title: Impaired β-adrenoceptor-induced relaxation in small mesenteric arteries from DOCA-salt hypertensive rats is due to reduced K(Ca) channel activity.
abstract: β-Adrenoceptor (β-AR)-mediated relaxation plays an important role in the regulation of vascular tone. β-AR-mediated vascular relaxation is reduced in various disease states and aging. We hypothesized that β-AR-mediated vasodilatation is impaired in DOCA-salt hypertension due to alterations in the cAMP pathway. β-AR-mediated relaxation was determined in small mesenteric arteries from DOCA-salt hypertensive and control uninephrectomized (Uni) rats. To exclude nitric oxide (NO) and cyclooxygenase (COX) pathways, relaxation responses were determined in the presence of l-NNA and indomethacin, NO synthase inhibitor and COX inhibitors, respectively. Isoprenaline (ISO)-induced relaxation was reduced in arteries from DOCA-salt compared to Uni rats. Protein kinase A (PKA) inhibitors (H89 or Rp-cAMPS) or adenylyl cyclase inhibitor (SQ22536) did not abolish the difference in ISO-induced relaxation between the groups. Forskolin (adenylyl cyclase activator)-induced relaxation was similar between the groups. The inhibition of IK(Ca)/SK(Ca) channels (TRAM-34 plus UCL1684) or BK(Ca) channels (iberiotoxin) reduced ISO-induced relaxation only in Uni rats and abolished the relaxation differences between the groups. The expression of SK(Ca) channel was decreased in DOCA-salt arteries. The expression of BK(Ca) channel α subunit was increased whereas the expression of BK(Ca) channel β subunit was decreased in DOCA-salt arteries. The expression of receptor for activated C kinase 1 (RACK1), which is a binding protein for BK(Ca) channel and negatively modulates its activity, was increased in DOCA-salt arteries. These results suggest that the impairment of β-AR-mediated relaxation in DOCA-salt mesenteric arteries may be attributable to altered IK(Ca)/SK(Ca) and/or BK(Ca) channels activities rather than cAMP/PKA pathway. Impaired β-AR-stimulated BK(Ca) channel activity may be due to the imbalance between its subunit expressions and RACK1 upregulation.
authors.affiliation: Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan. t-matsu@hoshi.ac.jp
authors.forename: Takayuki
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Theodora
authors.initials: T
authors.lastname: Szasz
authors.forename: Rita C
authors.initials: RC
authors.lastname: Tostes
authors.forename: R Clinton
authors.initials: RC
authors.lastname: Webb
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000473:Alkanes / Q000494:pharmacology; D000818:Animals; D003900:Desoxycorticosterone / Q000633:toxicity; D019204:GTP-Binding Proteins / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000503:physiopathology; D010455:Peptides / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D011806:Quinolinium Compounds / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000075370:Receptors for Activated C Kinase; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D012965:Sodium Chloride / Q000633:toxicity; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: C110349:6,10-diaza-3(1,3),8(1,4)dibenzena-1,5(1,4)diquinolinacyclodecaphane; D000318:Adrenergic beta-Agonists; D000473:Alkanes; D010455:Peptides; D024681:Potassium Channels, Calcium-Activated; D011720:Pyrazoles; D011806:Quinolinium Compounds; C550931:RACK1 protein, rat; D000075370:Receptors for Activated C Kinase; D011943:Receptors, Adrenergic, beta; C411671:TRAM 34; D003900:Desoxycorticosterone; D012965:Sodium Chloride; C064719:iberiotoxin; D019204:GTP-Binding Proteins; D007545:Isoproterenol