Cardiac contractility in endotoxemic rats treated with catecholamines is improved by high dose type IV phosphodiesterase (PDE4) inhibition with Ro 20-1724

Neal J. Thomas, Joseph A. Carcillo, William A. Herzer, Zaichuan Mi, Edwin K. Jackson

Research output: Contribution to journalArticle

Abstract

Introduction: Recently we reported that PDE4 inhibition with Ro 20-1724 (Ro20) improved survival and preserved renal and mesenteric blood flow in an acute model of overwhelming endotoxemia in the presence and absence of norepinephrine (NE) (CCM, 25, 1S, 1997; JPET, 279, 1997). We have also reported that PDE4 inhibition does not cause any significant cardiovascular effects in normal anesthetized rats in vivo in the presence and absence of catecholamines (JCP, 1998,in press). The purpose of this experiment was to determine if Ro20 has any effects on cardiac contractility in endotoxic rats in vivo in the presence and absence catecholamine infusions. Methods: Rats were anesthetized, instrumented (including a left ventricular catheter), and randomized to receive either vehicle (DMSO) (n=8), Ro20 at 10 mcg/kg/min (high Ro)(n=8), or Ro20 at 2 mcg/kg/min (low Ro) (n=5). Prior to endotoxin, each animal received 10 minutes of epinephrine (E) (1 mcg/kg/min) and NE (3 mcg/kg/min) followed by a 30 minute rest period to return to baseline after each infusion. Endotoxin (20 mg/kg) was bolused over 15 minutes, and each rat then received two more 10 minute infusions of each E and NE, in a randomized fashion, followed by subsequent equilibration periods. Results: Two-way repeated measures ANOVA revealed that high Ro improved contractility as measured by max dP/dt (p<0.01) and max dP/dt+pmax dP/dt (p<0.01). High Ro had no effect on the increase in cardiac contractility which resulted from NE or E infusions. Low Ro had no effect on cardiac contractility parameters when compared to control. Ventricular end diastolic pressure (VEDP; preload) was decreased by high Ro in endotoxemia (p<0.01), but ventricular peak systolic pressure (VPSP; afterload) was unchanged (p=NS). VEDP was unchanged (p=NS) by low Ro, but VPSP was decreased (p=0.04) Conclusions: In addition to maintaining renal and mesenteric perfusion, Ro20 at 10 mcg/kg/min increased cardiac contractility during endotoxemia. However, this effect appears to be dose responsive, as a lower dose of Ro20 does not effect cardiac performance during endotoxemia. Decreases in blood pressure that occur during administration of high doses of this drug may be preload dependent. Use of high doses of PDE4 inhibitors to improve survival during sepsis may require special attention to preload considerations.

Original languageEnglish (US)
JournalCritical Care Medicine
Volume27
Issue number1 SUPPL.
StatePublished - 1999

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4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone
Type 4 Cyclic Nucleotide Phosphodiesterase
Catecholamines
Endotoxemia
Norepinephrine
Blood Pressure
Endotoxins
Phosphodiesterase 4 Inhibitors
Renal Circulation
Dimethyl Sulfoxide
Epinephrine
Sepsis
Analysis of Variance
Catheters
Perfusion
Kidney

