Differential effects of fedotozine compared to other kappa agonists on diuresis in rats.

The aim of our study was to test the effect of fedotozine (0.1-30 mg/kg, s.c.), a novel kappa opioid agonist, on water diuresis in the conscious hydrated rat. Its effect was compared to that of morphine (2.5-10 mg/kg), a mu opioid agonist and to some of the recognized kappa agonists described in the literature: bremazocine (0.3-30 micrograms/kg), tifluadom (0.1-3 mg/kg), Cl 977 1-1000 micrograms/kg), (-)-cyclazocine (0.01-1 mg/kg), PD 117,302 (0.03-3 mg/kg), U-50,488h (0.25-10 mg/kg) and U-69,593 (0.3-3 mg/kg). The effect of fedotozine was also tested after intracerebroventricular administration (100 micrograms/kg) and compared to that of U-50,488h (10-30 micrograms) and dynorphins A(1-17), A(1-13) and B(1-13) (2.5-10 micrograms). All the reference kappa agonists administered by the s.c. route induced water diuresis, whereas morphine inhibited diuresis and electrolyte excretion. However, fedotozine (0.1-30 mg/kg s.c.) had no effect on diuresis, even after low doses of naloxone (0.1 mg/kg s.c.) or nor-BNI (10 mg/kg s.c.), and at 1 mg/kg had inconsistent effects on electrolyte elimination. When administered in the lateral ventricle of the brain, U-50,488h and dynorphin A(1-17) induced water diuresis, unlike fedotozine (100 micrograms), DYN A(1-13) and DYN B(1-13) that had no effect on urine output. Furthermore, fedotozine did not alter the diuretic effects of U-50,488h. These results suggest that fedotozine is an atypical kappa agonist, lacking activity on the kappa receptor subtypes regulating diuresis.

Induced low P50 in anesthetized rats: blood gas, circulatory and metabolic adjustments.

In anesthetized, normoxic or hypoxic rats the hemodynamic, metabolic and O2 transport characteristics following exchange transfusion with human erythrocytes containing a high O2 affinity hemoglobin (Hemoglobin Creteil, beta 89 Ser----Asp) have been studied. The in vivo oxygen partial pressure at 50% oxygen hemoglobin saturation (P50) decreased from 37.4 +/- 2.1 to 12.7 +/- 0.7 mm Hg; the arterial oxygen tension was reduced significantly from 109.9 +/- 7.7 to 87.3 +/- 12.0 mm Hg. There was a decrease in right ventricular partial pressure of oxygen (PvO2), (P less than 0.001), oxygen consumption (VO2), (P less than 0.001), arterio-venous difference, (P less than 0.001), and peripheral vascular resistance index, (P less than 0.01). Exchange transfusion with normal rat blood (P50 = 37.2 +/- 2.4 mm Hg) or with 2,3-diphosphoglycerate-enriched human red blood cells (P50 = 34.7 +/- 2.2 mm Hg), did not modify these variables in normoxic rats. In hypoxia, the reduction in P50 was associated with a further decrease in PvO2 an increase in serum lactate concentration and a VO2 decrease.

Pulmonary vasoconstrictor response to acute decrease in blood P50.

The O2 sensor that triggers hypoxic pulmonary vasoconstriction may be sensitive not only to alveolar hypoxia but also to hypoxia in mixed venous blood. A specific test of the blood contribution would be to lower mixed venous PO2 (PvO2), which can be accomplished by increasing hemoglobin-O2 affinity. When we exchanged transfused rats with cyanate-treated erythrocytes [PO2 at 50% hemoglobin saturation (P50) = 21 Torr] or with Créteil erythrocytes (P50 = 13.1 Torr), we lowered PvO2 from 39 +/- 5 to 25 +/- 4 and to 14 +/- 4 Torr, respectively, without altering arterial blood gases or hemoglobin concentration. Right ventricular systolic pressure increased from 32 +/- 2 to 36 +/- 3 Torr with cyanate erythrocytes and to 44 +/- 5 Torr with Créteil erythrocytes. Cardiac output was unchanged. Control exchange transfusions with normal rat or 2,3-diphosphoglycerate-enriched human erythrocytes had no effect on PvO2 or right ventricular pressure. Alveolar hypoxia plus high O2 affinity blood caused a greater increase in right ventricular systolic pressure than either stimulus alone. We concluded that PvO2 is an important determinant of pulmonary vascular tone in the rat.

