Impaired β-adrenoceptor-induced relaxation in small mesenteric arteries from DOCA-salt hypertensive rats is due to reduced K Ca channel activity

Takayuki Matsumoto, Theodora Szasz, Rita C. Tostes, R Clinton Webb

Research output: Contribution to journalArticle

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)537-545
Number of pages9
JournalPharmacological Research
Volume65
Issue number5
DOIs
StatePublished - May 1 2012

Keywords

  • Calcium-activated potassium channel
  • DOCA-salt
  • Mesenteric artery
  • RACK1
  • Relaxation
  • β-Adrenoceptor

ASJC Scopus subject areas

  • Pharmacology

Fingerprint Dive into the research topics of 'Impaired β-adrenoceptor-induced relaxation in small mesenteric arteries from DOCA-salt hypertensive rats is due to reduced K <sub>Ca</sub> channel activity'. Together they form a unique fingerprint.

  • Cite this