(Circulation. 1999;99:558-563.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Coronary Arteriolar Dilation to Acidosis
Role of ATP-Sensitive Potassium Channels and Pertussis Toxin–Sensitive G Proteins
From the Department of Medical Physiology, Microcirculation Research Institute, Texas A&M University Health Science Center, College Station (H.I., L.K.), and the Department of Bioengineering, University of California at San Diego, La Jolla (S.R.G., J.A.F.). Dr Ishizaka is currently affiliated with the 2nd Department of Internal Medicine, Hirosaki University School of Medicine, Hirosaki, Japan.
Correspondence to Lih Kuo, PhD, Department of Medical Physiology, Microcirculation Research Institute, Texas A&M University Health Science Center, College Station, TX 77843-1114. E-mail lkuo{at}tamu.edu
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Abstract |
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Background—We previously demonstrated that coronary arteriolar dilation in response to acidosis is mediated by the opening of ATP-sensitive potassium (KATP) channels. However, the signal transduction involved in the KATP-channel activation during acidosis has not been elucidated. A recent study in cardiac myocytes implied that pertussis toxin (PTX)–sensitive G proteins may be involved in the signal transduction for KATP-channel activation. However, it remains unclear whether this transduction process also occurs in the vascular tissue and, in particular, whether it exerts functional dilation in response to acidosis.
Methods and Results—To examine the signaling pathway for acidosis-induced dilation, porcine coronary arterioles were isolated, cannulated, and pressurized for in vitro study. The GTPase activity in reconstituted G proteins was examined at different levels of pH. Extravascular acidosis (pH 7.3 to 7.0) produced a graded dilation of coronary arterioles. This dilation was not affected by removal of endothelium but was significantly attenuated after inhibition of KATP channels and G proteins by glibenclamide and PTX, respectively. Glibenclamide and PTX attenuated the acidosis-induced arteriolar dilation to the same extent, and combined administration of both inhibitors did not further inhibit the vasodilation. These results indicated that both inhibitors act on the same vasodilatory pathway. Furthermore, vasodilation of coronary arterioles to the KATP-channel opener pinacidil and to the endothelium-independent vasodilator sodium nitroprusside was not affected by PTX. Because PTX inhibited acidosis-induced vasodilation without inhibiting KATP-channel function, it is suggested that PTX inhibits the vasodilatory pathway upstream from KATP channels. GTPase activity in reconstituted G proteins was significantly enhanced by a reduction in pH, indicating that G proteins were directly activated by acidosis.
Conclusions—On the basis of these findings, we conclude that acidosis-induced coronary arteriolar dilation is mediated by the opening of smooth muscle KATP channels through the activation of PTX-sensitive G proteins.
Key Words: vasodilation • arteries • potassium • proteins
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Introduction |
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ATP-sensitive potassium (KATP) channels have been shown to be involved in the regulation of membrane potential of vascular smooth muscle cells in various tissues,1 including coronary arteries.2 Activation of this potassium channel contributes to the regulation of coronary blood flow during reduction of perfusion pressure3 or under metabolic stresses such as hypoxia,4 ischemia,3 and increased metabolic demand,5 conditions generally associated with tissue acidosis. Recent in vitro studies have indicated that acidosis produces vascular relaxation/dilation via hyperpolarization,6 and we subsequently demonstrated that the opening of KATP channels is responsible for the dilation of coronary arterioles to acidosis.7 However, the signal transduction pathway involved in this vasodilation has not been elucidated. Because the majority of coronary resistance (>60%) resides in arterioles <150 µm in diameter8 and these vessels are responsible for the regulation of coronary blood flow, it is important to understand the basic vasomotor control mechanism of these arterioles in response to acidic stress.
