Departments of Anesthesiology and Pharmacology, Texas Tech University Health Sciences Center, Lubbock, Texas 79430; and Departments of Anesthesiology and Pharmacology, Tulane University Medical Center, New Orleans, Louisiana 70112
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ABSTRACT |
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The effects of Gö-6976, a
Ca2+-dependent protein kinase C (PKC) isozyme inhibitor,
and rottlerin, a PKC- isozyme/calmodulin (CaM)-dependent kinase III
inhibitor, on responses to vasopressor agents were investigated in the
feline pulmonary vascular bed. Injections of angiotensin II,
norepinephrine (NE), serotonin, BAY K 8644, and U-46619 into the lobar
arterial constant blood flow perfusion circuit caused increases in
pressure. Gö-6976 reduced responses to angiotensin II; however,
it did not alter responses to serotonin, NE, or U-46619, whereas
Gö-6976 enhanced BAY K 8644 responses. Rottlerin reduced
responses to angiotensin II and NE, did not alter responses to
serotonin or U-46619, and enhanced responses to BAY K 8644. Immunohistochemistry of feline pulmonary arterial smooth muscle cells
demonstrated localization of PKC-
and -
isozymes in response to
phorbol 12-myristate 13-acetate and angiotensin II. Localization of
PKC-
and -
isozymes decreased with administration of
Gö-6976 and rottlerin, respectively. These data suggest that
activation of Ca2+-dependent PKC isozymes and
Ca2+-independent PKC-
isozyme/CaM-dependent kinase III
mediate angiotensin II responses. These data further suggest that
Ca2+-independent PKC-
isozyme/CaM-dependent kinase III
mediate responses to NE. A rottlerin- or Gö-6976-sensitive
mechanism is not involved in mediating responses to serotonin and
U-46619, but these PKC isozyme inhibitors enhanced BAY K 8644 responses
in the feline pulmonary vascular bed.
angiotensin; norepinephrine; calmodulin-dependent kinase III; calcium; BAY K 8644
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INTRODUCTION |
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PROTEIN KINASE C is
an enzyme involved in the regulation of various cellular processes such
as growth, differentiation, metabolism, and smooth muscle contraction
(23, 29, 31). Protein kinase C is known to exist in
virtually all mammalian tissues and is thought to play an important
role in transducing extracellular signals such as hormones, growth
factors, neurotransmitters, and drugs by phosphorylation of specific
cellular target proteins (15, 22). It has been reported
that angiotensin II initiates the process of hydrolysis of a specific
class of membrane phosphoinositides and subsequently activates protein
kinase C. Angiotensin II has been shown to induce membrane
phosphoinositide hydrolysis and the subsequent generation of
diacylglycerol (1, 16, 20). Protein kinase C is then
activated by diacylglycerol and phosphorylates intracellular
substrates, which leads to cellular responses. Since 1986, numerous
different isozymic forms of protein kinase C have been described
(7, 19). These protein kinase C isozymes are divided into three categories. The classic isozyme group is composed of
-,
1-,
2-, and
-isozymes. This group is activated by
phosphatidylserine with sn-1,2-diacylglycerol in a
Ca2+-dependent manner. The novel isozyme group is composed
of
-,
-,
-, and
-isozymes. It is also activated by
phosphatidylserine with sn-1,2-diacylglycerol but in a
Ca2+-independent manner. The atypical group is composed of
- and
-isozymes. It is activated by phosphatidylserine in a
sn-1,2-diacylglycerol- and Ca2+-independent manner.
The alkaloid staurosporine, a product of the Streptomyces
species, has been described as the most potent inhibitor of protein kinase C (30). Alteration of this natural compound
has improved the selectivity with little decrease in potency in the
preferential discrimination between protein kinase C isozymes
(18). In particular, Gö-6976, an indolocarbazole,
has been shown to inhibit the classic Ca2+-dependent
isozyme group in nanomolar concentrations (18). Rottlerin (mallotoxin), a compound purified from Mallotus
philippinensis, is a potent inhibitor of protein kinase C-
isozyme, a Ca2+-independent protein kinase C isozyme,
and calmodulin (CaM)-dependent kinase III (6, 7). Topical
administration of rottlerin has been shown to suppress
12-O-tetradecanoylphorbol 13-acetate-induced mouse ear edema
(5). Although the effects of certain protein kinase C
isozymes have been investigated in in vitro experiments, little if
anything is known about the role of protein kinase C isozymes in
mediating responses in the pulmonary circulation. The present study was
therefore undertaken to investigate the effects of Gö-6976 and
rottlerin on vasoconstrictor responses to angiotensin II and other
pressor agents that act by various mechanisms in the pulmonary vascular
bed of the intact-chest cat.