All Science Journal Classification (ASJC) codes

  • Critical Care and Intensive Care Medicine

Cite this

@article{775994717547428eb126c4fc89941076,
title = "Cardiac contractility in endotoxemic rats treated with catecholamines is improved by high dose type IV phosphodiesterase (PDE4) inhibition with Ro 20-1724",
abstract = "Introduction: Recently we reported that PDE4 inhibition with Ro 20-1724 (Ro20) improved survival and preserved renal and mesenteric blood flow in an acute model of overwhelming endotoxemia in the presence and absence of norepinephrine (NE) (CCM, 25, 1S, 1997; JPET, 279, 1997). We have also reported that PDE4 inhibition does not cause any significant cardiovascular effects in normal anesthetized rats in vivo in the presence and absence of catecholamines (JCP, 1998,in press). The purpose of this experiment was to determine if Ro20 has any effects on cardiac contractility in endotoxic rats in vivo in the presence and absence catecholamine infusions. Methods: Rats were anesthetized, instrumented (including a left ventricular catheter), and randomized to receive either vehicle (DMSO) (n=8), Ro20 at 10 mcg/kg/min (high Ro)(n=8), or Ro20 at 2 mcg/kg/min (low Ro) (n=5). Prior to endotoxin, each animal received 10 minutes of epinephrine (E) (1 mcg/kg/min) and NE (3 mcg/kg/min) followed by a 30 minute rest period to return to baseline after each infusion. Endotoxin (20 mg/kg) was bolused over 15 minutes, and each rat then received two more 10 minute infusions of each E and NE, in a randomized fashion, followed by subsequent equilibration periods. Results: Two-way repeated measures ANOVA revealed that high Ro improved contractility as measured by max dP/dt (p<0.01) and max dP/dt+pmax dP/dt (p<0.01). High Ro had no effect on the increase in cardiac contractility which resulted from NE or E infusions. Low Ro had no effect on cardiac contractility parameters when compared to control. Ventricular end diastolic pressure (VEDP; preload) was decreased by high Ro in endotoxemia (p<0.01), but ventricular peak systolic pressure (VPSP; afterload) was unchanged (p=NS). VEDP was unchanged (p=NS) by low Ro, but VPSP was decreased (p=0.04) Conclusions: In addition to maintaining renal and mesenteric perfusion, Ro20 at 10 mcg/kg/min increased cardiac contractility during endotoxemia. However, this effect appears to be dose responsive, as a lower dose of Ro20 does not effect cardiac performance during endotoxemia. Decreases in blood pressure that occur during administration of high doses of this drug may be preload dependent. Use of high doses of PDE4 inhibitors to improve survival during sepsis may require special attention to preload considerations.",
author = "Thomas, {Neal J.} and Carcillo, {Joseph A.} and Herzer, {William A.} and Zaichuan Mi and Jackson, {Edwin K.}",
year = "1999",
language = "English (US)",
volume = "27",
journal = "Critical Care Medicine",
issn = "0090-3493",
publisher = "Lippincott Williams and Wilkins",
number = "1 SUPPL.",

}

Cardiac contractility in endotoxemic rats treated with catecholamines is improved by high dose type IV phosphodiesterase (PDE4) inhibition with Ro 20-1724. / Thomas, Neal J.; Carcillo, Joseph A.; Herzer, William A.; Mi, Zaichuan; Jackson, Edwin K.

In: Critical Care Medicine, Vol. 27, No. 1 SUPPL., 1999.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Cardiac contractility in endotoxemic rats treated with catecholamines is improved by high dose type IV phosphodiesterase (PDE4) inhibition with Ro 20-1724

AU - Thomas, Neal J.

AU - Carcillo, Joseph A.

AU - Herzer, William A.

AU - Mi, Zaichuan

AU - Jackson, Edwin K.

