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Abstract

Objective—To determine the effects of inhibition of Rho-kinase or Src-family protein tyrosine kinases (srcPTK) on agonist-induced contractile responses in equine laminar arteries and veins.

Sample Population—Laminar arteries and veins obtained from 13 adult mixed-breed horses.

Procedures—Laminar vessels were mounted on myographs and exposed to phenylephrine (PE), 5-hydroxytryptamine (5-HT), prostaglandin F (PGF), and endothelin-1 (ET-1) with or without the Rho-kinase inhibitor Y-27632 (10μM), srcPTK inhibitor PP2 (10μM), or a negative control analogue for PP2 (PP3; 10μM).

Results—Responses to PE were reduced by use of Y-27632 in laminar vessels (approx inhibition, 55%). However, Y-27632 reduced responses to 5-HT to a greater degree in veins than in arteries (approx inhibition of 55% and 35%, respectively). The Y-27632 also reduced responses of laminar veins to ET-1 by approximately 40% but had no effect on maximum responses of laminar arteries to ET-1, although a rightward shift in the concentration response curve was evident. Addition of PP2 reduced responses to PE, 5-HT, and PGF in laminar veins by approximately 40%, 60%, and 65%, respectively, compared with responses after the addition of PP3; PP2 had no effect on responses to ET-1. In laminar arteries, PP2 reduced 5-HT–induced contractions by approximately 50% but did not affect responses to PE or ET-1.

Conclusions and Clinical Relevance—Results of the study were consistent with activation of Rho-kinase being important during agonist-induced constriction in laminar vessels, activation of srcPTK being an agonist-dependent event, and more prominent roles for Rhokinase and srcPTK in veins than in arteries.

Full access
in American Journal of Veterinary Research

Abstract

Objective—To determine the effects of the protein kinase C (PKC) inhibitor, Ro-31-8220, on agonist-induced constriction of laminar arteries and veins obtained from horses.

Sample Population—Laminar arteries and veins obtained from 8 adult mixed-breed horses.

Procedures—Laminar arteries and veins were isolated and mounted on small vessel myographs for the measurement of isometric tension. Concentration-response curves were then obtained for the vasoconstrictor agonists phenylephrine, 5-hydroxytryptamine, prostaglandin F, and endothelin-1. All responses were measured with or without the addition of Ro-31-8220 (3μM).

Results—Laminar veins were more sensitive to vasoconstrictor agonists than laminar arteries, and incubation of laminar veins with Ro-31-8220 resulted in significantly smaller agonist-induced contractile responses for all agonists tested. In contrast, Ro-31-8220 had no effect on agonist-induced contractile responses of laminar arteries.

Conclusions and Clinical Relevance—Results of the study were consistent with activation of PKC being confined to agonist-induced contraction of laminar veins isolated from the laminar dermis of horses. Consequently, the possible involvement of PKC in the venoconstriction observed during the development of laminitis is worthy of further investigation.

Full access
in American Journal of Veterinary Research

Abstract

Objective—To characterize the relative contributions of voltage-gated and capacitative Ca2+ entry to agonist-induced contractions of equine laminar arteries and veins.

Animals—16 adult mixed-breed horses.

Procedures—Laminar arteries and veins were isolated and mounted on small vessel myographs for the measurement of isometric tension. Concentration-response curves were obtained for the vasoconstrictor agonists phenylephrine, 5-hydroxytryptamine (5-HT), prostaglandin F (PGF), and endothelin-1 (ET-1) either in the absence of extracellular Ca2+ or in the presence of the voltage-gated Ca2+ channel inhibitor diltiazem or the putative inhibitor of capacitative Ca2+ entry, trifluoromethylphenylimidazole.

