Effects of PKC isozyme inhibitors on constrictor responses in the feline pulmonary vascular bed

2001 ◽  
Vol 280 (1) ◽  
pp. L50-L57 ◽  
Author(s):  
Bracken J. De Witt ◽  
Alan D. Kaye ◽  
Ikhlass N. Ibrahim ◽  
Trinity J. Bivalacqua ◽  
Fiona M. D'Souza ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Bay K 8644 ◽  
Kinase C ◽  
Vascular Bed ◽  
Flow Perfusion ◽  
Dependent Protein ◽  
Vasopressor Agents ◽  
Pkc Isozymes ◽  
Pulmonary Arterial ◽  
Pulmonary Vascular Bed

The effects of Gö-6976, a Ca2+-dependent protein kinase C (PKC) isozyme inhibitor, and rottlerin, a PKC-δ 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-α and -δ isozymes in response to phorbol 12-myristate 13-acetate and angiotensin II. Localization of PKC-α and -δ isozymes decreased with administration of Gö-6976 and rottlerin, respectively. These data suggest that activation of Ca2+-dependent PKC isozymes and Ca2+-independent PKC-δ isozyme/CaM-dependent kinase III mediate angiotensin II responses. These data further suggest that Ca2+-independent PKC-δ 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.

Responses to L-163,491, a nonpeptide angiotensin II mimic, in the pulmonary vascular bed of the cat

1995 ◽  
Vol 287 (2) ◽  
pp. 163-168 ◽  
Author(s):  
Alan D. Kaye ◽  
Bobby D. Nossaman ◽  
Salah Kivlighn ◽  
Ikhlass N. Ibrahim ◽  
Bracken J. De Witt ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Vascular Bed ◽  
Pulmonary Vascular Bed

Pulmonary vasodilation to adrenomedullin: a novel peptide in humans

1995 ◽  
Vol 268 (6) ◽  
pp. H2211-H2215 ◽  
Author(s):  
J. Heaton ◽  
B. Lin ◽  
J. K. Chang ◽  
S. Steinberg ◽  
A. Hyman ◽  
...  
Keyword(s):  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Vasomotor Tone ◽  
Pulmonary Vasodilation ◽  
Vascular Bed ◽  
Pulmonary Vasodilator ◽  
Vasodilator Activity ◽  
Pulmonary Arterial ◽  
Cgrp Receptor Antagonist ◽  
Pulmonary Vascular Bed

The present study investigates the effects of human adrenomedullin (ADM) on the pulmonary vascular bed of isolated, blood-perfused rat lung. Because pulmonary blood flow and left atrial pressure were constant, changes in pulmonary arterial pressure directly reflect changes in pulmonary vascular resistance. Under conditions of resting (low) pulmonary vasomotor tone, intra-arterial bolus injections of ADM-(1-52) and two truncated sequences of ADM-(1-52) [ADM-(1-12) and ADM-(13-52)] did not alter pulmonary arterial pressure. When pulmonary vasomotor tone was increased by U-46619, a thromboxane A2 mimic, intra-arterial bolus injections of ADM-(1-52) and ADM-(13-52) at similar doses produced similar, dose-dependent reductions in pulmonary arterial pressure. On a molar basis, ADM-(1-52) had greater pulmonary vasodilator activity than isoproterenol. In contrast, ADM-(1-12) had no activity. When pulmonary vasomotor tone was actively increased to the same level using KCl, the pulmonary vasodilator activity of ADM-(13-52) was decreased 10-fold. The present data demonstrate that ADM-(1-52) dilates the pulmonary vascular bed and suggest that the pulmonary vasodilator activity of ADM is greater on pulmonary blood vessels preconstricted through a receptor-dependent mechanism. Because meclofenamate, nitro-L-arginine methyl ester, methysergide, BW A-1433U83, U-37883A, and calcitonin gene-related peptide [CGRP-(8-37)], a CGRP-receptor antagonist, did not alter the pulmonary vasodilator response to ADM-(1-52), the present data suggest that ADM dilates the pulmonary vascular bed independently of cyclooxygenase products, endothelium-derived relaxation factor, serotoninergic receptors, adenosine1 purinoreceptors, ATP-dependent potassium channels, and CGRP receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative responses to endothelin-2 and sarafotoxin 6b in the pulmonary vascular bed of the cat

1991 ◽  
Vol 69 (2) ◽  
pp. 211-214 ◽  
Author(s):  
R. K. Minkes ◽  
B. D. Nossaman ◽  
P. Kvamme ◽  
P. J. Kadowitz
Keyword(s):  
Arterial Pressure ◽  
Systemic Arterial Pressure ◽  
Significant Activity ◽  
Constant Flow ◽  
Carboxy Terminus ◽  
Flow Conditions ◽  
Vascular Bed ◽  
Natural Flow ◽  
Pulmonary Arterial ◽  
Pulmonary Vascular Bed

