Endothelium-derived hyperpolarizing factor determines resting and stimulated forearm vasodilator tone in health and in disease

Muhiddin A. Ozkor, Jonathan R Murrow, Ayaz M. Rahman, Nino Kavtaradze, Ji Lin, Amita Manatunga, Arshed A. Quyyumi

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Background-: We assessed the contribution of endothelium-derived hyperpolarizing factors to resting and agonist-stimulated vasodilator tone in health and disease. Tetraethylammonium chloride (TEA) was used to inhibit KCa channel activation and fluconazole was used to inhibit cytochrome P450 2C9-mediated epoxyeicosatrienoic acid synthesis. We hypothesized that endothelium-derived hyperpolarizing factors contribute to resting vascular tone by KCa channel activation and epoxyeicosatrienoic acid release and that endothelium-derived hyperpolarizing factors compensate for reduced nitric oxide bioavailability at rest and with endothelium-dependent vasodilators. Methods and results-: In 103 healthy subjects and 71 nonhypertensive subjects with multiple risk factors, we measured resting forearm blood flow (FBF) using venous occlusion plethysmography before and after intra-arterial infusions of N-monomethyl-L-arginine (L-NMMA), TEA, fluconazole, and their combination. The effects of these antagonists on resting FBF and on bradykinin- and acetylcholine-mediated vasodilation were studied. Resting FBF decreased with TEA and L-NMMA in all subjects (P<0.001); however, the vasoconstrictor response to L-NMMA was greater (P=0.04) and to TEA was lower (P=0.04) in healthy subjects compared with those with risk factors. Fluconazole decreased resting FBF in all subjects, and the addition of TEA further reduced FBF after fluconazole, suggesting that cytochrome P450 metabolites and other hyperpolarizing factor(s) activate KCa channels. Both L-NMMA and TEA attenuated bradykinin-mediated vasodilation in healthy and hypercholesterolemic subjects (P<0.001). In contrast, acetylcholine-mediated vasodilation remained unchanged with TEA in healthy subjects but was significantly attenuated in hypercholesterolemia (P<0.04). Conclusions-: First, by activating TEA-inhibitable KCa channels, endothelium-derived hyperpolarizing factors, together with nitric oxide, contribute to resting microvascular dilator tone. The contribution of KCa channel activation compared with nitric oxide is greater in those with multiple risk factors compared with healthy subjects. Second, activation of KCa channels is only partly through epoxyeicosatrienoic acid release, indicating the presence of other hyperpolarizing mechanisms. Third, bradykinin, but not acetylcholine, stimulates KCa channel-mediated vasodilation in healthy subjects, whereas in hypercholesterolemia, KCa channel-mediated vasodilation compensates for the reduced nitric oxide activity. Thus, enhanced endothelium-derived hyperpolarizing factor activity in conditions of nitric oxide deficiency contributes to maintenance of resting and agonist-stimulated vasodilation.

Original languageEnglish (US)
Pages (from-to)2244-2253
Number of pages10
JournalCirculation
Volume123
Issue number20
DOIs
StatePublished - May 24 2011

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Tetraethylammonium
Vasodilator Agents
Forearm
Endothelium
Vasodilation
omega-N-Methylarginine
Healthy Volunteers
Fluconazole
Health
Nitric Oxide
Bradykinin
Acetylcholine
Hypercholesterolemia
Cytochrome P-450 Enzyme System
Acids
Endothelium-Dependent Relaxing Factors
Intra Arterial Infusions
Plethysmography
Vasoconstrictor Agents
Biological Availability

Keywords

  • endothelium
  • endothelium-derived vasoconstrictor factors
  • nitric oxide
  • vasodilation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Endothelium-derived hyperpolarizing factor determines resting and stimulated forearm vasodilator tone in health and in disease. / Ozkor, Muhiddin A.; Murrow, Jonathan R; Rahman, Ayaz M.; Kavtaradze, Nino; Lin, Ji; Manatunga, Amita; Quyyumi, Arshed A.

In: Circulation, Vol. 123, No. 20, 24.05.2011, p. 2244-2253.

Research output: Contribution to journalArticle

Ozkor, Muhiddin A. ; Murrow, Jonathan R ; Rahman, Ayaz M. ; Kavtaradze, Nino ; Lin, Ji ; Manatunga, Amita ; Quyyumi, Arshed A. / Endothelium-derived hyperpolarizing factor determines resting and stimulated forearm vasodilator tone in health and in disease. In: Circulation. 2011 ; Vol. 123, No. 20. pp. 2244-2253.
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T1 - Endothelium-derived hyperpolarizing factor determines resting and stimulated forearm vasodilator tone in health and in disease

AU - Ozkor, Muhiddin A.

AU - Murrow, Jonathan R

AU - Rahman, Ayaz M.

AU - Kavtaradze, Nino

AU - Lin, Ji

AU - Manatunga, Amita

AU - Quyyumi, Arshed A.

