Vasopressin-mediated enhancement of adrenergic vasoconstriction involves both the tyrosine kinase and the protein kinase C pathways

Jochen Steppan, Sinead Nyhan, Gautam Sikka, Jorge Uribe, Ayushi Ahuja, Anthony R. White, Artin A Shoukas, Dan E Berkowitz

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Vasopressin is frequently used to treat catecholamine-resistant vasodilatory shock. It enhances the vasoconstrictor effects of catecholamines at concentrations of vasopressin that have none or only minimal intrinsic pressor effects. However, the vascular mechanisms underlying this combined pharmacological approach have not been fully elucidated. METHODS: We used isometric tension measurements in vascular rings to investigate potential cellular mechanisms. Vascular rings (0.2 mm diameter) were harvested from the superior mesenteric artery of Wistar rats (2 to 4 months of age). Dose-response relationships were derived for vasopressin (VP) and norepinephrine (NE), in the absence and presence of a subpressor dose of VP (10 M). The contribution of tyrosine kinase (TK), the TK pathway proteins SRC and PYK2, as well as protein kinase C (PKC) were determined by measuring the modulating influence of specific inhibitors on the pressor response to NE (10 M) alone and the augmented pressor response to VP (10 M). RESULTS: VP (10 M) had only minimal pressor effect alone (10% of maximal response), but significantly increased the Emax response to NE (587.8 ± 40.7 vs 331.2 ± 10.4 mg). TK inhibition completely abolished the pressor response to NE (100% vs 1.0% 0.5%) and the augmented VP response alone (100% vs 2.0% ± 1.01%). Both responses were significantly, but equally, decreased by SRC inhibition (63% ± 4.0% and 69% 1.0%). In contrast, inhibition of the TK molecule PYK2 with salicylate had differential inhibitory effects on the vasoconstrictor responses. Salicylate caused a greater inhibition of VP-induced augmented NE response in comparison with NE alone (62.1% ± 7% and 15% ± 2%). Inhibition of either the μ or γ PKC isoform significantly decreased both responses, but the magnitude of the inhibition was significantly different for each isoform. Inhibition of the γ PKC isoform significantly decreased the vasoconstriction responses to both NE and VP plus NE (82.9 ± 3.9 vs 32.8 ± 3.8). Inhibition of the μ PKC isoform significantly decreased both responses and completely abolished the VP-augmented response to NE. CONCLUSION: These data are consistent with a central role for TK in mediating both the NE response and the VP-augmented response. Moreover, PYK2 and the μ and γ isoforms of PKC seem to play a preferential role in mediating the augmented VP response. The apparent divergent roles of these pathways in mediating NE- versus VP-augmented pressor responses could potentially lead to new targeted therapies in catecholamine-resistant shock.

Original languageEnglish (US)
Pages (from-to)1290-1295
Number of pages6
JournalAnesthesia and Analgesia
Volume115
Issue number6
DOIs
StatePublished - Dec 2012

Fingerprint

Vasoconstriction
Vasopressins
Adrenergic Agents
Protein-Tyrosine Kinases
Protein Kinase C
Norepinephrine
Protein Isoforms
Catecholamines
Blood Vessels
Salicylates
Vasoconstrictor Agents
Shock
Superior Mesenteric Artery
Wistar Rats
Pharmacology

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Vasopressin-mediated enhancement of adrenergic vasoconstriction involves both the tyrosine kinase and the protein kinase C pathways. / Steppan, Jochen; Nyhan, Sinead; Sikka, Gautam; Uribe, Jorge; Ahuja, Ayushi; White, Anthony R.; Shoukas, Artin A; Berkowitz, Dan E.

In: Anesthesia and Analgesia, Vol. 115, No. 6, 12.2012, p. 1290-1295.

