Actions of sodium dichloroacetate in combination with insulin on hyperlactatemia and hyperpyruvicemia induced in dogs by phenformin]

In the normal anesthetized dog the combination of insulin, whether of exogenous or endogenous origin, with sodium dichloroacetate provoke a rapid and important reduction of the hyperlactatemia and hyperpyruvicemia induced by the intraduodenal injection of high doses of phenformin. Furthermore this combination prevents the progressive and important lowering of the arterial pH provoked by phenformin.     

Effect of cocarboxylase on hyperlactatemia and hyperpyruvicemia induced by phenformin in dogs]

In the normal anesthetized dog, a cocarboxylase perfusion considerably reduced the increase in blood lactate and pyruvate levels provoked by the intraduodenal injection of phenformin (30 mg/kg); furthermore it seems to counteract the increase of the lactates/pyruvates ratio and opposes the fall in blood pH.     

Effects of thiamine pyrophosphate and sodium dichloroacetate on the increase of lactate and insulin outputs induced by phenformin on the isolated and perfused rat pancreas]

Thiamine pyrophosphate and sodium dichloroacetate, substances which promote the aerobic metabolism of pyruvate, reduce the increase in lactate output induced by phenformin (100 mg/l) on the isolated and perfused rat pancreas. Both substances provoke a decrease in insulin secretion produced by phenformin.     

Hemodynamic modifications induced by hypoxia in the dog]

In non hypercapnic hypoxia (inhalation of a 4,5% O2 mixture during 10 minutes) blood pressure, heart rate, cardiac output, femoral and carotid blood flow inhance so that, in less extent, vertebral blood flow. Such a reaction is consequent with an hypoxic stimulation of adrenal glands.     

Effect of chlorpropamide and of phenformin on isolated liver plasmatic membranes]

Previous observations from this laboratory suggest that chlorpropamide and phenformin, two hypoglycemic drugs belonging to sulfonylureas and biguanides respectively, act on liver plasma membranes altering the activity of enzymes bound to plasma membrane as (Na+-K+)-ATPase. This enzyme, an integral membrane protein which shows a cooperative behavior, has been used as an allosteric probe able to give information on plasma membrane. Our experiments show that (Na+-K+)-ATPase has a positive cooperative behaviour, as suggested from Hill coefficient n > l. The two hypoglycemic drugs decrease the Hill coefficient; in addition both chlorpropamide and phenformin inhibit (Na+-K+)-dependent but not Mg2+-dependent ATPase activity.     

The metabolic effects of sodium dichloroacetate in the starved rat

1. Sodium dichloroacetate (300mg/kg body wt. per h) was infused in 24h-starved rats for 4h. 2. Blood glucose decreased significantly, an effect that had previously only been noted in diabetic animals 3. Plasma insulin concentration decreased by 63%; blood lactate and pyruvate concentrations decreased by 50 and 33%, whereas concentrations of 3-hydroxybutyrate and acetoacetate increased by 81 and 73% respectively. 4. Livers were freeze-clamped at the end of the 4h infusion. There were significant decreases in hepatic [glucose], [glucose 6-phosphate], [2-phosphoglycerate], the [lactate]/[pyruvate] ratio, [citrate] and [malate], and also [alanine], [glutamate] and [glutamine], suggesting a diminished supply of gluconeogenic substrates. 5. Animals subjected to a functional hepatectomy at the end of 2h infusions showed no difference in blood-glucose disappearance but a highly significant decrease in the rate of accumulation of lactate, pyruvate, glycerol and alanine, compared with control animals. Dichloroacetate decreased ketone-body clearance. 6. After functional hepatectomy an increase in glutamine accumulation appeared to compensate for the decrease in alanine accumulation. 7. It is concluded that dichloroacetate causes hypoglycaemia by decreasing the net release of gluconeogenic precursors from extrahepatic tissues while inhibiting peripheral ketone-body uptake. 8. These findings are consistent with the activation of pyruvate dehydrogenase (EC 1.2.4.1) in rat muscle by dichloroacetate previously described by Whitehouse & Randle (1973).     