Results—In the absence of extracellular Ca2+, maximal responses of veins to 5-HT, phenylephrine, ET-1 and PGF were reduced by 80%, 50%, 50%, and 45%, respectively; responses of arteries to 5-HT, phenylephrine, and ET-1 were reduced by 95%, 90%, and 20%, respectively. Although diltiazem did not affect the maximal responses of veins to any agonist, responses of arteries to 5-HT, phenylephrine, and ET-1 were reduced by 40%, 50%, and 27%, respectively. Trifluoromethylphenylimidazole did not affect maximal responses of veins, but did reduce their contractile responses to low concentrations of ET-1 and PGF.

Conclusions and Clinical Relevance—Results suggested that the contribution of extracellular Ca2+ to laminar vessel contractile responses differs between arteries and veins and also between contractile agonists, voltage-gated Ca2+ entry is more predominant in laminar arteries than in veins, and capacitative Ca2+ entry has a minor role in agonist-induced contractile responses of laminar veins.

Full access
in American Journal of Veterinary Research

Abstract

Objective—To compare characteristics and enzymatic products of leukocytes detected in the skin and laminar tissues of horses administered black walnut heartwood extract (BWHE) and horses administered purified lipopolysaccharide (LPS).

Animals—25 healthy 5- to 15-year-old horses.

Procedures—Horses were randomly assigned to receive LPS (20 ng of O55:B5 Escherichia coli endotoxin/kg; n = 5) IV or 6 L of BWHE (10) or water (control group; 10) via nasogastric intubation. Horses were euthanatized 12 hours after treatment or at onset of Obel grade 1 lameness. Laminar tissue samples and skin samples from the middle region of the neck were harvested at the time of euthanasia. Leukocyte emigration (determined via CD13 immunohistochemical analysis) and matrix metalloproteinase (MMP)-2 and MMP-9 gene expressions and activities (determined via reverse transcription PCR assay and gelatin zymography, respectively) were measured in skin and laminar tissue samples.

Results—Tissues of horses receiving BWHE contained significantly higher numbers of CD13-positive cells and increased MMP-9 gene expression and activity, compared with findings in the other 2 groups. Values for laminar tissue and skin from LPS-treated horses were not increased, compared with findings in the control group, in any experiment.

Conclusions and Clinical Relevance—Results indicated that BWHE administration causes increases in CD13-positive leukocyte numbers and MMP-9 expression and activity in laminar tissue and skin in horses; similar effects were not detected following LPS administration. Leukocyte emigration in horses with experimentally induced endotoxemia and in horses administered BWHE differed markedly, thereby providing additional evidence that the development of laminitis involves more complex mechanisms than endotoxemia-induced leukocyte activation alone.

Full access
in American Journal of Veterinary Research

Abstract

Objective—To provide insights into the role of prostaglandin F (PGF) in the developmental stages of laminitis induced in horses by ingestion of black walnut heartwood extract (BWHE).

Sample Population—10 adult mixed-breed horses.

Procedures—Horses were separated into 2 groups and were euthanatized at 12 hours after placebo (water) administration (control horses) or after BWHE administration and development of Obel grade 1 laminitis. Blood samples were obtained to determine plasma PGF concentrations hourly for the first 4 hours and subsequently every 2 hours after substance administration. Laminar arteries and veins were isolated, and responses to increasing concentrations of PGF were measured before and after preincubation of blood vessels with prostanoid and thromboxane receptor antagonists SQ 29,548, SC-19220, and AH 6809.

Results—Plasma PGF concentrations increased in horses given BWHE; the WBC count decreased concurrently. In control horses, PGF was a potent contractile agonist for laminar veins but not for laminar arteries. In horses given BWHE, PGF was similarly selective for laminar veins; however, the magnitude of PGF-induced venoconstriction was less than that in control horses. After preincubation with SQ 29,548, laminar veins from control horses responded to PGF with a small degree of dilation, whereas laminar veins from horses given BWHE did not.

Conclusions and Clinical Relevance—PGF may play a role in the inflammatory and vascular dysfunction associated with the prodromal stages of laminitis. Prostanoids such as PGF may be viable targets for the prevention of acute laminitis in horses.

Full access
in American Journal of Veterinary Research