Effect of Valsartan on Cerebellar Adrenomedullin System Dysregulation During Hypertension.
Adrenomedullin (AM) and its receptors components, calcitonin-receptor-like receptor (CRLR), and receptor activity-modifying protein (RAMP1, RAMP2, and RAMP3) are expressed in cerebellum. Cerebellar AM, AM binding sites and receptor components are altered during hypertension, suggesting a role for cerebellar AM in blood pressure regulation. Thus, we assessed the effect of valsartan, on AM and its receptor components expression in the cerebellar vermis of Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Additionally, we evaluated AM action on superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activity, and thiobarbituric acid reactive substances (TBARS) production in cerebellar vermis. Animals were treated with valsartan or vehicle for 11 days. Rats were sacrificed by decapitation; cerebellar vermis was dissected; and AM, CRLR, RAMP1, RAMP2, and RAMP3 expression was quantified by Western blot analysis. CAT, SOD, and GPx activity was determined spectrophotometrically and blood pressure by non-invasive plethysmography. We demonstrate that AM and RAMP2 expression was lower in cerebellum of SHR rats, while CRLR, RAMP1, and RAMP3 expression was higher than those of WKY rats. AM reduced cerebellar CAT, SOD, GPx activities, and TBARS production in WKY rats, but not in SHR rats. Valsartan reduced blood pressure and reversed the altered expression of AM and its receptors components, as well the loss of AM capacity to reduce antioxidant enzyme activity and TBARS production in SHR rats. These findings demonstrate that valsartan is able to reverse the dysregulation of cerebellar adrenomedullinergic system; and they suggest that altered AM system in the cerebellum could represent the primary abnormality leading to hypertension.
School of Pharmacy, Laboratory of Neuropeptides, Universidad Central de Venezuela, Santa Rosa de Lima, Las Mesetas, Calle La Cima, Res. Mara, Apto 82, Caracas, Venezuela.
Leticia
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Figueira
School of Pharmacy, Laboratory of Neuropeptides, Universidad Central de Venezuela, Santa Rosa de Lima, Las Mesetas, Calle La Cima, Res. Mara, Apto 82, Caracas, Venezuela. astern88@gmail.com.
Anita
A
Israel
D053607:Adrenomedullin / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D002374:Catalase / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D005979:Glutathione Peroxidase / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D011897:Random Allocation; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D058262:Receptor Activity-Modifying Protein 1 / Q000378:metabolism; D058263:Receptor Activity-Modifying Protein 2 / Q000378:metabolism; D058264:Receptor Activity-Modifying Protein 3 / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D000068756:Valsartan / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; C545508:Ramp1 protein, rat; C545509:Ramp2 protein, rat; C545510:Ramp3 protein, rat; D058262:Receptor Activity-Modifying Protein 1; D058263:Receptor Activity-Modifying Protein 2; D058264:Receptor Activity-Modifying Protein 3; D017392:Thiobarbituric Acid Reactive Substances; D053607:Adrenomedullin; D000068756:Valsartan; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase
Adrenomedullin; CRLR; Cerebellum; Dysregulation; Hypertension; RAMPs; Valsartan; Vermis