Mechanism of action of vasopressin on prostaglandin synthesis and vascular function in the isolated rat kidney

Effect of calcium antagonists and calmodulin inhibitors

C. L. Cooper, Kafait Malik

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32 Citations (Scopus)

Abstract

We have investigated the mechanism of action of arginine vasopressin (AVP) on vascular tone and renal output of prostaglandins (PGs) by examining the effect of Ca++ depletion, Ca++ antagonists and calmodulin inhibitors in the isolated Tyrode perfused rat kidney. Administration of AVP (0.027-0.27 nmol) into the kidney produced a dose-related renal vasoconstriction and an increase in the output of PGE2 and 6-keto-PGF(1α), the stable hydrolysis product of PGI2. Omission of Ca++ (1.8 mM) or addition of Ca++ channel blockers, diltiazem (6.0 x 10-5 M) or nimodipine (4.7 x 10-5 M), to the perfusion fluid attenuated the renal vasoconstriction, but not the output of PGs elicited by AVP. Infusion of intracellular Ca++ antagonists, Dantrium (3.1 x 10-5 M), TMB-8 (2.3 x 10-6 M) or ryanodine (2 x 10-6 M) or calmodulin inhibitors, trifluoperazine (2 x 10-6 M) or W-7 (2 x 10-6 M), abolished the rise in renal output of PGs produced by AVP during Ca++ depletion. Calmodulin inhibitors, which inhibited the AVP-induced release of PGs in the presence of Ca++, failed to alter the renal vasoconstrictor effect of the peptide. Administration of d(CH2)5Tyr(Me)AVP, a selective antagonist of pressor actions of AVP, abolished the renal vasoconstrictor response and release of PGs elicited by AVP. In contrast, d(CH2)5-D-ValVAVP, an antagonist of antidiuretic and to a lesser extent of pressor actions of AVP, failed to alter the renal vasoconstrictor response but attenuated the output of PGs produced by AVP. AVP antagonists did not alter the effect of angiotensin II (0.096 nmol) to cause renal vasoconstriction and enhance PG output. The effect of AVP to enhance PG output but not to produce renal vasoconstriction was abolished by indomethacin (2.8 x 10-6 M), a cyclooxygenase inhibitor, or mepacrine (2.1 x 10-5 M), a phospholipase A2 inhibitor. The renal output of PGE2 and 6-keto-PGF(1α) elicited by exogenous arachidonic acid (33 nmol) was blocked by indomethacin, but it remained unaltered during infusion of either mepacrine, Ca++ antagonists or calmodulin inhibitors. These data indicate that activation of AVP receptors results in increased influx of Ca++ and produces renal vasoconstriction by a mechanism independent of calmodulin. Interaction of AVP with its receptor sites also stimulates synthesis of PGs, presumably by mobilizing intracellular Ca++ that binds with calmodulin and activates an acyl hydrolase(s), most likely phospholipase A2, causing release of arachidonate for PG synthesis.

Original languageEnglish (US)
Pages (from-to)139-147
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume229
Issue number1
StatePublished - Jan 1 1984

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Arginine Vasopressin
Calmodulin
Vasopressins
Prostaglandins
Blood Vessels
Calcium
Kidney
Vasoconstriction
Vasoconstrictor Agents
Quinacrine
Prostaglandins F
Dinoprostone
Indomethacin
Dantrolene
Trifluoperazine
Vasopressin Receptors
Ryanodine
Nimodipine
Cyclooxygenase Inhibitors
Diltiazem