PY - 1999

Y1 - 1999

N2 - Introduction: Recently we reported that PDE4 inhibition with Ro 20-1724 (Ro20) improved survival and preserved renal and mesenteric blood flow in an acute model of overwhelming endotoxemia in the presence and absence of norepinephrine (NE) (CCM, 25, 1S, 1997; JPET, 279, 1997). We have also reported that PDE4 inhibition does not cause any significant cardiovascular effects in normal anesthetized rats in vivo in the presence and absence of catecholamines (JCP, 1998,in press). The purpose of this experiment was to determine if Ro20 has any effects on cardiac contractility in endotoxic rats in vivo in the presence and absence catecholamine infusions. Methods: Rats were anesthetized, instrumented (including a left ventricular catheter), and randomized to receive either vehicle (DMSO) (n=8), Ro20 at 10 mcg/kg/min (high Ro)(n=8), or Ro20 at 2 mcg/kg/min (low Ro) (n=5). Prior to endotoxin, each animal received 10 minutes of epinephrine (E) (1 mcg/kg/min) and NE (3 mcg/kg/min) followed by a 30 minute rest period to return to baseline after each infusion. Endotoxin (20 mg/kg) was bolused over 15 minutes, and each rat then received two more 10 minute infusions of each E and NE, in a randomized fashion, followed by subsequent equilibration periods. Results: Two-way repeated measures ANOVA revealed that high Ro improved contractility as measured by max dP/dt (p<0.01) and max dP/dt+pmax dP/dt (p<0.01). High Ro had no effect on the increase in cardiac contractility which resulted from NE or E infusions. Low Ro had no effect on cardiac contractility parameters when compared to control. Ventricular end diastolic pressure (VEDP; preload) was decreased by high Ro in endotoxemia (p<0.01), but ventricular peak systolic pressure (VPSP; afterload) was unchanged (p=NS). VEDP was unchanged (p=NS) by low Ro, but VPSP was decreased (p=0.04) Conclusions: In addition to maintaining renal and mesenteric perfusion, Ro20 at 10 mcg/kg/min increased cardiac contractility during endotoxemia. However, this effect appears to be dose responsive, as a lower dose of Ro20 does not effect cardiac performance during endotoxemia. Decreases in blood pressure that occur during administration of high doses of this drug may be preload dependent. Use of high doses of PDE4 inhibitors to improve survival during sepsis may require special attention to preload considerations.

AB - Introduction: Recently we reported that PDE4 inhibition with Ro 20-1724 (Ro20) improved survival and preserved renal and mesenteric blood flow in an acute model of overwhelming endotoxemia in the presence and absence of norepinephrine (NE) (CCM, 25, 1S, 1997; JPET, 279, 1997). We have also reported that PDE4 inhibition does not cause any significant cardiovascular effects in normal anesthetized rats in vivo in the presence and absence of catecholamines (JCP, 1998,in press). The purpose of this experiment was to determine if Ro20 has any effects on cardiac contractility in endotoxic rats in vivo in the presence and absence catecholamine infusions. Methods: Rats were anesthetized, instrumented (including a left ventricular catheter), and randomized to receive either vehicle (DMSO) (n=8), Ro20 at 10 mcg/kg/min (high Ro)(n=8), or Ro20 at 2 mcg/kg/min (low Ro) (n=5). Prior to endotoxin, each animal received 10 minutes of epinephrine (E) (1 mcg/kg/min) and NE (3 mcg/kg/min) followed by a 30 minute rest period to return to baseline after each infusion. Endotoxin (20 mg/kg) was bolused over 15 minutes, and each rat then received two more 10 minute infusions of each E and NE, in a randomized fashion, followed by subsequent equilibration periods. Results: Two-way repeated measures ANOVA revealed that high Ro improved contractility as measured by max dP/dt (p<0.01) and max dP/dt+pmax dP/dt (p<0.01). High Ro had no effect on the increase in cardiac contractility which resulted from NE or E infusions. Low Ro had no effect on cardiac contractility parameters when compared to control. Ventricular end diastolic pressure (VEDP; preload) was decreased by high Ro in endotoxemia (p<0.01), but ventricular peak systolic pressure (VPSP; afterload) was unchanged (p=NS). VEDP was unchanged (p=NS) by low Ro, but VPSP was decreased (p=0.04) Conclusions: In addition to maintaining renal and mesenteric perfusion, Ro20 at 10 mcg/kg/min increased cardiac contractility during endotoxemia. However, this effect appears to be dose responsive, as a lower dose of Ro20 does not effect cardiac performance during endotoxemia. Decreases in blood pressure that occur during administration of high doses of this drug may be preload dependent. Use of high doses of PDE4 inhibitors to improve survival during sepsis may require special attention to preload considerations.

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