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METHODS AND MATERIALS |
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Twenty-four adult mongrel cats of either sex weighing 3.0-4.5 kg were sedated with intramuscular ketamine hydrochloride (10-15 mg/kg) and were anesthetized with intravenous pentobarbital sodium (30 mg/kg). The animals were restrained in the supine position on a fluoroscopic table, and supplemental doses of anesthetic were administered as needed to maintain a uniform level of anesthesia. The trachea was intubated with a cuffed pediatric endotracheal tube, and the animals spontaneously breathed room air enriched with 100% O2. Systemic arterial (aortic) pressure was measured from a catheter inserted into the aorta from a femoral artery, and intravenous injections were made into a catheter positioned in the inferior vena cava from a femoral vein.
For perfusion of the left lower lung lobe, a triple lumen 6F balloon perfusion catheter was passed under fluoroscopic guidance from an external jugular vein into the artery to the left lower lung lobe. After the animal had been heparinized (1,000 U/kg iv), the lobar artery was vascularly isolated by distension of the balloon cuff on the perfusion catheter, and the lobe was perfused with a Harvard model 1210 perfusion pump (Harvard Apparatus, South Natick, MA) by way of the catheter lumen beyond the balloon cuff with blood withdrawn from a femoral artery. The perfusion rate was adjusted so that lobar arterial perfusion pressure approximated the mean pressure in the main pulmonary artery and was not changed thereafter. The flow rate ranged from 30 to 41 ml/min, and in four experiments, left atrial pressure was measured with a radiopaque 6F single-lumen or 6F double-lumen catheter passed transseptally into the left atrium from an external jugular vein. All vascular pressures were measured with SpectroMed DTX Plus (Viggo-Spectromed, Oxnard, CA) transducers zeroed at the right atrial level and were recorded on a Grass model 7D recorder (Grass Instruments, Quincy, MA).
The present experiments were divided into seven groups. In the first
series of experiments, the influence of Gö-6976 (10 µg · kg1 · min
1
intralobar infusion for 10 min) on responses to angiotensin II, serotonin, norepinephrine, BAY K 8644, and U-46619 was investigated. In
the second series of experiments, the influence of Gö-6976 (15 µg · kg
1 · min
1
intralobar infusion for 10 min) on responses to angiotensin II, serotonin, norepinephrine, BAY K 8644, and U-46619 was evaluated. In
the third series of experiments, the influence of Gö-6976 (30 µg · kg
1 · min
1
intralobar infusion for 10 min) on responses to angiotensin II, serotonin, norepinephrine, BAY K 8644, and U-46619 was evaluated. In
the fourth series of experiments, the influence of rottlerin (15 µg · kg
1 · min
1
intralobar infusion for 10 min) on responses to angiotensin II, serotonin, norepinephrine, BAY K 8644, and U-46619 was investigated. In
the fifth series of experiments, the influence of rottlerin (25 µg · kg
1 · min
1
intralobar infusion for 10 min) on responses to angiotensin II, serotonin, norepinephrine, BAY K 8644, and U-46619 was evaluated. In
the sixth series of experiments, the influence of administration of
Gö-6976 [30 µg/kg over 10 min intra-arterially (ia)]
and rottlerin (25 µg/kg over 10 min ia) or Gö-6976 (10 µg/kg
over 10 min ia) and rottlerin (15 µg/kg over 10 min ia) on the
responses to angiotensin II, serotonin, norepinephrine, BAY K 8644, and
U-46619 was also evaluated.
Immunocytochemistry experiments.
In the seventh series, passage 2 feline pulmonary arterial
smooth muscle cells were plated on single-chambered slides at a density
of 2 × 104 cells/ml. The pulmonary arterial smooth
muscle cells were plated in complete medium and allowed to attach for
24 h. The medium was aspirated, and fresh complete medium with
either 1) phorbol 12-myristate 13-acetate, 2)
angiotensin II, 3) angiotensin II and Gö-6976, or
4) angiotensin II and rottlerin (mallotoxin, Calbiochem, La
Jolla, CA) or complete medium alone was added to each well on the
single-chambered slides. Immunocytochemistry was performed with the
ImmunoCruz staining system (Santa Cruz Biotechnology, Santa Cruz, CA).
