PMID- 9734472
OWN - NLM
STAT- MEDLINE
DCOM- 19980924
LR  - 20190706
IS  - 0009-7330 (Print)
IS  - 0009-7330 (Linking)
VI  - 83
IP  - 5
DP  - 1998 Sep 7
TI  - Human coronary arteriolar dilation to arachidonic acid depends on cytochrome 
      P-450 monooxygenase and Ca2+-activated K+ channels.
PG  - 501-7
AB  - Endothelium-dependent hyperpolarization of vascular smooth muscle cells (VSMCs) 
      plays a crucial role in regulating vascular tone, especially in resistance 
      vessels. It has been proposed that metabolites of arachidonic acid (AA), formed 
      by cytochrome P-450 monooxygenase (P450), are endothelium-derived hyperpolarizing 
      factors (EDHFs). These metabolites have been reported to mediate dilation to 
      endogenous vasoactive compounds, such as bradykinin and acetylcholine. However, 
      it is not known whether these metabolites of AA contribute to dilation of human 
      resistance vessels. This is important since it has been proposed that EDHF serves 
      as a compensatory mechanism to maintain dilation in disease states. Therefore, we 
      studied the effect of AA on vessel diameter and VSMC membrane potential in 
      isolated human coronary microvessels. Arterioles (81+/-5 microm, n=70) were 
      dissected from right atrial appendages at the time of cardiac surgery and 
      cannulated at a distending pressure of 60 mm Hg and zero flow. Changes in 
      internal diameter were recorded with videomicroscopy. Some vessels were impaled 
      with glass microelectrodes to measure membrane potential of VSMCs while internal 
      diameters were simultaneously recorded. After constriction (47+/-2%) with 
      endothelin-1, AA (10(-10)to 10(-5)mol/L) induced substantial dilation of human 
      coronary microvessels, which was abolished by removal of the endothelium. 
      Treatment with 17-octadecynoic acid (17-ODYA, 10(-5) mol/L; a P450 inhibitor) 
      attenuated maximal dilation to AA (49+/-9% versus 91+/-4% [control]; P<0.05 
      versus control), whereas indomethacin (INDO, 10(-5) mol/L; a cyclooxygenase 
      inhibitor) and N omega-nitro-L-arginine methyl ester (L-NAME, 10(-4) mol/L; a NO 
      synthase inhibitor) were without effect. Both 17-ODYA and miconazole (10(-5) 
      mol/L, a chemically distinct P450 inhibitor) further reduced the dilation to AA 
      in the presence of INDO. The presence of 40 mmol/L KCl or charybdotoxin (10(-8) 
      mol/L, a blocker of large-conductance Ca2+-activated K+ channels) impaired 
      dilation to AA (19+/-9% [KCI] versus 76+/-5% [control] and 47+/-6% 
      [charybdotoxin] versus 91+/-3% [control]; P<0.05 for both). After depolarization 
      with endothelin-1 (-26+/-1 mV from -48+/-3 mV [before endothelin]), AA 
      (10(-5)mol/L) in the presence of INDO and L-NAME induced hyperpolarization of 
      VSMCs (-57+/-5 mV). In the presence of 17-ODYA together with INDO and L-NAME, 
      endothelin produced similar depolarization (-26+/-2 mV from - 48+/- 3 mV), but 
      hyperpolarization to AA was reduced (-33+/-2 mV; P<0.05 versus absence of 
      17-ODYA). AA metabolites formed primarily by P450 produce potent 
      endothelium-dependent dilation of human coronary arterioles via opening of 
      Ca2+-activated K+ channels and hyperpolarization of VSMCs. These findings support 
      an important role for P450 metabolites in the regulation of human coronary 
      arteriolar tone.
FAU - Miura, H
AU  - Miura H
AD  - Veterans Administration Medical Center, the Department of Internal Medicine, 
      University of Iowa College of Medicine, Iowa City 52246, USA.
FAU - Gutterman, D D
AU  - Gutterman DD
LA  - eng
GR  - HL-52869/HL/NHLBI NIH HHS/United States
PT  - Clinical Trial
PT  - Controlled Clinical Trial
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Circ Res
JT  - Circulation research
JID - 0047103
RN  - 0 (Cyclooxygenase Inhibitors)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Potassium Channels)
RN  - 0 (Vasodilator Agents)
RN  - 27YG812J1I (Arachidonic Acid)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - EC 1.13.11.12 (Lipoxygenase)
RN  - EC 1.14.99.1 (Prostaglandin-Endoperoxide Synthases)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Aged
MH  - Arachidonic Acid/*pharmacology
MH  - Arterioles/drug effects
MH  - Calcium/*pharmacology
MH  - Cardiopulmonary Bypass
MH  - Coronary Vessels/*drug effects
MH  - Cyclooxygenase Inhibitors/pharmacology
MH  - Cytochrome P-450 Enzyme System/*metabolism
MH  - Enzyme Inhibitors/pharmacology
MH  - Female
MH  - Humans
MH  - Lipoxygenase/metabolism
MH  - Male
MH  - Membrane Potentials/drug effects
MH  - Middle Aged
MH  - Potassium Channels/*agonists
MH  - Prostaglandin-Endoperoxide Synthases/drug effects/metabolism
MH  - Vasodilator Agents/*pharmacology
EDAT- 1998/09/12 00:00
MHDA- 1998/09/12 00:01
CRDT- 1998/09/12 00:00
PHST- 1998/09/12 00:00 [pubmed]
PHST- 1998/09/12 00:01 [medline]
PHST- 1998/09/12 00:00 [entrez]
AID - 10.1161/01.res.83.5.501 [doi]
PST - ppublish
SO  - Circ Res. 1998 Sep 7;83(5):501-7. doi: 10.1161/01.res.83.5.501.