Systemic blockage of nitric oxide synthase by L-NAME increases left ventricular systolic pressure, which is not augmented further by Intralipid®

Abstract

Intravenous lipid emulsions (LEs) are effective in the treatment of toxicity associated with various drugs such as local anesthetics and other lipid soluble agents. The goals of this study were to examine the effect of LE on left ventricular hemodynamic variables and systemic blood pressure in an in vivo rat model, and to determine the associated cellular mechanism with a particular focus on nitric oxide. Two LEs (Intralipid(®) 20% and Lipofundin(®) MCT/LCT 20%) or normal saline were administered intravenously in an in vivo rat model following induction of anesthesia by intramuscular injection of tiletamine/zolazepam and xylazine. Left ventricular systolic pressure (LVSP), blood pressure, heart rate, maximum rate of intraventricular pressure increase, and maximum rate of intraventricular pressure decrease were measured before and after intravenous administration of various doses of LEs or normal saline to an in vivo rat with or without pretreatment with the non-specific nitric oxide synthase inhibitor N(ω)-nitro-L-arginine-methyl ester (L-NAME). Administration of Intralipid(®) (3 and 10 ml/kg) increased LVSP and decreased heart rate. Pretreatment with L-NAME (10 mg/kg) increased LSVP and decreased heart rate, whereas subsequent treatment with Intralipid(®) did not significantly alter LVSP. Intralipid(®) (10 ml/kg) increased mean blood pressure and decreased heart rate. The increase in LVSP induced by Lipofundin(®) MCT/LCT was greater than that induced by Intralipid(®). Intralipid(®) (1%) did not significantly alter nitric oxide donor sodium nitroprusside-induced relaxation in endothelium-denuded rat aorta. Taken together, systemic blockage of nitric oxide synthase by L-NAME increases LVSP, which is not augmented further by intralipid(®).

Keywords: L-NAME.; blood pressure; left ventricular systolic pressure; lipid emulsion; nitric oxide.

Figure 1

Effect of Intralipid^® 20% (1.5 and 3 ml/kg) or normal saline on left ventricular hemodynamic variables including left ventricular systolic pressure (LVSP, A), heart rate (HR, B), maximum rate of intraventricular pressure increase (+dP/dt_max, C), and maximum rate of intraventricular pressure decrease (-dP/dt_max, D) in an in vivo rat model. Control group: normal saline (3 ml/kg) was infused intravenously. Values are expressed as the percentage of baseline hemodynamic variables before administration of normal saline or Intralipid^® and shown as means ± SD (n = 8/group). n indicates the number of rats. ^***P < 0.001 and ^*P < 0.05 versus control.

Figure 2

Effect of Intralipid^® 20% (10 ml/kg) or normal saline on left ventricular hemodynamic variables including left ventricular systolic pressure (LVSP, A), heart rate (HR, B), maximum rate of intraventricular pressure increase (+dP/dt_max, C), and maximum rate of intraventricular pressure decrease (-dP/dt_max, D) in an in vivo rat model. Control group: normal saline (10 ml/kg) was infused intravenously. Values are expressed as the percentage of baseline hemodynamic variables before administration of normal saline or Intralipid^® and are shown as means ± SD (n = 10/group). n indicates the number of rats. ^**P < 0.01 and ^*P < 0.05 versus control.

Figure 3

Effect of cumulative administration (0.3 to 10 ml/kg) of two lipid emulsions (Intralipid^® 20% and Lipofundin^® MCT/LCT [medium chain triglycerides/long-chain triglycerides] 20%) and normal saline on left ventricular hemodynamic variables, including left ventricular systolic pressure (LVSP, A), heart rate (HR, B), maximum rate of intraventricular pressure increase (+dP/dt_max, C) and maximum rate of intraventricular pressure decrease (-dP/dt_max, D) in an in vivo rat model. Values are expressed as the percentage of baseline hemodynamic variables before the administration of normal saline or lipid emulsion and shown as means ± SD (n = 6/group). n indicates the number of rats. A: *P < 0.001 versus control. †P < 0.01 and ‡P < 0.05 versus Intralipid^®. B: *P < 0.05 and †P < 0.01 versus control. C: *P < 0.001 versus control. †P < 0.05 versus Intralipid^®. D: *P < 0.001, †P < 0.01, and ‡P < 0.05 versus control.

Figure 4

Cumulative N^ω-nitro-L-arginine-methyl ester (L-NAME) dose-left ventricular systolic pressure (LVSP) response curves in an in vivo rat model. Values are expressed as the percentage of baseline LVSP before administration of L-NAME and are shown as mean ± SD (n = 8). n indicates the number of rats. ^*P < 0.05, ^**P < 0.01 and ^***P < 0.001 versus baseline.

Figure 5

The effects of subsequent administration of Intralipid^® 20% (3 ml/kg) on hemodynamic variables including left ventricular systolic pressure (LVSP, A), heart rate (HR, B), maximum rate of intraventricular pressure increase (+dP/dt_max, C) and maximum rate of intraventricular pressure decrease (-dP/dt_max, D) in an in vivo rat model pretreated with N^ω-nitro-L-arginine-methyl ester (L-NAME, 10 mg/kg), as described in Methods. Values are expressed as the percentage of baseline hemodynamic variable before the administration of L-NAME and are shown as means ± SD (n = 7/group). n indicates the number of rats. ^***P < 0.001, ^**P < 0.01, and ^*P < 0.05 compared with baseline.

Figure 6

The effects of administration of Intralipid^® 20% (10 ml/kg) on hemodynamic variables including left ventricular systolic pressure (LVSP, A), heart rate (HR, B), maximum rate of intraventricular pressure increase (+dP/dt_max, C), and maximum rate of intraventricular pressure decrease (-dP/dt_max, D) in an in vivo rat model after pretreatment with N^ω-nitro-L-arginine-methyl ester (L-NAME, 10 mg/kg), as described in Methods. Values are expressed as the percentage of baseline hemodynamic variable before the administration of L-NAME and are shown as means ± SD (n = 8/group). n indicates the number of rats. ^***P < 0.001, ^**P < 0.01, and ^*P < 0.05 compared with baseline. ^†P < 0.01 compared with L-NAME (10 mg/kg) alone.

Figure 7

Effect of Intralipid^® 20% (10 ml/kg) or normal saline on mean blood pressure (MBP, A), heart rate (HR, B), systolic blood pressure (SBP, C), and diastolic blood pressure (DBP, D) in an in vivo rat model. Control group: normal saline (10 ml/kg) was infused intravenously. Values are expressed as the percentage of baseline hemodynamic variables before administration of normal saline or Intralipid^® and are shown as means ± SD (n = 7/group). n indicates the number of rats. ^***P < 0.001 and ^**P < 0.01 versus control.

Figure 8

Effect of Intralipid^® (1%) on sodium nitroprusside-induced relaxation in isolated endothelium-denuded rat aorta. Values are expressed as the percentage relaxation of precontraction induced by phenylephrine (10^-7 M) and are shown as mean ± SD (n = 6/group). n indicates the number of rats.