PY - 2011/5/24

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N2 - Background-: We assessed the contribution of endothelium-derived hyperpolarizing factors to resting and agonist-stimulated vasodilator tone in health and disease. Tetraethylammonium chloride (TEA) was used to inhibit KCa channel activation and fluconazole was used to inhibit cytochrome P450 2C9-mediated epoxyeicosatrienoic acid synthesis. We hypothesized that endothelium-derived hyperpolarizing factors contribute to resting vascular tone by KCa channel activation and epoxyeicosatrienoic acid release and that endothelium-derived hyperpolarizing factors compensate for reduced nitric oxide bioavailability at rest and with endothelium-dependent vasodilators. Methods and results-: In 103 healthy subjects and 71 nonhypertensive subjects with multiple risk factors, we measured resting forearm blood flow (FBF) using venous occlusion plethysmography before and after intra-arterial infusions of N-monomethyl-L-arginine (L-NMMA), TEA, fluconazole, and their combination. The effects of these antagonists on resting FBF and on bradykinin- and acetylcholine-mediated vasodilation were studied. Resting FBF decreased with TEA and L-NMMA in all subjects (P<0.001); however, the vasoconstrictor response to L-NMMA was greater (P=0.04) and to TEA was lower (P=0.04) in healthy subjects compared with those with risk factors. Fluconazole decreased resting FBF in all subjects, and the addition of TEA further reduced FBF after fluconazole, suggesting that cytochrome P450 metabolites and other hyperpolarizing factor(s) activate KCa channels. Both L-NMMA and TEA attenuated bradykinin-mediated vasodilation in healthy and hypercholesterolemic subjects (P<0.001). In contrast, acetylcholine-mediated vasodilation remained unchanged with TEA in healthy subjects but was significantly attenuated in hypercholesterolemia (P<0.04). Conclusions-: First, by activating TEA-inhibitable KCa channels, endothelium-derived hyperpolarizing factors, together with nitric oxide, contribute to resting microvascular dilator tone. The contribution of KCa channel activation compared with nitric oxide is greater in those with multiple risk factors compared with healthy subjects. Second, activation of KCa channels is only partly through epoxyeicosatrienoic acid release, indicating the presence of other hyperpolarizing mechanisms. Third, bradykinin, but not acetylcholine, stimulates KCa channel-mediated vasodilation in healthy subjects, whereas in hypercholesterolemia, KCa channel-mediated vasodilation compensates for the reduced nitric oxide activity. Thus, enhanced endothelium-derived hyperpolarizing factor activity in conditions of nitric oxide deficiency contributes to maintenance of resting and agonist-stimulated vasodilation.

AB - Background-: We assessed the contribution of endothelium-derived hyperpolarizing factors to resting and agonist-stimulated vasodilator tone in health and disease. Tetraethylammonium chloride (TEA) was used to inhibit KCa channel activation and fluconazole was used to inhibit cytochrome P450 2C9-mediated epoxyeicosatrienoic acid synthesis. We hypothesized that endothelium-derived hyperpolarizing factors contribute to resting vascular tone by KCa channel activation and epoxyeicosatrienoic acid release and that endothelium-derived hyperpolarizing factors compensate for reduced nitric oxide bioavailability at rest and with endothelium-dependent vasodilators. Methods and results-: In 103 healthy subjects and 71 nonhypertensive subjects with multiple risk factors, we measured resting forearm blood flow (FBF) using venous occlusion plethysmography before and after intra-arterial infusions of N-monomethyl-L-arginine (L-NMMA), TEA, fluconazole, and their combination. The effects of these antagonists on resting FBF and on bradykinin- and acetylcholine-mediated vasodilation were studied. Resting FBF decreased with TEA and L-NMMA in all subjects (P<0.001); however, the vasoconstrictor response to L-NMMA was greater (P=0.04) and to TEA was lower (P=0.04) in healthy subjects compared with those with risk factors. Fluconazole decreased resting FBF in all subjects, and the addition of TEA further reduced FBF after fluconazole, suggesting that cytochrome P450 metabolites and other hyperpolarizing factor(s) activate KCa channels. Both L-NMMA and TEA attenuated bradykinin-mediated vasodilation in healthy and hypercholesterolemic subjects (P<0.001). In contrast, acetylcholine-mediated vasodilation remained unchanged with TEA in healthy subjects but was significantly attenuated in hypercholesterolemia (P<0.04). Conclusions-: First, by activating TEA-inhibitable KCa channels, endothelium-derived hyperpolarizing factors, together with nitric oxide, contribute to resting microvascular dilator tone. The contribution of KCa channel activation compared with nitric oxide is greater in those with multiple risk factors compared with healthy subjects. Second, activation of KCa channels is only partly through epoxyeicosatrienoic acid release, indicating the presence of other hyperpolarizing mechanisms. Third, bradykinin, but not acetylcholine, stimulates KCa channel-mediated vasodilation in healthy subjects, whereas in hypercholesterolemia, KCa channel-mediated vasodilation compensates for the reduced nitric oxide activity. Thus, enhanced endothelium-derived hyperpolarizing factor activity in conditions of nitric oxide deficiency contributes to maintenance of resting and agonist-stimulated vasodilation.

KW - endothelium

KW - endothelium-derived vasoconstrictor factors

KW - nitric oxide

KW - vasodilation

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