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

13 Citations (Scopus)

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

Fingerprint

Desoxycorticosterone Acetate
Mesenteric Arteries
Large-Conductance Calcium-Activated Potassium Channels
Adrenergic Receptors
Salts
Arteries
Isoproterenol
Cyclic AMP-Dependent Protein Kinases
Blood Vessels
Cyclooxygenase Inhibitors
Colforsin
Protein Kinase Inhibitors
Prostaglandin-Endoperoxide Synthases
Adenylyl Cyclases
Vasodilation
Nitric Oxide Synthase
Indomethacin
Carrier Proteins
Nitric Oxide
Up-Regulation

Keywords

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

ASJC Scopus subject areas

  • Pharmacology

Cite this

Impaired β-adrenoceptor-induced relaxation in small mesenteric arteries from DOCA-salt hypertensive rats is due to reduced K Ca channel activity. / Matsumoto, Takayuki; Szasz, Theodora; Tostes, Rita C.; Webb, R Clinton.

In: Pharmacological Research, Vol. 65, No. 5, 01.05.2012, p. 537-545.

Research output: Contribution to journalArticle

@article{574524b1c7cc4e7fb4a5dace0cfbda93,
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.",
keywords = "Calcium-activated potassium channel, DOCA-salt, Mesenteric artery, RACK1, Relaxation, β-Adrenoceptor",
author = "Takayuki Matsumoto and Theodora Szasz and Tostes, {Rita C.} and Webb, {R Clinton}",
year = "2012",
month = "5",
day = "1",
doi = "10.1016/j.phrs.2012.02.004",
language = "English (US)",
volume = "65",
pages = "537--545",
journal = "Pharmacological Research",
issn = "1043-6618",
publisher = "Academic Press Inc.",
number = "5",

}

TY - JOUR

T1 - Impaired β-adrenoceptor-induced relaxation in small mesenteric arteries from DOCA-salt hypertensive rats is due to reduced K Ca channel activity

AU - Matsumoto, Takayuki

AU - Szasz, Theodora

AU - Tostes, Rita C.

AU - Webb, R Clinton

PY - 2012/5/1

Y1 - 2012/5/1

N2 - 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.

AB - 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.

KW - Calcium-activated potassium channel

KW - DOCA-salt

KW - Mesenteric artery

KW - RACK1

KW - Relaxation

KW - β-Adrenoceptor

UR - http://www.scopus.com/inward/record.url?scp=84859796711&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84859796711&partnerID=8YFLogxK

U2 - 10.1016/j.phrs.2012.02.004

DO - 10.1016/j.phrs.2012.02.004

M3 - Article

C2 - 22388053

AN - SCOPUS:84859796711

VL - 65

SP - 537

EP - 545

JO - Pharmacological Research

JF - Pharmacological Research

SN - 1043-6618

IS - 5

ER -