Role of angiotensin I and glucagon in canine endotoxin shock: effect of converting enzyme inhibitor and prior immunization.
he intermediate and latter stages of canine endotoxin shock are characterized by a progressive decrease in cardiac output, increase in total peripheral resistance, and hypoglycemia. We have hypothesized that the renin-angiotensin system and glucagon may mediate the loss of cardiovascular and glucose homeostasis. E. Coli endotoxin shock (1 mg/kg; 055:B5) was induced in three groups of dogs and systemic hemodynamics, angiotensin I activity, and glucagon were monitored for 5 hr; endotoxin shock (n = 13); endotoxin shock + prior immunization with J5 mutant of E coli 0111 (n = 5); Endotoxin + captopril (20 micrograms/kg/hr; n = 9); and sham-operated time-matched controls (n = 8). Thirty minutes postshock, angiotensin I and glucagon began to increase. Angiotensin I activity reached a peak at 60 min postendotoxin (90 +/- 25 vs 5 +/- ng/ml/hr; p less than 0.001) and plateaued. Increased glucagon levels plateaued at 3.5 hr postshock (1500 +/- 200 vs 155 +/- 77 pg/ml; p less than 0.001). Cardiac output began to progressively decrease, total peripheral resistance began to increase, and persistent hypoglycemia developed at 3 hr postshock. Captopril inhibited the increase in total peripheral resistance and had no effect on the decrease in cardiac output or the hypoglycemia. The initial glucagon response was attenuated but there was no difference at 5 hr (950 +/- 150 vs 1200 +/- 200 pg/ml). Prior immunization significantly preserved cardiac output, total peripheral resistance, plasma glucose levels, glucagon levels, and angiotensin I activity. It is concluded that 1) the renin-angiotensin system is a physiologic and not a pathophysiologic compensatory mechanism during the course of endotoxin shock and that inhibition of this system is deleterious; 2) glucagon may serve as an important mediator of both the myocardial dysfunction and glucose dyshomeostasis of endotoxin shock; and 3) immunological inhibition of the initial phase of endotoxin shock significantly preserves cardiovascular and glucose homeostasis and adds support to the concept that the initial vascular phase of endotoxin shock plays a primary role in determining the severity of the endotoxin/septic shock syndrome.
D000803:Angiotensin I / Q000502:physiology*; D000806:Angiotensin-Converting Enzyme Inhibitors; D000809:Angiotensins / Q000502:physiology*; D000818:Animals; D001786:Blood Glucose / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology*; D002302:Cardiac Output / Q000187:drug effects; D004285:Dogs; D004731:Endotoxins / Q000276:immunology / Q000494:pharmacology*; D004926:Escherichia coli; D005260:Female; D005934:Glucagon / Q000502:physiology*; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D011392:Proline / Q000031:analogs & derivatives*; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System; D012772:Shock, Septic / Q000276:immunology / Q000503:physiopathology*; D014655:Vascular Resistance / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D000809:Angiotensins; D001786:Blood Glucose; D004731:Endotoxins; D005934:Glucagon; D000803:Angiotensin I; D011392:Proline; D002216:Captopril; D012083:Renin