the decline in ventilation is proportional to the size of the initial increase. This study was done to define the role of exogenous opioids in the ventilatory decline seen with prolonged hypoxia.

Methods: Ten healthy persons were exposed to isocapnic hypoxia for 25 min, followed by 5 min of isocapnic normoxia and 5 min of isocapnic hypoxia. These conditions were repeated during a computer-controlled alfentanil infusion.

Results: Serum alfentanil levels were constant among the volunteers (38 +/- 12 ng/ml). Alfentanil decreased both the initial and second acute hypoxic responses (from 1.27 +/- 0.73 to 0.99 +/- 0.39 l [middle dot] min-1 [middle dot] %-1, P < 0.05; and from 0.99 +/- 0.70 to 0.41 +/- 0.29 l [middle dot] min-1 [middle dot] %-1, P < 0.05, respectively). The magnitude of the decrease in ventilation during the 25 min of hypoxia was not changed (10 +/- 3.3 l/min for control; 12.3 +/- 7.5 l/min for alfentanil).     

Acute Pain and Central Nervous System Arousal Do Not Restore Impaired Hypoxic Ventilatory Response during Sevoflurane Sedation

Background: To quantify the effects of acute pain on ventilatory control in the awake and sedated human volunteer, the acute hypoxic ventilatory response was studied in the absence and presence of noxious stimulation before and during 0.1 minimum alveolar concentration sevoflurane inhalation.

Methods: Step decreases in end-tidal partial pressure of oxygen from normoxia into hypoxia (approximately 50 mmHg) were performed in 11 healthy volunteers. Four acute hypoxic ventilatory responses were obtained per subject: one in the absence of pain and sevoflurane (C), one in the absence of sevoflurane with noxious stimulation in the form of a 1-Hz electrical current applied to the skin over the tibial bone (C + P), one in the absence of pain during the inhalation of 0.1 minimum alveolar concentration sevoflurane (S), and one during 0.1 minimum alveolar concentration sevoflurane with noxious stimulation (S + P). The end-tidal partial pressure of carbon dioxide was held constant at a value slightly greater than baseline (44 mmHg). To assess the central nervous system arousal state, the bispectral index of the electroencephalogram was monitored. Values are mean+/-SE.

Results: Pain caused an increase in prehypoxic baseline ventilation before and during sevoflurane inhalation: C = 13.7+/-0.9 l *symbol* min-1, C + P = 16.0+/-1.0 l *symbol* min-1 (P < 0.05 vs. C and S), S = 12.7+/-1.2 l *symbol* min-1, and S + P = 15.9+/-1.1 l *symbol* min-1 (P < 0.05 vs. C and S). Sevoflurane decreased the acute hypoxic ventilatory response in the absence and presence of noxious stimulation: C = 0.69+/-0.20 l *symbol* min-1 (% change in arterial hemoglobin-oxygen saturation derived from pulse oximetry [SP O2])-1, C + P = 0.64 +/-0.13 l *symbol* min-1 *symbol* %SP O2-1, S = 0.48+/-0.15 l *symbol* min-1 *symbol* %SP O2-1 (P < 0.05 vs. C and C + P) and S + P = 0.46+/-0.12 l *symbol* min-1 *symbol* %SP O2-1 (P < 0.05 vs. C and C + P). The bispectral indexes were C = 96.2+/-0.7, C + P = 97.1 +/-0.4, S = 86.3+/-1.3 (P < 0.05), and S + P = 95.0 +/-1.0.     

Renal hemodynamics, urinary eicosanoids, and endothelin after liver transplantation.

Patients with hepatic cirrhosis develop widespread abnormalities in kidney function and vasoactive hormones. These change rapidly after liver transplantation during immunosuppression with cyclosporine. The role of changing eicosanoid excretion and endothelin levels in regulating renal function after transplantation in humans remains uncertain. We studied 32 patients with regard to renal hemodynamics, glomerular filtration, urinary prostacyclin (6-keto-PG-F1-alpha), thromboxane (TBX2), and endothelin before and during the first four weeks after orthotopic liver transplantation. Arterial pressure rose from 106 +/- 2/61 +/- 2 to 146 +/- 4/81 +/- 2 mmHg, (P less than .001), while renal blood flow fell (686 +/- 38 to 453 +/- 24 ml/min/1.73 m2, P less than .05), as did GFR. Pretransplant excretion of 6-keto and TBX2 was above that of normal subjects and fell progressively after transplant, as did plasma renin activity and aldosterone. The 6-keto levels fell below normal after two weeks. The ratio of TBX2/6-keto remained elevated compared with normal subjects throughout the month after transplant (1.54 +/- 0.38 vs. 0.54 +/- 0.07, P less than .01). Endothelin levels rose during the first week (7.4 +/- 1.4 vs. 12.4 +/- 2.7 pg/ml, P less than .05), but fell back to baseline thereafter. These results indicate that high levels of urinary eicosanoids in patients with liver disease fall rapidly after liver transplantation during CsA immunosuppression. Unlike results in many experimental models, these data suggest that renal vasoconstriction in humans may be associated primarily with suppression in renal prostacyclin excretion rather than stimulation of thromboxane.     