Pulmonary vascular responses to endothelin-2 and sarafotoxin 6b were investigated in the feline pulmonary vascular bed under natural flow and constant flow conditions. Injections of endothelin-2 and sarafotoxin 6b in a dose of 0.3 nmol/kg iv increased pulmonary arterial and left atrial pressures and cardiac output, and caused a biphasic change in calculated pulmonary vascular resistance. Endothelin-2 caused a biphasic change in systemic arterial pressure, while sarafotoxin 6b only decreased arterial pressure. Under constant flow conditions in the intact-chest cat, injections of endothelin-2 and sarafotoxin 6b in doses of 0.1–1 nmol into the perfused lobar artery increased lobar arterial pressure in a dose-related manner but were less potent than the thromboxane A2 mimic, U46619. An ET analog with only the Cys1–Cys15 disulfide bond and an amidated carboxy terminus had no significant activity in the pulmonary vascular bed. The present data show that endothelin-2 and sarafotoxin 6b have significant vasoconstrictor activity in the pulmonary vascular bed of the cat.Key words: pulmonary circulation, endothelin-2, sarafotoxin 6b.

Inhibitory effects of DuP 753 and EXP3174 on responses to angiotensin II in pulmonary vascular bed of the cat

1992 ◽  
Vol 73 (5) ◽  
pp. 2054-2061 ◽  
Author(s):  
T. J. McMahon ◽  
A. D. Kaye ◽  
J. S. Hood ◽  
R. K. Minkes ◽  
B. D. Nossaman ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Dose Response ◽  
Inhibitory Effect ◽  
Response Relationship ◽  
Norepinephrine Release ◽  
Inhibitory Effects ◽  
Dose Response Relationship ◽  
Vascular Bed ◽  
The Right ◽  
Pulmonary Vascular Bed

The effects of the non-peptide antagonist DuP 753 and its metabolite EXP3174 on responses to angiotensin II were investigated in the pulmonary vascular bed of the intact-chest cat. Under conditions of controlled blood flow and constant left atrial pressure, injections of angiotensin II into the perfused lobar artery caused dose-related increases in lobar arterial pressure. Responses to angiotensin II were reproducible and were not changed by meclofenamate or prazosin, indicating that prostaglandin or norepinephrine release does not mediate or modulate pulmonary vascular responses to the peptide. DuP 753 (1–5 mg/kg iv) decreased responses to angiotensin II in a competitive manner, and the duration of the blockade was related to dose of the antagonist. DuP 753 had no significant effect on responses to U-46619, norepinephrine, serotonin, endothelin-1, vasopressin, or BAY K 8644. EXP3174 also decreased responses to angiotensin II without altering responses to agents that act by a variety of mechanisms. The inhibitory effect of EXP3174 (1 mg/kg iv) was not overcome by angiotensin II in the range of doses studied, and the shift to the right of the dose-response curve was nonparallel, suggesting that the blockade was noncompetitive. The blockade was long in duration, and, when the dose of EXP3174 was decreased to 0.1 mg/kg iv, the blockade was surmounted and the shift to the right of the dose-response relationship was parallel. DuP 753 and EXP3174 had little effect on mean baseline pressures in the cat.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of phospholipase A2, 12-lipoxygenase, and cyclooxygenase inhibitors in the feline pulmonary bed

1997 ◽  
Vol 272 (4) ◽  
pp. L573-L579 ◽  
Author(s):  
A. D. Kaye ◽  
B. D. Nossaman ◽  
D. E. Smith ◽  
I. N. Ibrahim ◽  
J. D. Imig ◽  
...  
Keyword(s):  
Phospholipase A2 ◽  
Phospholipase C ◽  
Bay K 8644 ◽  
Cyclooxygenase Inhibitors ◽  
Ang Ii ◽  
Lipoxygenase Inhibitor ◽  
Arterial Perfusion ◽  
Vascular Bed ◽  
Phospholipase A2 Inhibitor ◽  
Pulmonary Vascular Bed