Guanine nucleotide–binding proteins (G proteins) are
known to be an important component of signal transduction pathways that
carry information received at the cell surface to the appropriate
cellular response.9 Pertussis toxin (PTX)
inactivates Gi and
Go proteins by means of ADP ribosylation of the
carboxyl termini of 
-subunits, the putative site of receptor–G
protein interaction. The holo–G protein (ß
) is required for
ADP ribosylation.10 There are 2 ways that PTX inhibits G
protein–mediated signaling. On the one hand, PTX blocks receptor–G
protein interactions11 ; on the other, ADP ribosylation by
PTX can also prevent the dissociation of the G
and Gß subunits and thus inhibit effector
function.12 It has been shown that inhibition of G protein
signal transduction by PTX inactivates
KATP channels of pancreatic cells13
and cardiac myocytes,14 suggesting that activation of
KATP channels may be through G proteins. However,
it remains unclear whether this transduction process also occurs in the
vascular tissue and, in particular, whether it exerts functional
dilation in response to acidosis. In addition, the direct effect of
acidosis on G protein activity has not been characterized. In the
present study, we tested the hypothesis that the opening of
KATP channels through activation of PTX-sensitive
G proteins is responsible for the signal transduction initiating
vasodilation in response to acidosis. To achieve this goal without
interference from neurohumoral and hemodynamic factors,
the experiments were performed in pressurized, isolated
coronary arterioles 50 to 100 µm in diameter and in G
protein–reconstituted liposomes.
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Methods |
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Animal Preparation
Pigs (8 to 12 weeks old, of either sex) were sedated with telazol 4.4 mg/kg IM and xylazine 2.2 mg/kg IM, then anesthetized and heparinized with pentobarbital sodium 20 mg/kg IV and heparin 1000 U/kg IV, respectively, through the marginal ear vein. Pigs were intubated and ventilated with room air. After a left thoracotomy was performed, the heart was electrically fibrillated, excised, and immediately placed in cold (5°C) saline solution.
Isolation and Cannulation of Microvessels
The techniques for isolation of porcine coronary
arterioles were described previously.15 In brief, a
mixture of india ink and gelatin in physiological
salt solution (PSS) containing (in mmol/L) NaCl 145.0, KCl 4.7,
CaCl2 2.0, MgSO4 1.17,
NaH2PO4 1.2, glucose 5.0,
pyruvate 2.0, EDTA 0.02, and MOPS 3.0 was perfused into the left
anterior descending artery and the circumflex artery to allow
visualization of the coronary microvessels. The subepicardial
coronary arterioles (50 to 100 µm in ID) were dissected
from surrounding cardiac tissue under cold (5°C) PSS containing
albumin (1%; Amersham) at pH 7.4. Each isolated microvessel
was then transferred for cannulation to a Lucite vessel chamber
containing albumin-PSS (pH 7.4) equilibrated with room air at
ambient temperature. Both ends of the vessel were cannulated with
micropipettes filled with albumin-PSS. The cannulated vessel
was securely tied to the micropipettes with 11-0 ophthalmic suture
(Alcon).
Instrumentation
After a vessel was cannulated, the preparation was transferred
to the stage of an inverted microscope (Diaphot 300, Nikon) coupled to
a CCD camera (TM-34KC, Pulnix) and video micrometer
(Microcirculation Research Institute, Texas A&M University Health
Science Center). The micropipettes were connected to independent
pressure reservoir systems,16 and intraluminal pressures
were measured through side arms of the 2 reservoir lines by
low-volume-displacement strain-gauge transducers (Statham P23 Db,
Gould). The isolated vessels were pressurized without flow by setting
both reservoirs at the same hydrostatic level (60
cm H2O). IDs of the vessel were measured
throughout the experiment by video microscopic techniques incorporated
with the MacLab (ADInstruments) data acquisition
system.16
Experimental Protocols for Isolated Vessel Studies
Each cannulated vessel was bathed in albumin-PSS and
equilibrated with room air, and the temperature was maintained at
36°C to 37°C. The vessel was set to its in situ length and allowed
to develop basal tone at 60 cm H2O intraluminal
pressure. After a stabilization period of 60 minutes, acidosis-induced
vasodilation was studied by incremental addition of HCl (0.05N) to the
vessel bath to reduce extravascular pH.7 The bath
PCO2 was not altered by addition of
HCl. Vessel diameter was measured at a pH of 7.4, 7.3, 7.2, 7.1, and
7.0 before and after disruption of endothelium by
perfusion of a nonionic detergent (CHAPS; 0.4%) to the vessel.
