Roles of calcium-activated and voltage-gated delayed rectifier potassium channels in endothelium-dependent vasorelaxation of the rabbit middle cerebral artery

Hui Dong, Gareth J. Waldron, William C. Cole, Christopher Triggle

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

1. The cellular mechanism(s) of action of endothelium-derived vasodilator substances in the rabbit middle cerebral artery (RMCA) were investigated. Specifically, the subtypes of potassium channels involved in the effects of endothelium-derived relaxing factors (EDRFs) in acetylcholine (ACh)-induced endothelium-dependent vasorelaxation in this vessel were systematically compared. 2. In the endothelium-intact RMCA precontracted with histamine (3 μM), ACh induced a concentration-dependent vasorelaxation, which was sensitive to indomethacin (10 μM) or N(G)-nitro-L-arginine (L-NOARG; 100 μM); pD2 values 8.36 vs 7.40 and 6.38, P < 0.01 for both, n = 6 and abolished by a combination of both agents. ACh caused relaxation in the presence of high K+ PSS (40 mM KCl), which was not affected by indomethacin, but abolished by L-NOARG and a combination of indomethacin and L-NOARG. 3. In the presence of indomethacin, relaxation to ACh in the endothelium-intact RMCA precontracted with histamine was unaffected by either glibenclamide (10 μM), an ATP-sensitive K+ channel (K(ATP)) blocker, 4-aminopyridine (4-AP, 1 mM) or dendrotoxin (DTX, 0.1 μM), delayed rectifier K+ channel (K(v)) blockers. However, relaxation responses to ACh were significantly inhibited by either LY83583 (10 μM) and 1H-[l,2,4]oxadiazolo[4.3.-a]quinoxalin-1-one (ODQ, 10 μM), guanylyl cyclase inhibitors, or charybdotoxin (CTX: 0.1 μM), iberiotoxin (ITX, 0.1 μM) and apamin (APA, 0.1 μM), large conductance Ca2+-activated K+ channels (BK(Ca)) blocker and small conductance Ca2+-activated K+ channel, (SK(Ca)) blocker, respectively. 4. In the presence of L-NOARG, relaxation to ACh was unaffected by glibenclamide or the cytochrome P450 mono-oxygenase inhibitor, clotrimazole (1 μM), but was significantly inhibited by either 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ 22,536, 10 μM) and 2',3'-dideoxyadenosine (2',3'-DDA, 30 μM, adenylyl cyclase inhibitors, or 4-AP, DTX, CTX, ITX and APA. 5. In the endothelium-denuded RMCA precontracted with histamine, authentic NO-induced relaxation was unaffected by glibenclamide, 4-AP and DTX, but significantly reduced by ODQ, ITX and APA. Authentic prostaglandin I2 (PGI2)-induced relaxation was unaffected by glibenclamide, but significantly reduced by 2',3'-DDA, 4-AP, DTX, ITX and APA. Forskolin-induced relaxation was significantly inhibited by high K+, CTX and 4-AP. 6. These results indicate that: (1) in the RMCA the EDRFs released by ACh are NO and a prostanoid (presumably PGI2), and there is no evidence for the release of a non-NO/PGI2 endothelium-derived hyperpolarizing factor (EDHF), (2) K(Ca) channels are involved in NO-mediated relaxation of the RMCA but both K(Ca) and K(v) channels are involved in PGI2-mediated relaxation.