Determination of the PO2 temperature blood factor from oxygen dissociation curves.

The variation with saturation of the temperature coefficient of PO2 in human blood (delta log PO2/delta T) was determined by continuous recording of the oxygen dissociation curve (ODC), at 37 degrees C and 25 degrees C, on the same blood samples. PCO2 and pH were held constant through an ODC run, and PCO2 was reduced at 25 degrees C to the value measured by anaerobic cooling of the same sample. delta log PO2/delta T was calculated from isosaturation points on the 37 and 25 degrees C curves. The temperature coefficient was also computed as an independent check on this method by determination of the effects of temperature (25, 30, 37 and 40 degrees C) on hemoglobin ligand interaction: fixed acid Bohr effect (delta log PO2/delta pH), carbamino-formation (delta log PO2/delta log PCO2) and hemoglobin oxygen affinity. The values of delta log PO2/delta T ratio obtained from the two different approaches were found to be in good agreement. The coefficient decreased when [H+] concentration was increased. A linear relationship between the Bohr factor and the temperature was found: delta log PO2/delta pH = 0.00267 T-0.520 (r = 0.85; n = 40) At 25 degrees C, the carbamino-formation was one order of magnitude lower than at 37 degrees C. Acid-base state and saturation value appeared to be major determinant factors for the temperature correction coefficient to be applied to blood PO2 values measured at standard (37 degrees C) temperature.

Consequences of an acute increase in P50 in anaesthetized guinea pigs.

In anaesthetized guinea pigs, ventilated with ambient air, the peripheral haemodynamics and oxygen transport characteristics have been studied following a blood exchange transfusion with rat erythrocytes suspended in guinea pig plasma. Since the rat haemoglobin exhibited a lower oxygen affinity than guinea pig haemoglobin, the oxygen partial pressure at 50% of oxygen haemoglobin saturation (P50) increased from 25.2 +/- 1.1 to 37.2 +/- 0.9 mm Hg (n = 10). This increase in P50 was accompanied by a significant increase in arterial oxygen partial pressure (PaO2) and in arterio-venous difference (AVDO2). Cardiac output (Q) was decreased significantly, but oxygen consumption (VO2) remained within control values. The increase in P50 was associated with a venous oxygen partial pressure (P-VO2) which remained constant but an increase in blood lactate concentration was observed. Control exchange transfusion with fresh guinea pig blood had no effect on acid-base status, on oxygen transport, or on peripheral resistance. The sudden reduction in haemoglobin oxygen affinity induced an increase in peripheral resistance with a decrease in cardiac output, the arterial systemic pressure being maintained. These results suggested that an acute decrease in haemoglobin oxygen affinity was compensated for by a simultaneous diminution of overall tissue blood flow and reduction of capillary recruitment.

Effects of chronic changes in hemoglobin-O2 affinity in rats.

We have assessed the characteristics of oxygen transport following chronic intraperitoneal administration of sodium cyanate (NaCNO, 90 mg/kg; P50 decreased), o-iodosodium benzoate (OISB, 300 mg/kg; P50 increased), or sodium chloride (NaCl; P50 unchanged) to rats at a rate of 5 times/wk for 16 wk. At the end of this period, the animals were exposed to a low inspired O2 concentration and were subjected to exercise stress. Hill's n50 at pH 6.90-7.60, hematocrit, and the saturation dependency of the Bohr effect (PCO2 constant) were altered by NaCNO only. Cyanate-treated rats gained less weight, probably due to a toxic side effect of the drug. Hypoxemia-induced lactatemia was greatest with a high P50 (OISB). Physical effort (swimming) was tolerated poorly at normal arterial PO2 when P50 was low (NaCNO). Although a left-shifted curve appears beneficial when FIO2 is reduced, reasons for the physiological advantage may be the result of other characteristics of the O2 dissociation curve, not P50 alone.