The effects of phosphonofluoridic acid, methyl-5,8,11,14-eicosatetraenyl ester (MAFP), a phospholipase A2 inhibitor, on pressor responses to angiotensin II (ANG II), norepinephrine (NE), serotonin (5-HT), the calcium channel opener BAY K 8644, and the thromboxane A2 mimic U-46619 were studied in the pulmonary vascular bed of the intact-chest cat. Under conditions of constant lobar blood flow, injections of ANG II, NE, 5-HT, U-46619, and BAY K 8644 into the lobar arterial perfusion circuit caused dose-related increases in lobar arterial pressure that were reproducible with respect to time. Infusion of MAFP into the perfused lobar artery at doses of 100 to 300 microg/kg for 10 min significantly reduced vasoconstrictor responses to ANG II; however, the phospholipase A2 inhibitor did not alter vasoconstrictor responses to BAY K 8644, 5-HT, NE, or U-46619. The combination of the higher dose of the phospholipase A2 inhibitor MAFP with the phospholipase C inhibitor U-73122 significantly affected vasoconstrictor responses to ANG II, NE, and 5-HT but not to BAY K 8644. In a separate series of animals, the effects of a lipoxygenase inhibitor, baicalein, were investigated. Infusion of baicalein into the perfused lobar artery at doses of 100 microg/kg for 10 min significantly reduced vasoconstrictor responses to ANG II but not the vasoconstrictor responses to BAY K 8644, 5-HT, NE, or U-46619. In a final series of experiments, the effects of a cyclooxygenase inhibitor, meclofenamate, were investigated, and intravenous injection of the meclofenamate at a dose of 2.5 mg/kg did not significantly affect vasoconstrictor responses to ANG II, 5-HT, BAY K 8644, NE, or U-46619. These data provide support for the hypothesis that pulmonary vasopressor responses to ANG II are mediated, in part, by the activation of phospholipase A2, phospholipase C, and the lipoxygenase pathway in the pulmonary vascular bed of the cat.

Influence of PLC and MLCK inhibitors and the role of L-calcium channels in the cat pulmonary vascular bed

1995 ◽  
Vol 269 (4) ◽  
pp. L507-L513 ◽  
Author(s):  
A. D. Kaye ◽  
B. D. Nossaman ◽  
I. N. Ibrahim ◽  
P. J. Kadowitz
Keyword(s):  
Calcium Channel ◽  
Calcium Channel Blocker ◽  
Channel Blocker ◽  
Kinase Inhibitor ◽  
Bay K 8644 ◽  
Ang Ii ◽  
Arterial Perfusion ◽  
Vascular Bed ◽  
Pressor Responses ◽  
Pulmonary Vascular Bed

The effects of U-73122, a phospholipase C (PLC) inhibitor, on pressor responses to angiotensin II (ANG II), norepinephrine (NE), serotonin (5-HT), BAY K 8644, and the thromboxane A2 (TxA2) mimic, U-46619, were studied in the pulmonary vascular bed of the intact-chest cat. Under conditions of constant lobar blood flow, injections of ANG II, NE, 5-HT, U-46619, and the calcium channel opener, BAY K 8644, into the lobar arterial perfusion circuit caused dose-related increases in lobar arterial pressure, which were reproducible with respect to time. Infusion of U-73122, a PLC inhibitor, into the perfused lobar artery at 10–100 micrograms/kg for 10 min significantly reduced responses to ANG II, serotonin, and NE; however, U-73122 did not alter responses to BAY K 8644 or to U-46619. In a separate series of animals, the effects of the myosin light chain kinase inhibitor, KT-5926, were investigated, and after infusion of KT-5926 into the perfused lobar artery at 1–2 micrograms/kg for 10 min, responses to ANG II, NE, 5-HT, BAY K 8644, and U-46619 were reduced significantly. In a final series of experiments, the effects of the L-type calcium channel blocker, nicardipine, were investigated, and infusion of the L-type calcium channel blocker into the perfused lobar artery at 0.5-1 microgram/kg for 10 min reduced responses to ANG II, BAY K 8644, and NE. However, nicardipine did not alter pressor responses to 5-HT or the TxA2 mimic, U-46619.(ABSTRACT TRUNCATED AT 250 WORDS)

Protein kinase C translocation and PKC-dependent protein phosphorylation during myocardial ischemia

1999 ◽  
Vol 276 (2) ◽  
pp. H642-H650 ◽  
Author(s):  
Carolyn J. Albert ◽  
David A. Ford
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Myocardial Ischemia ◽  
Protein Phosphorylation ◽  
Phorbol Ester ◽  
Adult Rat ◽  
Kinase C ◽  
Associated Proteins ◽  
Dependent Protein ◽  
Pkc Isozymes

The present study demonstrates that the α, ε, and ι isozymes of protein kinase C (PKC) are translocated to particulate fractions from the cytosol during brief intervals of global ischemia as well as reperfusion of ischemic rat myocardium. In contrast, phorbol ester treatment of perfused hearts resulted in the translocation of the α, δ, and ε isozymes of PKC to particulate fractions. Additionally, the α, δ, and ε isozymes of PKC are translocated to particulate fractions in phorbol ester-stimulated, isolated adult rat cardiac myocytes. Concomitant with the translocation of PKC isozymes to particulate fractions during myocardial ischemia, increased protein phosphorylation was observed, which was blocked by pretreatment of hearts with the selective PKC inhibitor bisindolylmaleimide I (50 nM). In particular, ischemia resulted in the phosphorylation of 26-, 20-, and 17-kDa particulate-associated proteins. Taken together, the present findings are the first to demonstrate that specific PKC isozymes are translocated to particulate fractions in the ischemic and the reperfused ischemic rat heart, resulting in the phosphorylation of specific particulate-associated proteins.

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