Research output: Contribution to journalArticle

@article{5449e69a54e04e3594a2bc3fc7b0949a,
title = "Vasopressin-mediated enhancement of adrenergic vasoconstriction involves both the tyrosine kinase and the protein kinase C pathways",
abstract = "BACKGROUND: Vasopressin is frequently used to treat catecholamine-resistant vasodilatory shock. It enhances the vasoconstrictor effects of catecholamines at concentrations of vasopressin that have none or only minimal intrinsic pressor effects. However, the vascular mechanisms underlying this combined pharmacological approach have not been fully elucidated. METHODS: We used isometric tension measurements in vascular rings to investigate potential cellular mechanisms. Vascular rings (0.2 mm diameter) were harvested from the superior mesenteric artery of Wistar rats (2 to 4 months of age). Dose-response relationships were derived for vasopressin (VP) and norepinephrine (NE), in the absence and presence of a subpressor dose of VP (10 M). The contribution of tyrosine kinase (TK), the TK pathway proteins SRC and PYK2, as well as protein kinase C (PKC) were determined by measuring the modulating influence of specific inhibitors on the pressor response to NE (10 M) alone and the augmented pressor response to VP (10 M). RESULTS: VP (10 M) had only minimal pressor effect alone (10{\%} of maximal response), but significantly increased the Emax response to NE (587.8 ± 40.7 vs 331.2 ± 10.4 mg). TK inhibition completely abolished the pressor response to NE (100{\%} vs 1.0{\%} 0.5{\%}) and the augmented VP response alone (100{\%} vs 2.0{\%} ± 1.01{\%}). Both responses were significantly, but equally, decreased by SRC inhibition (63{\%} ± 4.0{\%} and 69{\%} 1.0{\%}). In contrast, inhibition of the TK molecule PYK2 with salicylate had differential inhibitory effects on the vasoconstrictor responses. Salicylate caused a greater inhibition of VP-induced augmented NE response in comparison with NE alone (62.1{\%} ± 7{\%} and 15{\%} ± 2{\%}). Inhibition of either the μ or γ PKC isoform significantly decreased both responses, but the magnitude of the inhibition was significantly different for each isoform. Inhibition of the γ PKC isoform significantly decreased the vasoconstriction responses to both NE and VP plus NE (82.9 ± 3.9 vs 32.8 ± 3.8). Inhibition of the μ PKC isoform significantly decreased both responses and completely abolished the VP-augmented response to NE. CONCLUSION: These data are consistent with a central role for TK in mediating both the NE response and the VP-augmented response. Moreover, PYK2 and the μ and γ isoforms of PKC seem to play a preferential role in mediating the augmented VP response. The apparent divergent roles of these pathways in mediating NE- versus VP-augmented pressor responses could potentially lead to new targeted therapies in catecholamine-resistant shock.",
author = "Jochen Steppan and Sinead Nyhan and Gautam Sikka and Jorge Uribe and Ayushi Ahuja and White, {Anthony R.} and Shoukas, {Artin A} and Berkowitz, {Dan E}",
year = "2012",
month = "12",
doi = "10.1213/ANE.0b013e3182691c11",
language = "English (US)",
volume = "115",
pages = "1290--1295",
journal = "Anesthesia and Analgesia",
issn = "0003-2999",
publisher = "Lippincott Williams and Wilkins",
number = "6",

}

TY - JOUR

T1 - Vasopressin-mediated enhancement of adrenergic vasoconstriction involves both the tyrosine kinase and the protein kinase C pathways

AU - Steppan, Jochen

AU - Nyhan, Sinead

AU - Sikka, Gautam

AU - Uribe, Jorge

AU - Ahuja, Ayushi

AU - White, Anthony R.