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

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title = "Mechanism of action of vasopressin on prostaglandin synthesis and vascular function in the isolated rat kidney: Effect of calcium antagonists and calmodulin inhibitors",
abstract = "We have investigated the mechanism of action of arginine vasopressin (AVP) on vascular tone and renal output of prostaglandins (PGs) by examining the effect of Ca++ depletion, Ca++ antagonists and calmodulin inhibitors in the isolated Tyrode perfused rat kidney. Administration of AVP (0.027-0.27 nmol) into the kidney produced a dose-related renal vasoconstriction and an increase in the output of PGE2 and 6-keto-PGF(1α), the stable hydrolysis product of PGI2. Omission of Ca++ (1.8 mM) or addition of Ca++ channel blockers, diltiazem (6.0 x 10-5 M) or nimodipine (4.7 x 10-5 M), to the perfusion fluid attenuated the renal vasoconstriction, but not the output of PGs elicited by AVP. Infusion of intracellular Ca++ antagonists, Dantrium (3.1 x 10-5 M), TMB-8 (2.3 x 10-6 M) or ryanodine (2 x 10-6 M) or calmodulin inhibitors, trifluoperazine (2 x 10-6 M) or W-7 (2 x 10-6 M), abolished the rise in renal output of PGs produced by AVP during Ca++ depletion. Calmodulin inhibitors, which inhibited the AVP-induced release of PGs in the presence of Ca++, failed to alter the renal vasoconstrictor effect of the peptide. Administration of d(CH2)5Tyr(Me)AVP, a selective antagonist of pressor actions of AVP, abolished the renal vasoconstrictor response and release of PGs elicited by AVP. In contrast, d(CH2)5-D-ValVAVP, an antagonist of antidiuretic and to a lesser extent of pressor actions of AVP, failed to alter the renal vasoconstrictor response but attenuated the output of PGs produced by AVP. AVP antagonists did not alter the effect of angiotensin II (0.096 nmol) to cause renal vasoconstriction and enhance PG output. The effect of AVP to enhance PG output but not to produce renal vasoconstriction was abolished by indomethacin (2.8 x 10-6 M), a cyclooxygenase inhibitor, or mepacrine (2.1 x 10-5 M), a phospholipase A2 inhibitor. The renal output of PGE2 and 6-keto-PGF(1α) elicited by exogenous arachidonic acid (33 nmol) was blocked by indomethacin, but it remained unaltered during infusion of either mepacrine, Ca++ antagonists or calmodulin inhibitors. These data indicate that activation of AVP receptors results in increased influx of Ca++ and produces renal vasoconstriction by a mechanism independent of calmodulin. Interaction of AVP with its receptor sites also stimulates synthesis of PGs, presumably by mobilizing intracellular Ca++ that binds with calmodulin and activates an acyl hydrolase(s), most likely phospholipase A2, causing release of arachidonate for PG synthesis.",
author = "Cooper, {C. L.} and Kafait Malik",
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T1 - Mechanism of action of vasopressin on prostaglandin synthesis and vascular function in the isolated rat kidney

T2 - Effect of calcium antagonists and calmodulin inhibitors

AU - Cooper, C. L.

AU - Malik, Kafait

PY - 1984/1/1

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N2 - We have investigated the mechanism of action of arginine vasopressin (AVP) on vascular tone and renal output of prostaglandins (PGs) by examining the effect of Ca++ depletion, Ca++ antagonists and calmodulin inhibitors in the isolated Tyrode perfused rat kidney. Administration of AVP (0.027-0.27 nmol) into the kidney produced a dose-related renal vasoconstriction and an increase in the output of PGE2 and 6-keto-PGF(1α), the stable hydrolysis product of PGI2. Omission of Ca++ (1.8 mM) or addition of Ca++ channel blockers, diltiazem (6.0 x 10-5 M) or nimodipine (4.7 x 10-5 M), to the perfusion fluid attenuated the renal vasoconstriction, but not the output of PGs elicited by AVP. Infusion of intracellular Ca++ antagonists, Dantrium (3.1 x 10-5 M), TMB-8 (2.3 x 10-6 M) or ryanodine (2 x 10-6 M) or calmodulin inhibitors, trifluoperazine (2 x 10-6 M) or W-7 (2 x 10-6 M), abolished the rise in renal output of PGs produced by AVP during Ca++ depletion. Calmodulin inhibitors, which inhibited the AVP-induced release of PGs in the presence of Ca++, failed to alter the renal vasoconstrictor effect of the peptide. Administration of d(CH2)5Tyr(Me)AVP, a selective antagonist of pressor actions of AVP, abolished the renal vasoconstrictor response and release of PGs elicited by AVP. In contrast, d(CH2)5-D-ValVAVP, an antagonist of antidiuretic and to a lesser extent of pressor actions of AVP, failed to alter the renal vasoconstrictor response but attenuated the output of PGs produced by AVP. AVP antagonists did not alter the effect of angiotensin II (0.096 nmol) to cause renal vasoconstriction and enhance PG output. The effect of AVP to enhance PG output but not to produce renal vasoconstriction was abolished by indomethacin (2.8 x 10-6 M), a cyclooxygenase inhibitor, or mepacrine (2.1 x 10-5 M), a phospholipase A2 inhibitor. The renal output of PGE2 and 6-keto-PGF(1α) elicited by exogenous arachidonic acid (33 nmol) was blocked by indomethacin, but it remained unaltered during infusion of either mepacrine, Ca++ antagonists or calmodulin inhibitors. These data indicate that activation of AVP receptors results in increased influx of Ca++ and produces renal vasoconstriction by a mechanism independent of calmodulin. Interaction of AVP with its receptor sites also stimulates synthesis of PGs, presumably by mobilizing intracellular Ca++ that binds with calmodulin and activates an acyl hydrolase(s), most likely phospholipase A2, causing release of arachidonate for PG synthesis.