Cardiotrophin-1 is a prophylactic against the development of chronic hypoxic pulmonary hypertension in rats

BACKGROUND: Cardiotrophin-1 (CT-1) reduces arterial blood pressure by activating nitric oxide synthesis. This study attempted to elucidate the effect of CT-1 on pulmonary arteries of pulmonary hypertensive rats. METHODS: Pulmonary hypertension was induced in rats in a hypoxic chamber containing 10% to 11% oxygen. Rats kept in the hypoxic environment received either recombinant mouse CT-1 at a concentration of 50 micro g/kg (CT-1+hypoxia group, n = 21) or phosphate-buffered saline (hypoxia group, n = 30) once per day. Control rats housed in room air also received either the equivalent concentration of CT-1 (CT-1+normoxia group, n = 18) or phosphate-buffered saline (normoxia group, n = 39). Pulmonary arterial pressure, pulmonary vasorelaxation, and ventricular hypertrophy were measured. RESULTS: The mean pulmonary arterial pressures were as follows (from lowest to highest; p values are relative to the hypoxia group): normoxia group (20.3 +/- 4.0 mm Hg, p < 0.0001), CT-1+normoxia group (21.1 +/- 2.4 mm Hg, p < 0.0001), CT-1+hypoxia group (27.9 +/- 4.1 mm Hg, p = 0.0019), and hypoxia group (33.9 +/- 6.6 mm Hg). The endothelium-dependent vasorelaxation value was largest in the normoxia group (59.5% +/- 17.4%, p < 0.0001), with it decreasing in the other groups in the following order (p values are relative to the hypoxia group): CT-1+normoxia group (52.8% +/- 15.5%, p = 0.0005), CT-1+hypoxia group (42.3% +/- 14.8%, p = 0.0061), and hypoxia group (17.4% +/- 4.8%). Right ventricular hypertrophy was significant only in the hypoxia group. CONCLUSIONS: Our results demonstrate that treatment with CT-1 in a chronic hypoxic pulmonary hypertension model protects the endothelial function of the pulmonary artery; decreases pulmonary arterial pressure; and attenuates right ventricular hypertrophy.     

Pancreatitis-associated Protein Protects the Lung from Leukocyte-induced Injury

Background: Severe pancreatitis is often complicated by shock and acute lung failure. Little is known about the pathophysiologic impact of the 16.6-kD lectine, named pancreatitis-associated protein (PAP), which is expressed during pancreatitis and which reduces mortality in a rat model with severe pancreatitis. Therefore, the aim of this study was to investigate the effects of PAP on the pulmonary vasculature after leukocyte activation with N-formyl-Met-Leu-Phe (fMLP).

Methods: The experiments were performed in buffer-perfused isolated rabbit lungs. Mean pulmonary artery pressure, weight gain, and thromboxane A2 synthesis of the lungs were monitored. PAP was obtained by affinity chromatography of pancreas juice from pancreatitic rats. The authors tested whether treatment with PAP (260 [mu]g/l, n = 9; or 500 [mu]g/l, n = 6) before fMLP injection (10-6 M) influences mean pulmonary artery pressure and edema formation. Lungs that were treated only with fMLP (n = 6) served as controls. Additional experiments in which PAP was applied were performed to study whether PAP (260 [mu]g/l, n = 3; 500 [mu]g/l, n = 3; 1,000 [mu]g/l, n = 3) itself effects lung vasculature.

