EFFECTS OF ENDOPEPTIDASE-24.11 INHIBITION ON PLASMA AND TISSUE CONCENTRATIONS OF VASOACTIVE-INTESTINAL-PEPTIDE

1. In this study, we sought to determine the effect of endopeptidase 2 4.11 inhibition on the rate of metabolism of vasoactive intestinal pep tide. The effect of such inhibition on the concentration of vasoactive intestinal peptide in two tissues was also investigated. 2. Male Spra gue-Dawley rats were given the endopeptidase 24.11 blocker UK77,568 (1 0mg/kg) or vehicle as a single intravenous injection or as a daily inj ection for 4 days. Two hours after the final or single injection, the rats were anaesthetized and blood was sampled to determine plasma conc entrations of vasoactive intestinal peptide and angiotensin II. The he arts and kidneys were harvested and snap-frozen in liquid nitrogen. Th e plasma and tissue concentrations of vasoactive intestinal peptide an d the plasma concentration of angiotensin II were determined by radioi mmunoassay. In a separate group of experiments, male Sprague-Dawley ra ts were anaesthetized and carotid and jugular catheters were inserted. One hour after intravenous administration of UK77,568 oa vehicle, an infusion of vasoactive intestinal peptide (10 pmol min(-1) kg(-1)) was commenced via the jugular catheter. Blood was sampled to determine th e vasoactive intestinal peptide concentration Ih after commencing the vasoactive intestinal peptide infusion to calculate the metabolic clea rance rate. 3. Plasma vasoactive intestinal peptide increased after ac ute (P<0.05) but not chronic administration of UK77,568, while the con centration of vasoactive intestinal peptide in the heart increased aft er chronic administration (P<0.0005). The concentration of vasoactive intestinal peptide in the kidney was unchanged after both acute and ch ronic endopeptidase 24.11 blockade. Plasma angiotensin II decreased si gnificantly in the chronic group (P<0.05). The metabolic clearance rat e of vasoactive intestinal peptide decreased significantly after UK77, 568 administration (P<0.05). 4. These studies add to the existing indi rect evidence that endopeptidase 24.11 may metabolize vasoactive intes tinal peptide in addition to a number of other hormones.