Medium was aspirated from the slides, and the cells were fixed in
methanol (10°C) for 5 min. To quench endogenous peroxidase
activity, the fixed cells were incubated in a 0.3% solution of
hydrogen peroxide in PBS for 10 min. The cells were then incubated in
serum block for 20 min, and immediately after this incubation, the
cells were incubated with a rabbit primary antibody for protein kinase
C-
isozyme (1:200) and protein kinase C-
isozyme (1:200; Santa
Cruz Biotechnology) for 2 h. The cells were then treated with a
biotinylated secondary antibody for 30 min followed by treatment with
horseradish peroxidase (HRP)-streptavidin complex and exposed to
HRP-substrate mixture for 10 min. The slides were mounted and observed
under light microscopy.
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RESULTS |
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Influence of Gö-6976 on responses to angiotensin II.
Under conditions of controlled blood flow in the pulmonary
vascular bed of the intact-chest cat, injections of angiotensin II
(0.1-1 µg) into the lobar arterial perfusion circuit produced dose-related increases in lobar arterial perfusion pressure, and the
pressor responses to the angiotensin peptide were reproducible with
respect to time (Fig. 1).
Responses to angiotensin II were compared both before and 30 min after
infusion of Gö-6976 at 10, 15 (data not shown), and 30 µg · kg1 ·min
1 for 10 min into the lobar arterial perfusion circuit. The increases in lobar
arterial pressure in response to angiotensin II were significantly
reduced after administration of Gö-6976 (Fig. 1). Higher doses of
Gö-6976 (15 and 30 µg · kg
1 · min
1 ia)
produced a further reduction in the pressor response to angiotensin II
(Fig. 1). Administration of Gö-6976 into the lobar artery did not
significantly alter baseline arterial pressure (Table 1). The response to angiotensin
II returned to ~75% of control value within 60 min, and the response
was not significantly different from the control value 120 min after
administration of the Ca2+-dependent protein kinase C
isozyme inhibitor (data not shown).
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Influence of Gö-6976 on responses to norepinephrine, U-46619,
serotonin, and BAY K 8644.
Injections of norepinephrine, U-46619 (the thromboxane
A2 mimic), serotonin, and BAY K 8644 into the lobar
arterial perfusion circuit produced dose-related increases in lobar
arterial pressure (Figs. 1 and 2).
Responses to the agents were compared before and after infusion of
Gö-6976 at 10, 15 (data not shown), and 30 µg · kg1 ·min
1 for 10 min into the lobar arterial perfusion circuit. The increases in lobar
arterial pressure in response to serotonin, U-46619, and norepinephrine
were not altered after administration of Gö-6976. However,
responses to BAY K 8644 were significantly enhanced after treatment
with Gö-6976 (Fig. 2).
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Influence of rottlerin on responses to angiotensin II.
Responses to angiotensin II were compared before and 30 min after
infusion of rottlerin at 15 and 25 µg · kg1 ·min
1 for 10 min into the lobar arterial perfusion circuit. The increases in lobar
arterial pressure in response to angiotensin II were significantly
reduced after administration of rottlerin (Fig. 3). A higher dose of rottlerin (25 µg · kg
1 · min
1 ia)
produced further reductions in the response to angiotensin II (Fig. 3).
Administration of rottlerin into the lobar artery did not significantly
alter baseline arterial pressure (Table 1). The response to angiotensin
II returned to ~75% of control value within 75 min, and the response
was not significantly different from the control value 135 min after
administration of the protein kinase C blocker (data not shown).
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Influence of rottlerin on responses to norepinephrine, U-46619,
serotonin, and BAY K 8644.
Responses to norepinephrine, U-46619, serotonin, and BAY K 8644 were compared before and 30 min after infusion of rottlerin at 15 µg · kg1 · min
1 for 10 min into the lobar arterial perfusion circuit. The increases in lobar
arterial pressure in response to serotonin and U-46619 were not altered
after administration of rottlerin (Figs. 3 and 4). However, the pressor response to
norepinephrine was significantly reduced by treatment with
rottlerin. Responses to BAY K 8644 were enhanced after treatment
with rottlerin in the pulmonary vascular bed of the intact-chest cat
(Fig. 4).