Results: Application of fMLP resulted in an increase of mean pulmonary artery pressure (+/- SD) from 8 +/- 2 mmHg up to 26 +/- 13 mmHg (P < 0.01) at a flow of 150 ml/min. Pretreatment with PAP reduced the peak pressure developed after fMLP to 15 +/- 7 mmHg (PAP 260 [mu]g/l;P < 0.05) and to 9 +/- 4 mmHg (PAP 500 [mu]g/l), respectively. In addition, the fMLP-induced lung weight gain of 9 +/- 7 g in the controls was prevented by pretreatment with PAP after 150 min in either concentration. In parallel to the attenuated pressure increase, thromboxane A2 release was significantly suppressed in the 260-[mu]g/l (200 +/- 220 pmol [middle dot] ml-1 [middle dot] min-1;P < 0.01) and 500-[mu]g/l (285 +/- 70 pmol [middle dot] ml-1 [middle dot] min-1;P < 0.05) PAP groups compared with controls (1,138 +/- 800 pmol [middle dot] ml-1 [middle dot] min-1). Treatment with PAP alone in either concentration did not induce any changes in mean pulmonary artery pressure, weight gain, or thromboxane A2 release.     

Diphenhydramine Increases Ventilatory Drive during Alfentanil Infusion

Background: Diphenhydramine is used as an antipruritic and antiemetic in patients receiving opioids. Whether it might exacerbate opioid-induced ventilatory depression has not been determined.

Methods: The ventilatory response to carbon dioxide during hyperoxia and the ventilatory response to hypoxia during hypercapnia (end-tidal pressure of carbon dioxide [PETCO2] [almost equal to] 54 mmHg) were determined in eight healthy volunteers. Ventilatory responses to carbon dioxide and hypoxia were calculated at baseline and during an alfentanil infusion (estimated blood levels [almost equal to] 10 ng/ml) before and after diphenhydramine 0.7 mg/kg.

Results: The slope of the ventilatory response to carbon dioxide decreased from 1.08 +/- 0.38 to 0.79 +/- 0.36 l [middle dot] min-1 [middle dot] mmHg-1 (x +/- SD, P < 0.05) during alfentanil infusion; after diphenhydramine, the slope increased to 1.17 +/- 0.28 l [middle dot] min-1 [middle dot] mmHg-1 (P < 0.05). The minute ventilation (VE) at PETCO2 [almost equal to] 46 mmHg (VE 46) decreased from 12.1 +/- 3.7 to 9.7 +/- 3.6 l/min (P < 0.05) and the VE at 54 mmHg (V (E) 54) decreased from 21.3 +/- 4.8 to 16.6 +/- 4.7 l/min during alfentanil (P < 0.05). After diphenhydramine, VE 46 did not change significantly, remaining lower than baseline at 9.9 +/- 2.9 l/min (P < 0.05), whereas VE 54 increased significantly to 20.5 +/- 3.0 l/min. During hypoxia, VE at Sp O2 = 90% (VE 90) decreased from 30.5 +/- 9.7 to 23.1 +/- 6.9 l/min during alfentanil (P < 0.05). After diphenhydramine, the increase in VE 90 to 27.2 +/- 9.2 l/min was not significant (P = 0.06).     

In vivo insulin resistance induced by amylin primarily through inhibition of insulin-stimulated glycogen synthesis in skeletal muscle

We examined the in vivo mechanisms of amylin-induced resistance in concious rats (n = 18). During 180-min euglycemic insulin-clamp (21.5 pmol.kg-1.min-1) studies, amylin (50, 200, or 500 pmol.kg-1.min-1; plasma concentration from 3 x 10(-10) to 9 x 10(-9) M) infusion determined a 19-27% reduction in glucose uptake (117.8 +/- 7.0 vs. 145.8 +/- 11.0, 107.1 +/- 9.2 vs. 145.1 +/- 6.7, and 105.0 +/- 7.2 vs. 144.4 +/- 7.0 mumol.kg-1.min-1 at 50, 200, or 500 pmol.kg-1.min-1, respectively, P less than 0.01) versus insulin alone, whereas 10-pmol.kg-1.min-1 amylin infusion (plasma concn 5 x 10(-11) M) failed to affect insulin-mediated glucose disposal. After amylin infusion, the contribution of whole-body glycolysis to overall glucose disposal increased from 43-48 to 62-79%, whereas muscle glycogen synthesis decreased significantly at all peptide concentrations greater than 3 x 10(-10) M, completely accounting for the decrease in glucose uptake. Skeletal muscle glucose-6-phosphate concentration rose from 0.219 +/- 0.038 mumol/g (insulin alone) to 0.350 +/- 0.018, 0.440 +/- 0.020, and 0.505 +/- 0.035 mumol/g (insulin plus amylin at 50, 200, or 500 pmol.kg-1.min-1, P less than 0.01). Suppression of hepatic glucose production by insulin was unaffected by a 50-pmol.kg-1.min-1 amylin infusion (18.5 +/- 4.3 vs. 21.7 +/- 2.9 mumol.kg-1.min-1), whereas it was slightly but significantly impaired by amylin infusion at 200 pmol.kg-1.min-1 (17.8 +/- 3.9 vs. 24.7 +/- 4.5 mumol.kg-1.min-1, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Prostanoid production and pulmonary hypertension after fat embolism are not modified by methylprednisolone