Denudation of the endothelium was verified by the
absence of vasodilation to the endothelium-dependent
vasodilator bradykinin 100 nmol/L as described
previously.7 The contribution of
KATP channels to acidosis-induced dilation was
examined by a specific KATP-channel
inhibitor glibenclamide (5 µmol/L, 15 minutes of
incubation). The role of PTX-sensitive G proteins in acidosis-induced
vasodilation was examined after incubation of the vessels with PTX 100
ng/mL for 60 minutes. The KATP-channel opener
pinacidil 0.03 to 3 µmol/L and the
endothelium-independent vasodilator sodium
nitroprusside 1 nmol/L to 10 µmol/L were used to examine
KATP-channel and vascular smooth muscle function,
respectively. All chemicals were administered to the vessel bath. At
the end of each experiment, each vessel was relaxed completely with
sodium nitroprusside 100 µmol/L to obtain the maximum diameter
at 60 cm H2O intraluminal pressure.
Preparation of Reconstituted G Proteins
To directly examine the effect of acidosis on G protein
activity, heterotrimeric G proteins were purified from bovine brain by
previously described procedures.17 The protein purity and
activity were monitored by SDS-PAGE/immunoblotting and
[35S]GTP--S binding.17 The
homogeneous G protein preparation was reconstituted into
liposomes by use of detergent-mediated methods, and the reconstitution
efficiency was measured in each preparation as described
previously.17
Effect of pH on G Protein Activity
G protein–reconstituted vesicles were resuspended with
reconstitution buffer into aliquots (pH preadjusted to 7.0, 7.1, 7.2,
7.3, and 7.4 with HCl) and were equilibrated for 3 hours on ice. The
-32P–labeled GTP (10 µmol/L final
concentration, 10 µL) was added in appropriate pH buffer to the
vesicles (40 µL) and incubated at 37°C for 1 minute (each treatment
was done in triplicate). Steady-state GTP hydrolysis as a function of
GTPase activity was measured by the charcoal adsorption method
previously described.18 Briefly, 5% charcoal in 20
mmol/L ice-cold phosphoric acid was added to the reaction mixture, and
the samples were moved onto ice. Samples were mixed thoroughly and
centrifuged at 20 000g for 10 minutes at 4°C to
pellet the charcoal. Radioactivity was measured in the supernatants for
released Pi from GTP: Pi
released=(nmol GTP added)(sample cpm)/total cpm added.
Experiments with liposomes containing zero protein were performed simultaneously, and the values were subtracted for nonspecific activity. GTP hydrolysis by pure G proteins (without phospholipid) was used as a control. All values were normalized for protein concentration and time.
Chemicals
Drugs and chemicals were obtained from Sigma Chemical Co except
as specifically stated. Phospholipids were from Avanti Polar Lipids,
Inc. [-32P]GTP was from Amersham. PTX and
sodium nitroprusside were dissolved in PSS. Glibenclamide and pinacidil
were dissolved in dimethyl sulfoxide (DMSO), then diluted in PSS to
obtain the desired final concentration. The concentration of DMSO in
the vessel bath was <0.03%. A vehicle control study indicated that
this concentration of DMSO influenced neither resting diameter nor
arteriolar responses to acidosis, as reported
previously.7
Data Analysis
All diameter changes were normalized to the maximum dilation in
the presence of sodium nitroprusside 100 µmol/L and expressed as
percentage of maximum dilation. G protein activity was expressed as
Pi released from GTP. All data are
presented as mean±SEM. Differences in baseline diameter before
and after pharmacological interventions were compared by Student's
paired t test. Statistical comparisons of acidosis-induced
vasodilation and the alteration of G protein activity under different
treatments were performed with 1-way or 2-way ANOVA and tested with
Fisher's protected least significant difference multiple range test
when appropriate. Significance was accepted at P<0.05.