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Influence of Gö-6976 and rottlerin on responses to angiotensin II, norepinephrine, U-46619, serotonin, and BAY K 8644. Responses to angiotensin II, norepinephrine, U-46619, serotonin, and BAY K 8644 were supposed to be investigated before and after administration of Gö-6976 (30 µg/kg over 10 min ia) and rottlerin (25 µg/kg over 10 min ia); however, on administration of the agents, the experimental animals expired. The protocol was repeated with lower doses of the agents Gö-6976 (10 µg/kg over 10 min ia) and rottlerin (15 µg/kg over 10 min ia), with the same lethal results.
Immunohistochemistry experiments.
Immunohistochemistry of cultured feline pulmonary arterial smooth
muscle cells demonstrated localization of protein kinase C- and -
isozymes in response to phorbol 12-myristate 13-acetate (data not
shown) and angiotensin II (Fig. 5).
Simultaneous administration of angiotensin II with Gö-6976
decreased localization of protein kinase C-
isozyme (a
Ca2+-dependent protein kinase C isozyme; Fig. 5). Also,
simultaneous administration of angiotensin II with rottlerin decreased
localization of protein kinase C-
isozyme (Fig. 5).
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DISCUSSION |
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Recent studies (10-12) in the pulmonary vascular
bed of the cat have suggested that the protein kinase C pathway plays
an important role in mediating responses to angiotensin and
norepinephrine. Results of the present study extend the results of the
previous studies by showing that protein kinase C isozyme inhibitors
can block responses to various constrictor agents. Pressor responses to
angiotensin II were inhibited after infusion of Gö-6976
(10-30 µg · kg1 · min
1) and
rottlerin (15-25
µg · kg
1 · min
1). Neither
inhibitor altered pressor responses to serotonin or U-46619, but
rottlerin inhibited responses to norepinephrine. The pressor response
to BAY K 8644 was enhanced after administration of Gö-6976 and
rottlerin. When Gö-6976 and rottlerin were administered simultaneously, there were lethal results. Immunocytochemistry of
cultured pulmonary arterial smooth muscle cells demonstrated protein
kinase C-
and -
isozyme localization in response to angiotensin
II. Protein kinase C-
isozyme and protein kinase C-
isozyme
localization were decreased after inhibition with Gö-6976 and
rottlerin, respectively. These data provide support for the hypothesis
that responses to angiotensin II are mediated, in part, by the protein
kinase C pathway and that responses to serotonin and U-46619, the
thromboxane A2 analog, appear to be mediated by some other
mechanism. Furthermore, these data support the hypothesis that the
pressor response to norepinephrine is mediated through a
rottlerin-sensitive mechanism in the pulmonary vascular bed of the cat.
Responses to these various pressor agents were reproducible with
respect to time so that tachyphylaxis to the agents did not play a role
in the present studies with the protein kinase C isozyme inhibitors.
The inhibitory effects of Gö-6976 and rottlerin were long in
duration because pressor responses returned to approximately control
values 120-135 min after infusion of the protein kinase C isozyme inhibitors.
Many agonists including norepinephrine, acetylcholine, vasopressin, cholecystokinin, and angiotensin II exert some of their biological effects by increasing the levels of Ca2+ and sn-1,2-diacylglycerol in their target cells. These responses appear to involve an initial mobilization of Ca2+ from the endoplasmic/sarcoplasmic reticulum and perhaps other intracellular Ca2+ stores, followed by alterations in the flux of Ca2+ across the plasma membrane. The Ca2+ changes are consistently associated with increased turnover of cellular phosphoinositides. The most rapid response is breakdown of phosphatidylinositol 4,5-bisphosphate in the plasma membrane. myo-Inositol 1,4,5-trisphosphate produced by phosphatidylinositol 4,5-bisphosphate breakdown rapidly releases Ca2+ from the endoplasmic and sarcoplasmic reticulum. sn-1,2-Diacylglycerol, the other product of phosphatidylinositol 4,5-bisphosphate breakdown, also acts as a second messenger in that it activates protein kinase C, a Ca2+-phospholipid-dependent protein kinase, by lowering its requirement for Ca2+. The cellular substrates for protein kinase C and its role in the different physiological responses to the Ca2+-mediated agonists are under investigation. The major intracellular target for Ca2+ is the Ca2+-dependent regulatory protein CaM. This binds Ca2+ with high affinity, and the resulting complex interacts with a variety of enzymes and other cellular proteins, modifying their activities. A major target is the multifunctional CaM-dependent protein kinase that phosphorylates and alters the activities of many proteins including myosin light chain kinase. Myosin light chain kinase, by phosphorylation of myosin light chain, is thought to be the primary mechanism for activating smooth muscle contraction (23).