Bilateral cemented arthroplasty (BCA) in anaesthetized mongrel dogs produces particulate fat and marrow embolism of the lung. Methylprednisolone sodium succinate (MPSS) has been advocated for post-traumatic fat embolism to prevent acute lung injury. We used the BCA procedure to produce acute fat and marrow embolism, and tested the efficacy of MPSS (30 mg.kg-1) in preventing physiological and pathological markers of acute lung injury. Dogs (n = 6) pre-treated with MPSS demonstrated similar acute increases in pulmonary artery pressure (PAP) within one minute of BCA (17.8 +/- 7.3 mmHg) as the untreated (control n = 7) dogs (18.6 +/- 12.6). Pulmonary vascular resistance (PVR) increased to the same degree in both groups (455 +/- 323 and 319 +/- 137 dyne.sec.cm-5) and PaO2 decreased by 18.3 +/- 6.4 mmHg in the control group as opposed to 12.4 +/- 7.7 mmHg in the MPSS group within five minutes of BCA. Circulating arterial and mixed venous plasma concentrations of thromboxane B2 (TxB2) increased within one minute of BCA in both groups with no increase in the transpulmonary gradient. Arterial plasma 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) increased (0.91 +/- 0.29 ng.ml-1 and 0.87 +/- 0.43 ng.ml-1) in both groups one minute after BCA. Mixed venous 6-keto PGF1 alpha plasma concentration also increased, but a significant transpulmonary 6-keto PGF1 alpha gradient was found.(ABSTRACT TRUNCATED AT 250 WORDS)     

Low plasma renin activity in diabetes. Relation to urine prostaglandin excretion

Renal functional abnormalities, occurring before overt renal disease and possibly due to abnormal vascular control mechanisms, have been described in diabetes mellitus. We used intravenous (i.v.) furosemide, which stimulates renal prostaglandin (PG) synthesis and renin release, to compare these vasoactive systems in 14 diabetic and 23 normal control subjects. Using urine thromboxane B2 (TXB2) as an index of renal synthesis of the vasoconstrictor prostanoid TXA2, and urine 6keto-PGF1 alpha for the vasodilator PGI2, we found evidence of increased renal TXA2 synthesis in diabetic subjects in response to furosemide. The increased TXA2 synthesis did not occur at the expense of PGI2 synthesis, as urine 6keto-PGF1 alpha was not reduced. Increased TXB2 excretion in diabetic subjects was particularly marked in the first 10 min after i.v. furosemide. During this time, diabetic males excreted 31 +/- 6 ng of TXB2 compared with 10 +/- 1 ng for normal males (P less than 0.05), while diabetic females excreted 15 +/- 3 ng compared with 7 +/- 1 ng for normal females (P less than 0.05). Also, 6keto-PGF1 alpha excretion at 10 min was increased in diabetic subjects: males, 29 +/- 3 ng versus 19 +/- 3 (P less than 0.05); females, 33 +/- 8 versus 16 +/- 3 (P less than 0.05). The ratio of TXB2 to 6keto-PGF1 alpha tended to be higher in diabetic males.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of acute and chronic counterregulatory hormone infusions on glucose tolerance and insulin sensitivity in diabetic dogs.

