Hemin, a carbon monoxide donor, improves systemic vascular compliance by inhibiting the RhoA-Rhokinase pathway in spontaneous hypertensive rats.
Carbon monoxide donors have nitrite oxide vasorelaxant properties. We performed this study in order to determine the impact of Hemin on smooth muscle layer vasoreactivity in spontaneous hypertensive rats as compared to control Wistar rats. Twenty-one days of peritoneal administration of Hemin decreased the mean arterial blood pressure in spontaneous hypertensive rats (150+/-5 mmHg in spontaneous hypertensive rats treated with Hemin=30 vs. 166+/-6 mmHg in spontaneous control n=30, P<0.05). The passive relaxation of isolated aortic rings after the initial stretch was more important in spontaneous hypertensive treated with Hemin as compared to spontaneous hypertensive treated by Hemin and decreased the maximal contractile force induced by phenylephrine in Wistar aortic rings (C, n=10; H, n=10) although EC(50) values remained unchanged. In spontaneous hypertensive rats, contractile force was impaired in control rats and increased slightly with Hemin treatment. Global potassium channels were decreased in spontaneous hypertensive rats treated with Hemin and this decrease was predominant on Kv channels sensitive current attested by a patch clamp and confirmed by a reduced Kv 1.5 protein expression. On the other hand, the relaxation of the precontracted aortic ring induced by Y27632, an inhibitor of Rhokinase activity, was altered with Hemin. In Wistar rats, the magnitude of relaxation by Y27632 at 310(-7)M was 30% in Hemin-treated rats and 40% in control rats (P>0.05), when expressed as the amplitude of the 80 mM KCl-solution-induced contraction. At the same concentration, the relaxation induced by Y27632 was 115% in spontaneous hypertensive rats -C and 90% in spontaneous hypertensive rats -H (P<0.05). Moreover, western blotting showed that Hemin treatment decreased the amount of the active form of GTP-RhoA but the total RhoA remained unchanged.
Awede
Bonaventure
B
LAB.P.ART.-EA3852, Faculty of Medicine, University of Tours, 10 bis boulevard Tonnellé, 37032 Tours, France.
Lemaire
Marie-Chistine
MC
Hyvelin
Jean-Marc
JM
Halimi
Jean-Michel
JM
Bonnet
Pierre
P
Eder
Veronique
V
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D001808:Blood Vessels / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002248:Carbon Monoxide / Q000737:chemistry*; D005786:Gene Expression Regulation / Q000187:drug effects; D006427:Hemin / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D015221:Potassium Channels / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D015221:Potassium Channels; D006427:Hemin; D002248:Carbon Monoxide; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein