Characterization of endothelium-derived relaxing factor involvement in the potentiating effect of parathyroidectomy on norepinephrine-induced rat aortic contraction.
Previous results have shown that the contractile response to norepinephrine (NE) was enhanced in isolated aortae from SHR and normotensive Wistar parathyroidectomized rats. In this work we sought to characterize the contribution of endothelium-derived relaxing factor (EDRF) release to this effect which is not linked to hypertension. Parathyroidectomy (PTX) was performed by surgery on 5 week-old male Wistar rats. Five weeks later intact (E+) and rubbed (E-) aortic rings were mounted in an organ chamber for isometric tension recording. KCl-induced contractions were potentiated in PTX E+ aortae compared to sham operated (SO), (P < 0.05), but not in denuded E- aortae. Similarly NE (1 nM- 10 microM) induced a potentiated contractile response in PTX E+ (P < 0.01), but not in PTX E- rings; nevertheless the sensitivity did not change. After removal of endothelium, the expected enhanced contraction and sensitivity observed in SO rats was not present in PTX. The NO synthase inhibitor L-NAME (20 microM), enhanced sensitivity to NE in SO but not in PTX E+ aortic rings. In addition, hemoglobin (Hb, 10 microM) enhanced NE contraction in SO (P < 0.01) aortic rings, but to a lesser extent in PTX rat aortae. Moreover, in the presence of L-NAME or Hb, SO and PTX aortae displayed a similar contraction. Superoxide dismutase (SOD, 150 U/ml) diminished the NE contraction since NO was protected from degradation but the difference was still present between SO and PTX rat aortae, ruling out the possible implication of superoxide anions in the hyperreactivity of PTX aortae. On the other hand, A23187, which induces EDRF release, reduced the level of NE contraction as expected, but suppressed the PTX enhancing effect and in calcium-free solution the enhancement of contraction after PTX was not observed. These experiments extend to the rat the observations previously obtained in rabbit aorta: extracellular calcium is a major determining factor in NO production. Acetylcholine and A23187 (cumulative doses) produced an endothelium-dependent relaxation which was not significantly modified in NE-pre-contracted PTX aortae compared to SO aortae. L-arginine (100 microM), reversed the L-NAME inhibitory effect and induced an attenuated endothelium-dependent relaxation in PTX vessels (P < 0.01). In conclusion, in rat isolated aortae the enhancing effect of parathyroidectomy on norepinephrine and KCl contractions is due to a diminished endothelial nitric oxide production. This might arise via a decrease of the constitutive NO synthase activity in an extracellular calcium-dependent manner.
Boulebda
N
N
CNRS URA 600, Faculté de Pharmacie, Université Louis Pasteur Strasbourg, Illkirch, France.
Gairard
A
A
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006454:Hemoglobins / Q000502:physiology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology*; D016105:Parathyroidectomy; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000494:pharmacology
D006454:Hemoglobins; D009569:Nitric Oxide; D000001:Calcimycin; D011189:Potassium Chloride; D001120:Arginine; D013482:Superoxide Dismutase; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester; D009638:Norepinephrine