The effects of elevated EPI and CORT levels on KG, SI, and SG were studied in dogs with alloxan-induced diabetes. Conscious dogs received SAL, EPI 20 ng.kg-1.min-1 for 30 min (short EPI) or 72 h (long EPI), or CORT 200 micrograms.kg-1.min-1 for 60 min (short CORT) or 72 h (long CORT) before assessment of glucose metabolism by rapid sampling for glucose and insulin levels after 300 mg/kg i.v. glucose and exogenous insulin infusion designed to simulate the normal secretory pattern. With EPI infusion, KG fell acutely from 2.9 +/- 0.4 to 2.0 +/- 0.2%/min (SAL vs. short EPI, P < 0.05), but rose to 3.4 +/- 0.4%/min during long EPI. Minimal-model analysis of the glucose response with the insulin data as input showed that SI decreased acutely from 4.7 +/- 1.8 to 2.5 +/- 0.6 x 10(-5) min-1/pM (SAL vs. short EPI, P < 0.05), but rose to 4.5 +/- 2.5 x 10(-5) min-1/pM during long EPI. The effects of EPI on SG paralleled the results for KG and SI, with acute decline from 3.9 +/- 0.4 to 2.1 +/- 0.4 x 10(-2) min-1 (SAL vs. short EPI, P < 0.05) and recovery to 3.3 +/- 0.3 x 10(-2) min-1 during long EPI. During CORT infusion, KG tended to fall (SAL 2.9 +/- 0.4 vs. short CORT 2.5 +/- 0.5 vs. long CORT 2.2 +/- 0.5%/min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of trimethaphan on arterial blood histamine and systemic hemodynamics in humans

Because of lack of direct evidence of histamine release by trimethaphan, the authors determined serum histamine levels and hemodynamic responses to trimethaphan administration in 19 consecutive patients. Group 1 patients (n = 7) received a single intravenous injection of trimethaphan, 0.5 mg X kg-1, while awake and again during stable halothane-nitrous oxide anesthesia. Group 2 patients (n = 6) were pretreated with intravenous H1 (chlorpheniramine, 0.1 mg X kg-1) and H2 (cimetidine, 4 mg X kg-1) receptor antagonists administered 15 min before trimethaphan, 0.5 mg X kg-1, in the awake and anesthetized states. In Group 3 (n = 6), the effects of infusion of trimethaphan, 3 mg X min-1 for 15 min, were studied during halothane-nitrous oxide anesthesia. In Group 1, bolus doses of trimethaphan were associated with maximal increases in serum histamine from 0.56 +/- 0.14 to 2.56 +/- 0.35 ng X ml-1 (P less than 0.01) and from 0.60 +/- 0.11 to 2.58 +/- 0.33 ng X ml-1 (P less than 0.01) 2 min after drug administration in the awake and anesthetized states, respectively; there were also clinical manifestations of histamine release. Mean arterial pressure decreased maximally after 5 min in the awake (from 92.0 +/- 3.4 to 69.9 +/- 2.2 mmHg; P less than 0.01) and anesthetized (from 82.6 +/- 3.7 to 57.3 +/- 2.5 mmHg; P less than 0.01) states, and was associated with increases in cardiac output and heart rate; stroke volume increased in the awake state only.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanism of impaired natriuretic response to furosemide during prolonged therapy

The mechanism of the diuretic braking phenomenon was studied in nine male hypertensive patients by assessing the diurnal pattern of renal sodium (Na) excretion during furosemide therapy, and the response to a test dose of furosemide (10 to 15 mg hr-1 i.v.) infused alone and with chlorothiazide (500 mg bolus i.v.). Patients were studied after one month of twice-daily administration of: placebo (P): chlorothiazide 500 mg (C); furosemide 40 mg (F); furosemide with spironolactone (100 mg b.i.d.) for the last 36 hours (F + S; N = 6). During F therapy, furosemide-induced natriuresis was followed by six hour periods of decreased UNaV. Diuretic therapy with F or C for one month reduced BP, but did not alter body weight, plasma volume (PV), glomerular filtration rate or PAH clearance. After P, the test infusion of furosemide increased fractional Na excretion (FENa) by +10.5 +/- 0.7%; this increment was reduced after therapy with F (+8.9 +/- 0.7%; P less than 0.05), C (+8.5 +/- 1.0%; P less than 0.01), or F + S (+8.9 +/- 0.9%; P less than 0.05). Renal furosemide excretion was greater (P less than 0.05) after F and C treatments (133 +/- 10 micrograms.min-1 and 130 +/- 13 micrograms.min-1, respectively) compared with P (94 +/- 9 micrograms.min-1). After P, a test dose of chlorothiazide given during furosemide infusion increased FENa further (+7.5 +/- 1.2%); this increment was greater after therapy with F (+10.1 +/- 1.4%; P less than 0.01) and F + S (+11.3 +/- 0.8%; P less than 0.05) but not after C (+6.3 +/- 1.5%; P greater than 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)     