Original languageEnglish
Pages (from-to)821-832
Number of pages12
JournalBritish Journal of Pharmacology
Volume123
Issue number5
DOIs
Publication statusPublished - 1998
Externally publishedYes

Fingerprint

Delayed Rectifier Potassium Channels
Voltage-Gated Potassium Channels
Middle Cerebral Artery
Vasodilation
Acetylcholine
Endothelium
Rabbits
Calcium
Glyburide
Nitroarginine
Epoprostenol
Indomethacin
Histamine
Calcium-Activated Potassium Channels
Endothelium-Dependent Relaxing Factors
6-anilino-5,8-quinolinedione
Dideoxyadenosine
Adenosine Triphosphate
Charybdotoxin
Clotrimazole

Keywords

  • Acetylcholine
  • Adenylyl cyclase
  • Calcium-activated potassium channels
  • Cerebral arteries
  • Guanylyl cyclase
  • Nitric oxide
  • Prostacyclin
  • Vasorelaxation
  • Voltage-gated delayed rectifier potassium channels

ASJC Scopus subject areas

  • Pharmacology

Cite this

Roles of calcium-activated and voltage-gated delayed rectifier potassium channels in endothelium-dependent vasorelaxation of the rabbit middle cerebral artery. / Dong, Hui; Waldron, Gareth J.; Cole, William C.; Triggle, Christopher.

In: British Journal of Pharmacology, Vol. 123, No. 5, 1998, p. 821-832.

Research output: Contribution to journalArticle

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T1 - Roles of calcium-activated and voltage-gated delayed rectifier potassium channels in endothelium-dependent vasorelaxation of the rabbit middle cerebral artery

AU - Dong, Hui

AU - Waldron, Gareth J.

AU - Cole, William C.

AU - Triggle, Christopher

PY - 1998

Y1 - 1998

N2 - 1. The cellular mechanism(s) of action of endothelium-derived vasodilator substances in the rabbit middle cerebral artery (RMCA) were investigated. Specifically, the subtypes of potassium channels involved in the effects of endothelium-derived relaxing factors (EDRFs) in acetylcholine (ACh)-induced endothelium-dependent vasorelaxation in this vessel were systematically compared. 2. In the endothelium-intact RMCA precontracted with histamine (3 μM), ACh induced a concentration-dependent vasorelaxation, which was sensitive to indomethacin (10 μM) or N(G)-nitro-L-arginine (L-NOARG; 100 μM); pD2 values 8.36 vs 7.40 and 6.38, P < 0.01 for both, n = 6 and abolished by a combination of both agents. ACh caused relaxation in the presence of high K+ PSS (40 mM KCl), which was not affected by indomethacin, but abolished by L-NOARG and a combination of indomethacin and L-NOARG. 3. In the presence of indomethacin, relaxation to ACh in the endothelium-intact RMCA precontracted with histamine was unaffected by either glibenclamide (10 μM), an ATP-sensitive K+ channel (K(ATP)) blocker, 4-aminopyridine (4-AP, 1 mM) or dendrotoxin (DTX, 0.1 μM), delayed rectifier K+ channel (K(v)) blockers. However, relaxation responses to ACh were significantly inhibited by either LY83583 (10 μM) and 1H-[l,2,4]oxadiazolo[4.3.-a]quinoxalin-1-one (ODQ, 10 μM), guanylyl cyclase inhibitors, or charybdotoxin (CTX: 0.1 μM), iberiotoxin (ITX, 0.1 μM) and apamin (APA, 0.1 μM), large conductance Ca2+-activated K+ channels (BK(Ca)) blocker and small conductance Ca2+-activated K+ channel, (SK(Ca)) blocker, respectively. 4. In the presence of L-NOARG, relaxation to ACh was unaffected by glibenclamide or the cytochrome P450 mono-oxygenase inhibitor, clotrimazole (1 μM), but was significantly inhibited by either 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ 22,536, 10 μM) and 2',3'-dideoxyadenosine (2',3'-DDA, 30 μM, adenylyl cyclase inhibitors, or 4-AP, DTX, CTX, ITX and APA. 5. In the endothelium-denuded RMCA precontracted with histamine, authentic NO-induced relaxation was unaffected by glibenclamide, 4-AP and DTX, but significantly reduced by ODQ, ITX and APA. Authentic prostaglandin I2 (PGI2)-induced relaxation was unaffected by glibenclamide, but significantly reduced by 2',3'-DDA, 4-AP, DTX, ITX and APA. Forskolin-induced relaxation was significantly inhibited by high K+, CTX and 4-AP. 6. These results indicate that: (1) in the RMCA the EDRFs released by ACh are NO and a prostanoid (presumably PGI2), and there is no evidence for the release of a non-NO/PGI2 endothelium-derived hyperpolarizing factor (EDHF), (2) K(Ca) channels are involved in NO-mediated relaxation of the RMCA but both K(Ca) and K(v) channels are involved in PGI2-mediated relaxation.

