saralasin and phosphoramidon

To determine the role of endothelin (ET)-ETA receptor mediation and endogenous production of endothelin-1 (ET-1) in the retinal response to hyperoxia.. Brown-Norway rats (n = 30) were injected intravitreally with an ETA receptor-selective antagonist, BQ-123, and an inhibitor of ET-converting enzyme (ECE), phosphoramidon, and were exposed to a 100% oxygen breathing mixture. Control rats underwent intravitreal injection of vehicle alone (2.5% Emulphor in phosphate-buffered saline). The retinal hemodynamic responses were analyzed using video-based fluorescein angiography (VFA) methodology. Baseline measurements were made with the animals breathing room air, and this was followed by intravitreal injections of the above agents. Subsequent VFA measurements were made after 5, 10, and 15 minutes of breathing 100% oxygen.. The 10 rats injected with vehicle alone demonstrated the expected retinal response to hyperoxia, with significant (P < 0.001) vessel constriction (18% +/- 5%), an increase in retinal mean circulation time (0.84 +/- 0.13 seconds in room air and 1.59 +/- 0.27 seconds in 100% oxygen), and a decrease in blood flow (110.7 +/- 19.2 pixel2/second in room air and 41.9 +/- 9.0 pixel2/second in 100% oxygen), compared to values measured during room air breathing. The hyperoxic response in rats (n = 9) injected with 10(-4) M BQ-123 was significantly (P < 0.001) blunted compared to the group injected with vehicle alone. In contrast, intravitreal injection of saralasin, a specific angiotensin II receptor antagonist, had no significant effect on the retinal response to hyperoxia (n = 5). Intravitreal phosphoramidon (10(-3) M, n = 6) injection also resulted in a significantly (P < 0.001) blunted circulatory response to hyperoxia compared to rats injected with vehicle alone. This blunted response after ECE inhibition was comparable to that measured after ETA receptor antagonism with BQ-123 injection.. These results demonstrate that the enhancement of ET-1 action, possibly caused by the activation of ECE, plays a primary role in regulating the retinal hemodynamic response to hyperoxia.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Aspartic Acid Endopeptidases; Blood Circulation; Blood Flow Velocity; Cells, Cultured; Endothelin Receptor Antagonists; Endothelin-Converting Enzymes; Endothelins; Endothelium, Vascular; Fluorescein Angiography; Gene Expression; Glycopeptides; Hyperoxia; Male; Metalloendopeptidases; Peptides, Cyclic; Protease Inhibitors; Rats; Rats, Inbred BN; Receptors, Angiotensin; Receptors, Endothelin; Respiration; Retinal Vessels; Saralasin; Vasoconstriction

The influence of kinins and angiotensin II on the regulation of renal cortical and papillary blood flow and sodium and water excretion was examined in rats. Superficial cortical and papillary blood flows were measured using a laser-Doppler flowmeter. Papillary blood flow increased 50% after enalaprilat (60 micrograms/kg) and phosphoramidon (5.5 micrograms.kg-1.min-1) were given along with 0.3 M sodium bicarbonate solution to inhibit degradation of kinins and enhance urinary kallikrein activity. Infusion of a kinin antagonist, D-Arg-Hyp-Thi-D-Phe-bradykinin (5 micrograms/min), returned papillary blood flow to control levels. Urine flow and sodium excretion increased after the administration of the kininase inhibitors and sodium bicarbonate, while glomerular filtration rate (GFR) and outer cortical blood flow were unaltered. The kinin antagonist did not alter sodium and water excretion in rats receiving the kininase inhibitors and bicarbonate. Administration of the kinin antagonist alone lowered papillary blood flow by 20%, without affecting outer cortical blood flow or GFR. Urine flow decreased and urine osmolality increased after the rats received the kinin antagonist, but sodium excretion remained unaltered. To assess the role of angiotensin II in the control of papillary blood flow, kinin receptors were blocked by infusion of an antagonist, and the effects of enalaprilat and saralasin were studied. Papillary blood flow increased after blockade of the angiotensin II system in rats receiving the kinin antagonist. These results indicate that the kallikrein-kinin and renin-angiotensin systems participate in the regulation of papillary blood flow.

Topics: Angiotensin II; Animals; Bicarbonates; Bradykinin; Enalapril; Glomerular Filtration Rate; Glycopeptides; Kidney Cortex; Kidney Medulla; Kinins; Male; Rats; Rats, Inbred Strains; Reference Values; Regional Blood Flow; Saralasin; Sodium; Sodium Bicarbonate