The enflurane sparing effect of sufentanil in dogs

There is a ceiling to the reduction of enflurane MAC by fentanyl in the dog. Sufentanil (SUF), a more potent narcotic, may be more efficacious in reducing enflurane MAC. To test this hypothesis, 25 mongrel dogs were studied in three groups. Group 1 (n = 8) received SUF in progressively increasing infusion rates from 0.005 micrograms . kg-1 . min-1 to a maximum of 1.215 micrograms . kg-1 . min-1. MAC was determined at stable SUF concentrations in plasma [SUF] during each infusion rate. Group 2 (n = 10) received SUF at a dose rate (0.007 micrograms . kg-1 . min-1) designed to produce approximately 35% MAC reduction, and MAC determinations were made at regular intervals over a mean infusion time of 7.6 +/- 0.43 h (mean +/- SEM). Group 3 (n = 7) received 1.215 micrograms . kg-1 . min-1 and were studied as in group 2 over an infusion time of 6.7 +/- 0.42 h. In group 1, the highest infusion rate (1.215 micrograms . kg-1 . min-1) produced [SUF] = 48 ng/ml and reduced MAC by 71 +/- 6%. This was not statistically different from the reduction which occurred at [SUF] = 0.92 ng/ml (57 +/- 7%; infusion rate 0.015 micrograms . kg-1 . min-1; P = 0.21). In group 2, the degree of MAC reduction achieved by stable [SUF] (0.54 +/- 0.08 ng/ml) declined over time (MAC reduction at start = 34 +/- 2% versus 18 +/- 4.0% at the end of the infusion; P = 0.001), suggesting the development of tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)     

The adrenergic contribution to glucose counterregulation in type I diabetes mellitus. Dependency on A-cell function and mediation through beta 2-adrenergic receptors

In order to assess the adrenergic contribution to hypoglycemic glucose counterregulation in type I diabetes mellitus and to determine whether the adrenergic contribution is mediated through beta 1- or beta 2-adrenergic receptors, hypoglycemia was induced by an i.v. insulin infusion (30 mU/m2 x min) for 60 min in 11 insulin-dependent diabetic patients (IDDM), 5 with normal plasma glucagon responses and 6 with blunted responses, and also in 7 age-weight-matched nondiabetic subjects. Rates of plasma glucose decrease and postnadir increase, as well as plasma concentrations of free insulin and of counterregulatory hormones, were measured when insulin was infused alone, and when insulin was infused along with propranolol (a beta 1- and beta 2-adrenergic receptor antagonist) or metoprolol (a selective beta 1-antagonist). Postnadir plasma glucose recovery was decreased in IDDM with blunted plasma glucagon responses (21 +/- 0.8 mumol x L-1 x min-1, P less than 0.001), but was normal in patients with normal plasma glucagon responses (30 +/- 0.4 versus 33 +/- 0.5 mumol x L-1 x min-1 in nondiabetic subjects, P = NS). Postnadir plasma glucose recovery was not affected by either propranolol or metoprolol in normal subjects and in IDDM with normal glucagon responses. However, in IDDM with blunted plasma glucagon responses, postnadir plasma glucose recovery was further decreased by propranolol (14 +/- 0.6 mumol x L-1 x min-1, P less than 0.01), but was unaffected by metoprolol (22 +/- 0.9 mumol x L-1 x min-1, P = NS).(ABSTRACT TRUNCATED AT 250 WORDS)     

In vitro modulation of monocyte chemoattractant protein-1 release in human pancreatic islets