Metformin and phenformin block the peripheral antinociception induced by diclofenac and indomethacin on the formalin test

AimsRecent evidence has shown that systemic administration of sulfonylureas and biguanides block the diclofenac-induced antinociception, but not the effect produced by indomethacin. However, there are no reports about the peripheral interaction between analgesics and the biguanides metformin and phenformin. Therefore, this work was undertaken to determine whether glibenclamide and glipizide and the biguanides metformin and phenformin have any effect on the peripheral antinociception induced by diclofenac and indomethacin.Main methodsDiclofenac and indomethacin were administered locally in the formalin-injured rat paw, and the antinociceptive effect was evaluated using the 1% formalin test. To determine whether peripheral antinociception induced by diclofenac or indomethacin was mediated by either the ATP-sensitive K⁺ channels or biguanides-induced mechanisms, the effect of pretreatment with the appropriates vehicles or glibenclamide, glipizide, metformin and phenformin on the antinociceptive effect induced by local peripheral diclofenac and indomethacin was assessed.Key findingsLocal peripheral injections of diclofenac (50–200 μg/paw) and indomethacin (200–800 μg/paw) produced a dose-dependent antinociception during the second phase of the test. Local pretreatment with glibenclamide, glipizide, metformin and phenformin blocked the diclofenac-induced antinociception. On the other hand, the pretreatment with glibenclamide and glipizide did not prevent the local antinociception produced by indomethacin. Nonetheless, metformin and phenformin reversed the local antinociception induced by indomethacin.SignificanceData suggest that diclofenac could activate the K⁺ channels and biguanides-dependent mechanisms to produce its peripheral antinociceptive effects in the formalin test. Likewise, a biguanides-dependent mechanism could be activated by indomethacin consecutively to generate its peripheral antinociceptive effect.     

Effect of citidoline on hemodynamics in the normobaric hypoxic dog]

In dogs submitted to a normobaric hypoxia, we found an elevation of the arterial blood pressure, of the heart rate, of the cardiac output and of the regional blood flows, the total peripheral resistance remaining unchanged. Treatment with citidoline abolishes these hemodynamic responses and the authors hypothetize that this effect is correlated with the agonist dopaminergic effect of the drug.     

Reactivity of the arterial system during vasodilation induced by sodium nitroprusside]

A stepwise decrease in the blood pressure by means of sodium nitroprusside infusion led to progressing diminishing of mesatone pressor effects in anaesthetised rats. Cardiac output changes due to mesatone administration did not depend on the initial blood pressure. The latter being lower than physiological limits, a direct linear correlation occurred between pressor responses and shifts of general peripheral resistance, on one hand, and the degree of the blood pressure initial drop, on the other hand. The constrictor responses under study are discussed in respect to their dependence on initial tone of arterial vessels.     

Effect of dichloroacetate on lactate concentration in exercising humans

The precise mechanism responsible for the increase in plasma lactate concentration during exercise in humans is not known. We have used dichloroacetate to test the hypothesis that a limitation in pyruvate dehydrogenase activity is responsible for the rise in plasma lactate. Dichloroacetate stimulates the activity of pyruvate dehydrogenase, which is normally the regulatory enzyme in the oxidation of glucose when tissue oxygenation is adequate. Six subjects were studied twice according to a randomized, crossover protocol, involving one test with saline infusion and another with dichloroacetate infusion. Exercise load on a bicycle ergometer was increased progressively until exhaustion. Blood samples were drawn each minute throughout exercise and periodically throughout 120 min of recovery. Dichloroacetate significantly lowered the lactate concentration during exercise performed at less than 80% of the average maximal O2 consumption. The peak concentration of lactate at exhaustion was not affected by dichloroacetate treatment, but dichloroacetate did lower lactate concentration throughout recovery. These results suggest that a limitation in pyruvate dehydrogenase activity contributes to the increase in plasma lactate during submaximal exercise and recovery.     

Effect of ventilation on sodium excretion in the anesthetized dog with unilateral renal denervation

We studied if the effect of mechanical ventilation induced to keep arterial blood gas values within normal physiological limits has any influence on renal sodium excretion in anesthetized dogs (n = 17) subjected to acute unilateral renal denervation. Compared to the control and the postcontrol periods, ventilation elevated arterial pO2 from 86 +/- 5 to 96 +/- 5 mmHg and blood pH from 7.37 +/- 0.02 to 7.41 +/- 0.01 while arterial pCO2 was decreased from 38 +/- 2 to 33 +/- 1 mmHg (p less than 0.05 in all cases). Compared to the innervated kidney urine flow, urinary sodium and potassium excretion from the denervated kidney were markedly elevated both during spontaneous respiration and during mechanical ventilation but GFR and cPAH were similar on the two sides. Ventilation decreased sodium excretion by the denervated kidney from 314 +/- 26 to 252 +/- 31 mumols/min/100 g k. w. (p less than 0.05). No other excretory changes were noted either in the innervated or in the denervated kidneys. Difference in sodium excretion between innervated and denervated kidneys was decreased from 209 +/- 19 to 126 +/- 20 mumole/min/100 g k. w. (p less than 0.001), due to the ventilation induced diminution of sodium excretion from the denervated kidney. It is concluded that mechanical ventilation of anesthetized dogs modifies sodium excretion, and this phenomenon can be demonstrated only in the denervated kidney.