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Results |
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Acidosis-Induced Coronary Arteriolar Dilation
All isolated arterioles developed a similar level of basal tone (Table
) within 40 minutes at
36°C to 37°C bath temperature with 60 cm H2O
intraluminal pressure. Acidosis produced dilation of coronary
arterioles in a hydrogen ion concentration–dependent manner, ie,
16±1%, 28±2%, 54±3%, and 73±3% of maximum dilation at pH 7.3,
7.2, 7.1, and 7.0, respectively (Figure 1).
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Effects of Endothelial Denudation, Glibenclamide,
and PTX on Acidosis-Induced Dilation
Disruption of endothelium abolished
coronary arteriolar dilation to 100 nmol/L bradykinin, ie,
diameter increased from 77±13 to 101±20 µm and from 75±14 to
76±13 µm before and after denudation, respectively. However,
coronary arteriolar dilation to acidosis (pH 7.3 to 7.0) was
not altered in these denuded vessels (Figure 1
), indicating that
this vasodilatory response was not mediated by the
endothelium. Incubation of the vessels with
glibenclamide 5 µmol/L or PTX 100 ng/mL did not affect resting
vascular tone (Table), but acidosis-induced vasodilation was
significantly attenuated (Figure 1). The efficacy of
glibenclamide and PTX in inhibiting vasodilation to acidosis was not
different.
To examine whether glibenclamide and PTX had additive
inhibitory effects on acidosis-induced vasodilation, the
vascular response to acidosis was examined in the presence of
glibenclamide, PTX, or combined glibenclamide and PTX. Both
glibenclamide and PTX inhibited arteriolar dilation to acidosis (pH 7.2
and 7.0) in a comparable manner (Figure 2), which is in agreement with the
results shown in Figure 1. In addition, combined administration
of PTX and glibenclamide did not potentiate the inhibitory
effect produced by PTX or by glibenclamide alone (Figure 2).
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Effect of PTX on Vasodilation to Pinacidil and Sodium
Nitroprusside
To examine whether KATP channels and
vasodilatory function of smooth muscle were directly inhibited by PTX
and glibenclamide, the vasomotor responses of isolated coronary
arterioles to a KATP-channel opener, pinacidil,
0.03 to 3 µmol/L, and to an
endothelium-independent vasodilator, sodium
nitroprusside, 0.001 to 10 µmol/L, were studied in the absence
and presence of these inhibitors. Both pinacidil and sodium
nitroprusside produced dilation of isolated coronary arterioles
in a dose-dependent manner (Figure 3).
PTX 100 ng/mL did not influence pinacidil-induced arteriolar dilation
(Figure 3A), indicating that KATP-channel
function was not altered by PTX. In addition, vasodilation to sodium
nitroprusside was not affected by combined administration of PTX 100
ng/mL and glibenclamide 5 µmol/L (Figure 3B), indicating
that these 2 inhibitors did not influence vasodilatory
function of vascular smooth muscle.
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Effect of Acidosis on G Protein Activity
To directly assess the effect of pH on G protein activity, the
release of Pi (as an index of G protein activity)
from GTP in G protein–reconstituted liposomes was determined under
various pH conditions (pH 7.4 to 7.0). The GTPase activity in
reconstituted G proteins was inversely related to the reduction of pH,
ie, a 4-fold increase in GTPase activity was observed when pH was
reduced in a stepwise manner from 7.4 to 7.0 (Figure 4).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In the present study, using isolated vessel preparations, we demonstrated that acidosis-induced dilation in coronary arterioles is endothelium-independent and is mediated by the activation of KATP channels and PTX-sensitive G proteins, because this dilation is inhibited by either glibenclamide or PTX in an identical manner. Combined administration of these 2 inhibitors does not produce additional inhibitory effects. Furthermore, purified G proteins in phospholipid vesicles are activated in the acidic environments. Because PTX does not inhibit KATP-channel and vascular smooth muscle function and the acidosis directly activates G proteins, it is suggested that acidosis-induced dilation of coronary arterioles is mediated by the opening of smooth muscle KATP channels through activation of PTX-sensitive G proteins. The present study is the first to show the involvement of PTX-sensitive G protein in the KATP channel–mediated vasodilation and the direct activation of G proteins by acidosis. To provide a perspective for our observations and conclusions, methodological considerations such as the inhibitory effects of glibenclamide and PTX will be addressed, and the possible signaling pathway for acidosis-induced dilation will be suggested. Finally, the physiological and pathophysiological significance of our findings will be discussed.