AB - We have investigated the mechanism of action of arginine vasopressin (AVP) on vascular tone and renal output of prostaglandins (PGs) by examining the effect of Ca++ depletion, Ca++ antagonists and calmodulin inhibitors in the isolated Tyrode perfused rat kidney. Administration of AVP (0.027-0.27 nmol) into the kidney produced a dose-related renal vasoconstriction and an increase in the output of PGE2 and 6-keto-PGF(1α), the stable hydrolysis product of PGI2. Omission of Ca++ (1.8 mM) or addition of Ca++ channel blockers, diltiazem (6.0 x 10-5 M) or nimodipine (4.7 x 10-5 M), to the perfusion fluid attenuated the renal vasoconstriction, but not the output of PGs elicited by AVP. Infusion of intracellular Ca++ antagonists, Dantrium (3.1 x 10-5 M), TMB-8 (2.3 x 10-6 M) or ryanodine (2 x 10-6 M) or calmodulin inhibitors, trifluoperazine (2 x 10-6 M) or W-7 (2 x 10-6 M), abolished the rise in renal output of PGs produced by AVP during Ca++ depletion. Calmodulin inhibitors, which inhibited the AVP-induced release of PGs in the presence of Ca++, failed to alter the renal vasoconstrictor effect of the peptide. Administration of d(CH2)5Tyr(Me)AVP, a selective antagonist of pressor actions of AVP, abolished the renal vasoconstrictor response and release of PGs elicited by AVP. In contrast, d(CH2)5-D-ValVAVP, an antagonist of antidiuretic and to a lesser extent of pressor actions of AVP, failed to alter the renal vasoconstrictor response but attenuated the output of PGs produced by AVP. AVP antagonists did not alter the effect of angiotensin II (0.096 nmol) to cause renal vasoconstriction and enhance PG output. The effect of AVP to enhance PG output but not to produce renal vasoconstriction was abolished by indomethacin (2.8 x 10-6 M), a cyclooxygenase inhibitor, or mepacrine (2.1 x 10-5 M), a phospholipase A2 inhibitor. The renal output of PGE2 and 6-keto-PGF(1α) elicited by exogenous arachidonic acid (33 nmol) was blocked by indomethacin, but it remained unaltered during infusion of either mepacrine, Ca++ antagonists or calmodulin inhibitors. These data indicate that activation of AVP receptors results in increased influx of Ca++ and produces renal vasoconstriction by a mechanism independent of calmodulin. Interaction of AVP with its receptor sites also stimulates synthesis of PGs, presumably by mobilizing intracellular Ca++ that binds with calmodulin and activates an acyl hydrolase(s), most likely phospholipase A2, causing release of arachidonate for PG synthesis.

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