AB - 1. The cellular mechanism(s) of action of endothelium-derived vasodilator substances in the rabbit middle cerebral artery (RMCA) were investigated. Specifically, the subtypes of potassium channels involved in the effects of endothelium-derived relaxing factors (EDRFs) in acetylcholine (ACh)-induced endothelium-dependent vasorelaxation in this vessel were systematically compared. 2. In the endothelium-intact RMCA precontracted with histamine (3 μM), ACh induced a concentration-dependent vasorelaxation, which was sensitive to indomethacin (10 μM) or N(G)-nitro-L-arginine (L-NOARG; 100 μM); pD2 values 8.36 vs 7.40 and 6.38, P < 0.01 for both, n = 6 and abolished by a combination of both agents. ACh caused relaxation in the presence of high K+ PSS (40 mM KCl), which was not affected by indomethacin, but abolished by L-NOARG and a combination of indomethacin and L-NOARG. 3. In the presence of indomethacin, relaxation to ACh in the endothelium-intact RMCA precontracted with histamine was unaffected by either glibenclamide (10 μM), an ATP-sensitive K+ channel (K(ATP)) blocker, 4-aminopyridine (4-AP, 1 mM) or dendrotoxin (DTX, 0.1 μM), delayed rectifier K+ channel (K(v)) blockers. However, relaxation responses to ACh were significantly inhibited by either LY83583 (10 μM) and 1H-[l,2,4]oxadiazolo[4.3.-a]quinoxalin-1-one (ODQ, 10 μM), guanylyl cyclase inhibitors, or charybdotoxin (CTX: 0.1 μM), iberiotoxin (ITX, 0.1 μM) and apamin (APA, 0.1 μM), large conductance Ca2+-activated K+ channels (BK(Ca)) blocker and small conductance Ca2+-activated K+ channel, (SK(Ca)) blocker, respectively. 4. In the presence of L-NOARG, relaxation to ACh was unaffected by glibenclamide or the cytochrome P450 mono-oxygenase inhibitor, clotrimazole (1 μM), but was significantly inhibited by either 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ 22,536, 10 μM) and 2',3'-dideoxyadenosine (2',3'-DDA, 30 μM, adenylyl cyclase inhibitors, or 4-AP, DTX, CTX, ITX and APA. 5. In the endothelium-denuded RMCA precontracted with histamine, authentic NO-induced relaxation was unaffected by glibenclamide, 4-AP and DTX, but significantly reduced by ODQ, ITX and APA. Authentic prostaglandin I2 (PGI2)-induced relaxation was unaffected by glibenclamide, but significantly reduced by 2',3'-DDA, 4-AP, DTX, ITX and APA. Forskolin-induced relaxation was significantly inhibited by high K+, CTX and 4-AP. 6. These results indicate that: (1) in the RMCA the EDRFs released by ACh are NO and a prostanoid (presumably PGI2), and there is no evidence for the release of a non-NO/PGI2 endothelium-derived hyperpolarizing factor (EDHF), (2) K(Ca) channels are involved in NO-mediated relaxation of the RMCA but both K(Ca) and K(v) channels are involved in PGI2-mediated relaxation.

KW - Acetylcholine

KW - Adenylyl cyclase

KW - Calcium-activated potassium channels

KW - Cerebral arteries

KW - Guanylyl cyclase

KW - Nitric oxide

KW - Prostacyclin

KW - Vasorelaxation

KW - Voltage-gated delayed rectifier potassium channels

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