Islet transplantation is a new approach to treat type 1 diabetic patients. Despite its great potential and progressively increasing success rate, islet engraftment still represents an unsolved problem. Only part of the transplanted beta-cell mass survives after infusion due to hypoxia and inflammatory reactions, principally mediated by macrophages. We have demonstrated that human islets release monocyte chemoattractant protein-1 (MCP-1), one of the most powerful macrophage chemokines, which may impair the fate of a transplant. In this study we have attempted to modulate in vitro MCP-1 release by human islets. Human islets isolated using the automated method were cultured in CMRL or M199 standard culture media alone or supplemented with (1) two intracellular kinase inhibitors (10 micromol/L RO8220, a protein kinase C inhibitor, and rcAMP 20 micromol/L, a protein kinase A inhibitor) or (2) two antioxidant and cell-protective agents (vitamin E, vitamin B); or (3) immunosuppressive drugs (0.001 to 10 ng/mL cyclosporine, 0.1 to 100 ng/mL rapamycin, 0.1 to 10 ng/mL tacrolimus, 0.001 to 10 ng/mL mycophenolate acid). We observed that the only culture condition that significantly decreased MCP-1 in human islets were CMRL (31 +/- 12 in CMRL vs 539 +/- 184 pg/mL, in M199, P <.05) or cyclosporine (514 +/- 83 pg/mL in control islet vs 307 +/- 13, 231 +/- 44, 192 +/- 4, 242 +/- 113, 169 +/- 15 pg/mL in islet plus cyclosporine ranging from 0.001 to 10 ng/mL, respectively, P >.05). The capacity of in vitro factors to decrease human islet MCP-1 release suggests strategies to increase the success of islet transplantation.     

A rat model of progressive chronic glomerular sclerosis: the role of thromboxane inhibition.

In order to evaluate a possible role of thromboxane A2 (TxA2) in the pathophysiology of chronic glomerular disease, we studied the effect of a 12-wk combined treatment with the thromboxane receptor blocker Daltroban (D) and the thromboxane synthesis inhibitor UK 38485 (UK) on glomerular function and morphology in a rat model of chronic progressive glomerular injury. The glomerular lesion was induced in unilaterally nephrectomized rats by the repeated i.v. injection of an antibody directed against mesangial cells. Control rats were uninephrectomized. Three months after the first antibody injection before D and UK treatment, albuminuria (35.8 +/- 3.6 mg/24 h) and glomerular TxB2 formation (146 +/- 20 pg/mg of protein/min) were significantly higher compared with control values (albuminuria, 14.3 +/- 3.5 mg/24 h; TxB2, 59 +/- 16 pg/mg/min). Six months after antibody, albuminuria in nephritic rats had increased to 135 +/- 17 mg/24 h. In nephritic rats treated with D plus UK, albuminuria (44 +/- 12 mg/24 h), however, was significantly (P less than 0.001) inhibited. Quantitative morphological analysis (glomerular damage index) 6 months after antibody revealed significantly (P less than 0.001) increased glomerular lesions in nephritic rats (0.353 +/- 0.095) compared with that in uninephrectomized controls (0.045 +/- 0.014). The treatment of rats with D and UK significantly (P less than 0.001) reduced the glomerular damage index (0.101 +/- 0.004) in nephritic rats. D plus UK treatment reduced glomerular TxB2 formation but increased prostaglandin E2 and 6-keto prostaglandin F1 alpha release by isolated glomeruli. This study demonstrates that interventional treatment with D and UK ameliorates albuminuria and glomerular morphological lesions in a rat model of immunologically induced progressive glomerular injury.     

The effect of concomitant radiofrequency ablation and surgical technique (repair versus replacement) on release of cardiac biomarkers during mitral valve surgery

All patients undergoing heart surgery experience a certain amount of nonspecific myocardial injury documented by the release of cardiac biomarkers and associated with poor outcome. We investigated the role of unipolar radiofrequency ablation of atrial fibrillation on the release of cardiac biomarkers in 71 patients undergoing mitral valve surgery and concomitant left atrial ablation case-matched with 71 patients undergoing isolated mitral surgery. The study was powered to detect a 3 ng/mL difference. There was no difference between the 2 groups in terms of cardiac troponin I (10 +/- 5.3 versus 12 + 10.4 ng/mL; P = 0.7) or creatine kinase-MB (50 +/- 21.8 versus 57 +/- 62.0 ng/mL; P = 0.5) release. Postoperative peak cardiac troponin I levels had univariate associations with the duration of cardiopulmonary bypass (P = 0.002) and aortic cross-clamping (P = 0.001) and with the surgical technique (15 +/- 12 ng/mL for mitral valve replacement versus 9 +/- 4.8 for mitral valve repair; P = 0.0007) at univariate analysis. Mitral valve replacement was the only independent predictor of postoperative peak release of cardiac troponin I identified with multivariate analysis (P = 0.005). Radiofrequency ablation of atrial fibrillation does not significantly increase cardiac biomarker release compared with isolated mitral surgery; mitral valve repair is associated with less release of cardiac biomarkers compared with mitral valve replacement.