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 language | English (US) |
|---|---|
| Pages (from-to) | 537-545 |
| Number of pages | 9 |
| Journal | Pharmacological Research |
| Volume | 65 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 1 2012 |
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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 journal › Article
}
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 -