Glibenclamide has been shown to be a selective antagonist
of KATP channels.1 We previously
showed that the concentration of glibenclamide, 5 µmol/L, used
in the present study does not influence the resting diameter and
the vasodilatory response to sodium nitroprusside,7
indicating that the inhibitory action of glibenclamide on
acidosis-induced dilation is not the result of a nonspecific loss of
vasodilatory capacity or damage of vascular smooth muscle. In addition,
PTX neither affected resting vascular tone (Table) nor altered
vasodilation to pinacidil or sodium nitroprusside (Figure 3). It
appears that the inhibitory action of PTX is selective for
acidosis-induced vasodilation rather than a nonspecific inactivation of
KATP channels or damage of vascular smooth muscle
for vasodilation.
We have previously shown that nitric oxide and
prostaglandin signaling pathways are not involved in the
activation of KATP channels during vasodilation
to acidosis.7 It appears that this vasomotor response is
primarily endothelium-independent, because removal of
endothelium had no effect on the vasodilatory process
elicited by acidosis (Figure 1). The present study further
demonstrated that activation of PTX-sensitive G proteins in smooth
muscle is essential for this vasodilatory event (Figure 1).
Recently, it was speculated that the KATP channel
may be directly coupled to the receptor-associated
Gi protein in vascular smooth
muscle,2 as has been shown in other cell
types.13 14 However, there is no functional evidence to
support this idea. In the present study, the dilation of
coronary arterioles to acidosis was inhibited by either
glibenclamide or PTX in an identical fashion (Figure 1), and
combined administration of these 2 agents did not further potentiate
the inhibitory effect (Figure 2). These results
suggested that these 2 agents inhibit the same pathway for vasodilation
to acidosis. Because PTX inhibited acidosis-induced vasodilation
without inhibiting KATP-channel function (Figure 3A), this result indicates that PTX inhibits the vasodilatory
pathway upstream from the KATP channels.
Therefore, it is believed that opening of KATP
channels during acidosis is through the activation of PTX-sensitive G
proteins.
The involvement of G proteins in acidosis-induced dilation was
also supported by the reconstituted G protein studies. A widely
accepted model for the association of extrinsically bound proteins with
acidic phospholipid–containing membranes is that the protein-membrane
interaction induces a domain of acidic phospholipids that serve as the
protein binding site.19 Acidic phospholipids are known to
influence membrane-bound enzymes.20 In fact, a number of
key proteins involved in signal transduction (eg, phospholipase C,
protein kinase C, myristylated alanine-rice C kinase substrate,
pp60src protein, and G proteins) require
acidic phospholipids on the plasma membranes.21 22 In the
present study, we reconstituted G proteins in liposomes containing
the acidic phospholipids phosphatidyl ethanolamine and phosphatidyl
serine. A decrease in pH may cause an electrostatic repulsion between
the negatively charged head groups of acidic phospholipids. This, in
turn, changes the overall molecular organization of the lipid bilayer,
which could possibly activate the bound enzyme molecules, ie, G
proteins in this case. Although activation of G proteins is generally
believed to be through a receptor-dependent mechanism, a recent study
demonstrated that shear stress can activate membrane-bound G
proteins in the absence of protein receptors.17 It is
possible that alteration of local pH may elicit a pathway that bypasses
membrane receptors for G protein activation, thus leading to vascular
dilation. However, the major limitation of the present
reconstituted G protein study is that these proteins were isolated from
brain tissue rather than from the microvessels, because of the
technical difficulties in obtaining a sufficient amount of
microvascular G proteins. Therefore, extrapolating these data to
vascular tissue, especially in relation to
physiological function, is somewhat uncertain and
deserves further consideration. Nevertheless, it might implicate a
potential role of G protein activation in transducing messages related
to acidic stress of cells. Currently, the subcellular mechanism for G
protein–associated activation of KATP channels
is not available. It is possible that ß-subunits dissociating from
G proteins during acidosis may play a role in
KATP-channel activation. Irrespective of these
speculations, additional work is needed to address this possibility and
to define the cellular and molecular basis for the G
protein–associated KATP-channel function in
vascular smooth muscle.
