L-canavanine, an inhibitor of inducible nitric oxide synthase, improves venous return in endotoxemic rats.

Abstract

OBJECTIVE:

To investigate the hemodynamic effects of L-canavanine (an inhibitor of inducible, but not of constitutive, nitric oxide synthase) in endotoxic shock.

DESIGN:

Controlled, randomized, experimental study.

SETTING:

Animal laboratory.

SUBJECTS:

Wistar rats.

INTERVENTIONS:

Rats were anesthetized with pentobarbital, and hemodynamically monitored. One hour after an intravenous challenge with 5 mg/kg of Escherichia coli endotoxin, the rats were randomized to receive a continuous infusion of either L-canavanine (20 mg/kg/hr; n = 8) or vehicle only (isotonic saline, n = 11). In all animals, the infusion was given over 5 hrs at a rate of 2 mL/kg/hr. These experiments were repeated in additional rats challenged with isotonic saline instead of endotoxin (sham experiments).

MEASUREMENTS AND MAIN RESULTS:

Arterial blood pressure, heart rate, thermodilution cardiac output, central venous pressure, mean systemic filling pressure, urine output, arterial blood gases, blood lactate concentration, and hematocrit were measured. In sham experiments, hemodynamic stability was maintained throughout and L-canavanine had no detectable effect. Animals challenged with endotoxin and not treated with L-canavanine developed progressive hypotension and low cardiac output. After 6 hrs of endotoxemia, both central venous pressure and mean systemic filling pressure were significantly below their baseline values, indicating relative hypovolemia as the main determinant of reduced cardiac output. In endotoxemic animals treated with L-canavanine, hypotension was less marked, while cardiac output, central venous pressure, and mean systemic filling pressure were maintained throughout the experiment. L-canavanine had no effect on the time-course of hematocrit. L-canavanine significantly increased urine output and reduced the severity of lactic acidosis.

CONCLUSIONS:

Six hours after an endotoxin challenge in rats, low cardiac output develops, which appears to be primarily related to relative hypovolemia. L-canavanine, a selective inhibitor of the inducible nitric oxide synthase, increases the mean systemic filling pressure, thereby improving venous return, under these conditions.

• Authors: D Fishman, L Liaudet, R Lazor, C H Perret, F Feihl
• Journal: Critical care medicine (Crit Care Med) Vol. 25 Issue 3 Pg. 469-75 (Mar 1997) ISSN: 0090-3493 [Print] United States
• PMID: 9118664 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Canavanine
• Nitric Oxide Synthase

Topics

• Animals
• Blood Pressure (drug effects)
• Canavanine (therapeutic use)
• Cardiac Output (drug effects)
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Endotoxemia (drug therapy, physiopathology)
• Escherichia coli Infections (drug therapy, physiopathology)
• Male
• Nitric Oxide Synthase (antagonists & inhibitors)
• Random Allocation
• Rats
• Rats, Wistar