dihydroergotoxine and Shock--Septic

Catecholamine therapy is often ineffective in reversing the peripheral vasodilatation and hypotension of septic shock. This suggests that catecholamines might not be able to activate alpha 1-adrenergic receptors to cause vasoconstriction. Despite elevations in endogenous catecholamines, hypoglycemia is also a complication of human sepsis, suggesting that among many other causes, hepatic alpha 1-receptors might be altered. To better understand the pathophysiologic basis for this pharmacologic dilemma, we studied the effect of experimental sepsis on alpha 1-adrenergic receptors in hepatic tissue, a rich source of alpha 1-receptors, from septic and control Sprague-Dawley rats. alpha 1-adrenergic receptors were measured with [3H]-prazosin and data analyzed by a computerized nonlinear least-square regression algorithm. Twenty-four hours following cecal ligation with puncture, a decreased number of alpha 1-adrenergic receptors was noted in crude and purified plasma membrane fractions (23 and 40% reductions respectively) from septic animals. No changes in either agonist or antagonist affinity for receptors from septic animals were noted. These data indicate that the catecholamine refractoriness seen in septic shock may be a result of alterations in alpha 1-adrenergic receptor number or receptor-effector coupling.

Topics: Animals; Bacterial Infections; Chronic Disease; Dihydroergotoxine; Disease Models, Animal; Glucose; Guanylyl Imidodiphosphate; In Vitro Techniques; Kinetics; Liver; Male; Prazosin; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Shock, Septic; Tritium

The effects of endotoxin administration on alpha-adrenergic receptors in dog liver plasma membranes were studied using [3H]dihydroergocryptine as a radioactive ligand. The Scatchard analysis revealed a two-component binding characteristic both in control and endotoxin-injected dogs. The Kd (dissociation constant) of the high-affinity component was increased by 32.5% (0.4 +/- 0.04 nM for control vs 0.53 +/- 0.06 nM for endotoxic; P less than 0.05) with no significant change in the Kd for the low-affinity component (3.0 +/- 0.44 nM for control vs 3.4 +/- 0.44 nM for endotoxic) 2 hr following endotoxin administration. The maximum binding capacity of the high-affinity component was decreased by 38.1% (460 +/- 19.3 and 285 +/- 14.8 fmole/mg protein for control and endotoxic, respectively; P less than 0.01) and that of the low-affinity component was decreased by 34.2% (1050 +/- 66.4 and 690 +/- 44.6 fmole/mg protein for control and endotoxic, respectively; P less than 0.05) 2 hr after endotoxin injection. The competitive inhibition studies show that the apparent Kd values for (-)-epinephrine, (-)-norepinephrine, and prazosin were increased 15, 13, and 25 times, respectively, with no significant change in the apparent Kd values for yohimbine or phentolamine 2 hr postendotoxin. These data demonstrate that the binding affinity of the high-affinity component and the number of alpha-adrenergic receptor binding sites were decreased in endotoxic shock. A modification of the alpha-adrenergic receptors in dog livers induced by endotoxin administration may play an important role in the development of hepatic glucose dyshomeostasis during shock.

Topics: Animals; Binding, Competitive; Cell Membrane; Dihydroergotoxine; Endotoxins; Female; Liver; Male; Receptors, Adrenergic; Receptors, Adrenergic, alpha; Shock, Septic

Shock is to define by clinical symptoms, measurable haemodynamic and metabolic changes, clotting failure and disorders of fluid, electrolyte and acid-base balance. It is essential to remove hypovolemia, acidosis, cardiovascular failure, pulmonary and renal insufficiency. Quite a lot of proved and controversial pharmacological substances are placed at physician's disposal. However, the mortality of cardiogenic shock and gram-negative septic shock is more than 80% respectively 30%, often caused by shock lung or irreversible injury to the kidneys. Shock due to depletion of extracellular fluid, poisoning and acute pancreatitis require specific treatment.

Topics: Bicarbonates; Dehydration; Dihydroergotoxine; Furosemide; Glucagon; Humans; Methylprednisolone; Peritoneal Dialysis; Plasma Substitutes; Shock; Shock, Cardiogenic; Shock, Septic; Spironolactone; Sympathomimetics; Theophylline