Quantitative changes in pharmacodynamic parameters of noradrenaline in different rat aorta preparations: influence of endogenous EDRF.
1. The aim of the present study was to assess the role of endothelial cells in the modulation of vasocontractile responses to noradrenaline in rat isolated aorta when cut as standard helical strips or as ring segments. 2. Noradrenaline-potency in helical strip preparations evaluated as -logEC50 was greater than that obtained in endothelium-intact ring preparations (9.45 +/- 0.28 versus 8.69 +/- 0.09, respectively) (P < 0.05). The maximum contractile response of helical strips was significantly higher than the response of ring preparations (P < 0.05). 3. Subsequent experiments were performed on helical strips and ring preparations where the endothelium was removed by rubbing the luminal surface of the aorta with filter paper. Removal of the endothelium potentiated the noradrenaline-induced contraction in ring preparations, but not in the helical strips. 4. The nitric oxide synthase inhibitors L-NAME (3 x 10(-5)-3 x 10(-4) M) or L-NNA (1 x 10(4)-3 x 10(-4) M) which were added to the tissue bath potentiated the noradrenaline-induced contraction in the endothelium-intact ring preparations, although only L-NNA induced a statistically significant potentiation. Both L-NAME and L-NNA had no effect on the noradrenaline-contraction induced in rings without endothelium, or in helical strips with or without endothelium. 5. Vascular acetylcholine-induced relaxation is dependent on endothelium derived relaxing factor (nitric oxide). Acetylcholine (10(-9)-10(-6) M) induced a concentration-dependent relaxation in noradrenaline preconstricted intact rings. The relaxant response was strongly reduced by L-NAME (3 x 10(-5)-1 x 10(-4) M). The relaxant response to acetylcholine was very weak in ring and helical strip preparations without endothelium, but also, surprisingly, in unrubbed standard helical strips. 6. The present results suggest that the endothelium of standard helical strip preparations may be greatly damaged, a view confirmed by morphological studies. The structural and functional damage of the endothelium induced very important changes in pharmacodynamic parameters such as in the potency and the maximal responses of vascular preparations to noradrenaline. Therefore, caution must be observed when the potency and intrinsic activity of agonists evaluated on different preparations are compared, even if these come from the same vascular segment.
Zonta
F
F
Institute of Pharmacology, University of Pavia, Italy.
Barbieri
A
A
Reguzzoni
M
M
Calligaro
A
A
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000648:ultrastructure; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008854:Microscopy, Electron; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D014662:Vasoconstrictor Agents; D019335:Nitroarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester; D009638:Norepinephrine