Increases in membrane phosphoinositide hydrolysis and intracellular
Ca2+ have been shown after 1-adrenergic,
serotonin, and angiotensin II activation (2, 25).
Norepinephrine-, serotonin-, and angiotensin II-induced
vasoconstriction have been demonstrated (10, 11) to be
dependent on phospholipase C and protein kinase C activation in the rat
and cat. Previous studies (10, 21) involving serotonin demonstrated species differences in the effects of protein kinase C
inhibitors in the rat basilar artery and in the pulmonary vascular bed.
The results of the present study support the hypothesis that responses
to serotonin are not mediated by a protein kinase C mechanism in the
pulmonary vascular bed of the cat.
Protein kinase C is involved in the contraction of vascular smooth
muscle (26, 29, 31). Staurosporine and other nonselective protein kinase C inhibitors have been reported to inhibit
12-O-tetradecanoylphorbol 13-acetate-induced contraction of
rat aortic smooth muscle (27). In smooth muscle cell
preparations, protein kinase C isozymes have been implicated in
contractile responses (13, 14). Recently, protein kinase
C- and -
isozymes were demonstrated to be involved in rat
mesenteric arterial contraction in response to phorbol esters
(24). However, specific protein kinase C isozymes involved in smooth muscle contractions in the pulmonary vascular bed have not
been described. These data support the finding that protein kinase C
isozymes play a role in mediating angiotensin II and norepinephrine
responses in vivo.
The roles of protein kinase C isozymes in mediating responses in the pulmonary circulation in the intact animal are difficult to investigate because little is known about the pharmacokinetic and pharmacodynamic properties of these agents in this system. The specificity profiles for Gö-6976 and rottlerin have been described in in vitro experiments. Recent kinetic studies suggest that Gö-6976, along with other staurosporine-related protein kinase C inhibitors, interferes with binding of ATP to the kinase and that rottlerin also at least partially interacts with the ATP binding site of protein kinase C (7, 18). Responses to angiotensin II were attenuated to a greater degree after administration of rottlerin than after Gö-6976. However, complete inhibition of pulmonary pressor responses was not seen in our study, suggesting that mechanisms other than protein kinase C isozyme activation may be involved. A previous study (11) has demonstrated that binding of angiotensin II to angiotensin type I receptors results in the activation of phospholipase C, which hydrolyzes phosphatidylinositol 4,5-bisphosphate to diacylglycerol and inositol 1,4,5-trisphosphate. The data with Gö-6976 and rottlerin suggest that protein kinase C isozyme/CaM-dependent kinase III activation plays a role in mediating vasoconstrictor responses to angiotensin II and norepinephrine. However, additional studies are needed to provide an exact definition of the role of protein kinase C isozymes and other mechanisms that may be involved in the mediation of responses to angiotensin II and norepinephrine in the pulmonary vascular bed of the cat.
Previous results (12) have shown that the
nonselective protein kinase C inhibitors staurosporine and calphostin C
reduced pulmonary vasoconstriction of angiotensin II and norepinephrine and that pulmonary vasoconstrictor responses to the thromboxane A2 analog U-46619 were not altered in the cat. Furthermore,
these data suggested that protein kinase C plays a role in mediating vasoconstrictor responses in the pulmonary vascular bed of the cat and
rat and that there are species differences in certain vasoconstrictor
responses (12). It has also been demonstrated that protein
kinase C plays a role in mediating norepinephrine-induced contraction
in isolated vascular smooth muscle preparations (3, 31).