Because arteriolar dilation to acidosis is a major mechanism for the metabolic regulation of coronary blood flow, PTX-sensitive G proteins and KATP channels are believed to play an important role in this regard, especially during metabolic stress. Recent studies indicated that KATP channels3 and PTX-sensitive G proteins23 are involved in the coronary arteriolar dilation in response to hypoperfusion, ischemia, and increased metabolic demand, the conditions that are generally involved in tissue acidosis.24 Our results suggested that activation of the KATP channel through the PTX-sensitive G protein signaling pathway may contribute to the vasodilation observed during these metabolic disturbances. Under pathophysiological conditions such as hypercholesterolemia25 and certain forms of hypertension,26 the alteration of G protein function in vascular smooth muscle may have significant impact on the vasodilatory function of coronary arterioles in response to acidic stress, resulting in an inadequate flow and oxygen supply to the tissue during intense metabolic demands.
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Acknowledgments |
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This study was supported by National Heart, Lung, and Blood Institute grants HL-48179 and HL-03693 (Research Career Development Award) to Dr Kuo. We thank Dr Travis W. Hein for his suggestions and review of the manuscript.
Received May 15, 1998; revision received September 9, 1998; accepted September 25, 1998.
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D. Merkus, D. B. Haitsma, T.-Y. Fung, Y. J. Assen, P. D. Verdouw, and D. J. Duncker Coronary blood flow regulation in exercising swine involves parallel rather than redundant vasodilator pathways Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H424 - H433. [Abstract] [Full Text] [PDF]
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J. Mao, J. Wu, F. Chen, X. Wang, and C. Jiang Inhibition of G-protein-coupled Inward Rectifying K+ Channels by Intracellular Acidosis J. Biol. Chem., February 21, 2003; 278(9): 7091 - 7098. [Abstract] [Full Text] [PDF]
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T. Tanikawa, H. Kanatsuka, R. Koshida, M. Tanaka, A. Sugimura, T. Kumagai, M. Miura, T. Komaru, and K. Shirato Role of pertussis toxin-sensitive G protein in metabolic vasodilation of coronary microcirculation Am J Physiol Heart Circ Physiol, October 1, 2000; 279(4): H1819 - H1829. [Abstract] [Full Text] [PDF]
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T. W. Hein and L. Kuo cAMP-Independent Dilation of Coronary Arterioles to Adenosine : Role of Nitric Oxide, G Proteins, and KATP Channels Circ. Res., October 1, 1999; 85(7): 634 - 642. [Abstract] [Full Text] [PDF]
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S. Fukuda, T. Toriumi, H. Xu, H. Kinoshita, H. Nishimaki, S. Kokubun, N. Fujiwara, H. Fujihara, and K. Shimoji Enhanced beta -receptor-mediated vasorelaxation in hypoxic porcine coronary artery Am J Physiol Heart Circ Physiol, October 1, 1999; 277(4): H1447 - H1452. [Abstract] [Full Text] [PDF]
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H. Xu, N. Cui, Z. Yang, J. Wu, L. R. Giwa, L. Abdulkadir, P. Sharma, and C. Jiang Direct Activation of Cloned KATP Channels by Intracellular Acidosis J. Biol. Chem., April 13, 2001; 276(16): 12898 - 12902. [Abstract] [Full Text] [PDF]
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