AU - Shoukas, Artin A

AU - Berkowitz, Dan E

PY - 2012/12

Y1 - 2012/12

N2 - BACKGROUND: Vasopressin is frequently used to treat catecholamine-resistant vasodilatory shock. It enhances the vasoconstrictor effects of catecholamines at concentrations of vasopressin that have none or only minimal intrinsic pressor effects. However, the vascular mechanisms underlying this combined pharmacological approach have not been fully elucidated. METHODS: We used isometric tension measurements in vascular rings to investigate potential cellular mechanisms. Vascular rings (0.2 mm diameter) were harvested from the superior mesenteric artery of Wistar rats (2 to 4 months of age). Dose-response relationships were derived for vasopressin (VP) and norepinephrine (NE), in the absence and presence of a subpressor dose of VP (10 M). The contribution of tyrosine kinase (TK), the TK pathway proteins SRC and PYK2, as well as protein kinase C (PKC) were determined by measuring the modulating influence of specific inhibitors on the pressor response to NE (10 M) alone and the augmented pressor response to VP (10 M). RESULTS: VP (10 M) had only minimal pressor effect alone (10% of maximal response), but significantly increased the Emax response to NE (587.8 ± 40.7 vs 331.2 ± 10.4 mg). TK inhibition completely abolished the pressor response to NE (100% vs 1.0% 0.5%) and the augmented VP response alone (100% vs 2.0% ± 1.01%). Both responses were significantly, but equally, decreased by SRC inhibition (63% ± 4.0% and 69% 1.0%). In contrast, inhibition of the TK molecule PYK2 with salicylate had differential inhibitory effects on the vasoconstrictor responses. Salicylate caused a greater inhibition of VP-induced augmented NE response in comparison with NE alone (62.1% ± 7% and 15% ± 2%). Inhibition of either the μ or γ PKC isoform significantly decreased both responses, but the magnitude of the inhibition was significantly different for each isoform. Inhibition of the γ PKC isoform significantly decreased the vasoconstriction responses to both NE and VP plus NE (82.9 ± 3.9 vs 32.8 ± 3.8). Inhibition of the μ PKC isoform significantly decreased both responses and completely abolished the VP-augmented response to NE. CONCLUSION: These data are consistent with a central role for TK in mediating both the NE response and the VP-augmented response. Moreover, PYK2 and the μ and γ isoforms of PKC seem to play a preferential role in mediating the augmented VP response. The apparent divergent roles of these pathways in mediating NE- versus VP-augmented pressor responses could potentially lead to new targeted therapies in catecholamine-resistant shock.

AB - BACKGROUND: Vasopressin is frequently used to treat catecholamine-resistant vasodilatory shock. It enhances the vasoconstrictor effects of catecholamines at concentrations of vasopressin that have none or only minimal intrinsic pressor effects. However, the vascular mechanisms underlying this combined pharmacological approach have not been fully elucidated. METHODS: We used isometric tension measurements in vascular rings to investigate potential cellular mechanisms. Vascular rings (0.2 mm diameter) were harvested from the superior mesenteric artery of Wistar rats (2 to 4 months of age). Dose-response relationships were derived for vasopressin (VP) and norepinephrine (NE), in the absence and presence of a subpressor dose of VP (10 M). The contribution of tyrosine kinase (TK), the TK pathway proteins SRC and PYK2, as well as protein kinase C (PKC) were determined by measuring the modulating influence of specific inhibitors on the pressor response to NE (10 M) alone and the augmented pressor response to VP (10 M). RESULTS: VP (10 M) had only minimal pressor effect alone (10% of maximal response), but significantly increased the Emax response to NE (587.8 ± 40.7 vs 331.2 ± 10.4 mg). TK inhibition completely abolished the pressor response to NE (100% vs 1.0% 0.5%) and the augmented VP response alone (100% vs 2.0% ± 1.01%). Both responses were significantly, but equally, decreased by SRC inhibition (63% ± 4.0% and 69% 1.0%). In contrast, inhibition of the TK molecule PYK2 with salicylate had differential inhibitory effects on the vasoconstrictor responses. Salicylate caused a greater inhibition of VP-induced augmented NE response in comparison with NE alone (62.1% ± 7% and 15% ± 2%). Inhibition of either the μ or γ PKC isoform significantly decreased both responses, but the magnitude of the inhibition was significantly different for each isoform. Inhibition of the γ PKC isoform significantly decreased the vasoconstriction responses to both NE and VP plus NE (82.9 ± 3.9 vs 32.8 ± 3.8). Inhibition of the μ PKC isoform significantly decreased both responses and completely abolished the VP-augmented response to NE. CONCLUSION: These data are consistent with a central role for TK in mediating both the NE response and the VP-augmented response. Moreover, PYK2 and the μ and γ isoforms of PKC seem to play a preferential role in mediating the augmented VP response. The apparent divergent roles of these pathways in mediating NE- versus VP-augmented pressor responses could potentially lead to new targeted therapies in catecholamine-resistant shock.

UR - http://www.scopus.com/inward/record.url?scp=84870253354&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84870253354&partnerID=8YFLogxK

U2 - 10.1213/ANE.0b013e3182691c11

DO - 10.1213/ANE.0b013e3182691c11

M3 - Article

C2 - 22886838

AN - SCOPUS:84870253354

VL - 115

SP - 1290

EP - 1295

JO - Anesthesia and Analgesia

JF - Anesthesia and Analgesia

SN - 0003-2999

IS - 6

ER -