There are data (4, 14) to suggest that norepinephrine uses
Ca2+-independent isoforms of protein kinase C for signal
transduction. In ferret aortic cells with constant Ca2+,
phenylephrine-induced contraction was observed and inhibited by an
antagonist of protein kinase C (4, 14). These data further
inferred that the protein kinase C- isozyme (a
Ca2+-independent protein kinase C isozyme) was responsible
for this contraction. Furthermore, in human tracheal epithelial cells, rottlerin, the protein kinase C-
isozyme/CaM-dependent kinase III
inhibitor, blocked norepinephrine-induced
1-adrenergic
activation of the Na+-K+-2Cl
cotransport (17). However, in rat mesenteric artery, it
has been suggested that the protein kinase C-
isozyme does not
mediate norepinephrine responses (24). The reason for the
difference in response to norepinephrine between the isolated rat
mesenteric artery and the pulmonary vascular bed of the cat is unknown
but may be related to species, sex, the vascular bed studied, or in vivo versus in vitro preparation. The present results demonstrate that
responses to norepinephrine were not altered by Gö-6976, whereas
norepinephrine responses were attenuated after administration of
rottlerin; this suggests a protein kinase C-
isozyme/CaM-dependent kinase III-mediated mechanism in the pulmonary vascular bed of the cat.
Results of the present study demonstrate that responses to angiotensin II are inhibited by both Gö-6976 and rottlerin, whereas norepinephrine responses are inhibited by rottlerin. The reason for the difference between angiotensin II, norepinephrine, and the other vasoconstrictor substances studied is unknown. However, it may be related to the signal transduction mechanisms involved in mediating the various responses. Angiotensin II is well known to be a smooth muscle cell growth promoter or mitogen. This effect of angiotensin II, as opposed to the other vasoconstrictor agents, may be partially responsible for the stimulation of multiple protein kinase C isozyme stimulation. The results also demonstrated that simultaneous administration of Gö-6976 and rottlerin produced lethal results. The reason for this is unknown and requires further study, but it supports the concept of the necessary and ubiquitous nature of protein kinase C.
The importance of Ca2+ in mediating smooth muscle contraction is well known. However, the interaction between protein kinase C and Ca2+ in smooth muscle contraction is less well understood. It has been reported that angiotensin II amplifies norepinephrine-induced contraction without an associated augmentation of 45Ca2+ influx or net Ca2+ uptake. This amplification is prevented by the protein kinase C inhibitor staurosporine (8). Furthermore, staurosporine reduced norepinephrine-induced tone in rabbit aortic rings (9). However, previous results (11) demonstrated that Ca2+ uptake or influx is critical for angiotensin II-induced vasoconstriction. In the present study, responses to BAY K 8644, the Ca2+ channel agonist, were significantly enhanced after administration of Gö-6976 and rottlerin, suggesting that inhibition of these protein kinase C isozymes enhances the vascular smooth muscle response to increases in intracellular free Ca2+. The explanation for the enhanced response requires further study but may be related to an increased sensitivity to intracellular free Ca2+ or an alteration in the Ca2+ gradient after inhibition of protein kinase C isozymes in the pulmonary vascular bed of the cat.
In summary, the results of the present study show that the protein
kinase C isozyme inhibitors Gö-6976 and rottlerin reduced pulmonary vasoconstriction by angiotensin II. Both protein kinase C
isozyme inhibitors did not alter pressor responses to serotonin or
U-46619, whereas only rottlerin inhibited responses to norepinephrine. The pressor response to BAY K 8644 was enhanced after administration of
the protein kinase C isozyme inhibitors. These data suggest that the
pulmonary arterial pressor responses to angiotensin II are mediated, in
part, by the activation of Ca2+-dependent protein kinase C
isozymes and the Ca2+-independent protein kinase C-
isozyme/CaM-dependent kinase III. These data further suggest that the
norepinephrine pressor response is mediated, in part, by the
Ca2+-independent protein kinase C-
isozyme/CaM-dependent
kinase III. A rottlerin- or Gö-6976-sensitive mechanism is not
involved in the mediation of pressor responses to serotonin and U-46619
in the pulmonary vascular bed of the cat.
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FOOTNOTES |
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Address for reprint requests and other correspondence: A. D. Kaye, Dept. of Anesthesiology, Texas Tech Univ. School of Medicine, 3601 4th St., Rm. 1C-282, Lubbock, Texas 79430 (E-mail: aneadk{at}ttuhsc.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 23 March 1999; accepted in final form 8 June 2000.
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