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Anesth Analg 2005;100:629-635
© 2005 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000145065.20816.B5

CARDIOVASCULAR ANESTHESIA

The Effects of Dexmedetomidine on Left Ventricular Function During Hypoxia and Reoxygenation in Isolated Rat Hearts

Huan Guo, MD, Shunji Takahashi, MD, Sungsam Cho, MD, Tetsuya Hara, MD, Shiro Tomiyasu, MD, and Koji Sumikawa, MD

Department of Anesthesiology, Nagasaki University School of Medicine, Nagasaki, Japan

Address correspondence and reprint requests to Sungsam Cho, MD, Department of Anesthesiology, Nagasaki University School of Medicine, 1–7–1 Sakamoto, Nagasaki 852–8501, Japan. Address e-mail to chos{at}net.nagasaki-u.ac.jp.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Hypoxia resulting from apnea in patients with sleep apnea is an important factor in heart disease. We designed the present study to determine whether dexmedetomidine (DEX) has a direct protective effect against hypoxia-reoxygenation-induced left ventricular dysfunction without systemic hemodynamic and humoral effects. Isolated rat hearts were exposed to 60-min hypoxia followed by 30-min reoxygenation with 0, 10, or 100 nM DEX prehypoxia administration (n = 7 each group). In a second experiment (n = 7), 100 nM DEX was administered posthypoxia. In a third experiment (n = 7 each group), an {alpha} 2 antagonist, yohimbine was given with and without 100 nM DEX prehypoxia administration. DEX prehypoxia, but not posthypoxia, administration significantly improved the recovery of left ventricular developed pressure after reoxygenation (0, 10, 100 nM DEX prehypoxia or 100 nM DEX posthypoxia values were 53 ± 6, 64 ± 9, 78 ± 13, or 62 ± 12 mm Hg [mean ± sd]) and reversed by yohimbine, 58 ± 8 mm Hg, respectively. We conclude that DEX exerts the direct protective effect on the left ventricular dysfunction caused by hypoxia-reoxygenation through mainly {alpha} 2-adrenergic stimulation before and during the hypoxic period.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Tissue hypoxia resulting from apnea-related hypoxia in patients with sleep apnea is an important factor in heart disease (1). Hypoxia and reoxygenation expose the myocardium to extremes in redox stress, which can result in the initiation of a series of cellular pathways leading to tissue injury and death. Myocardial hypoxia reduces left ventricular (LV) contractile performance (2–4), and reoxygenation is associated with additional damage to the myocardium by oxidation of cellular components and activation of the inflammatory cascade (5).

Dexmedetomidine (DEX), a highly specific and selective {alpha} 2-adrenergic agonist, decreased the risk of adverse cardiac events, including myocardial ischemia during the perioperative period in a human study (6). It is also reported that {alpha} 2-adrenergic stimulation has beneficial in vivo effects on ischemic myocardium and that this protective effect is attributable to sympatholytic and heart rate decreasing effects by a central nervous system action (7–9). However, we know little about the effect of {alpha} 2-adrenergic stimulation on the LV function and oxygen consumption during hypoxia and reoxygenation.

In human study, DEX increases preload and afterload and decreases heart rate and cardiac output (10,11). DEX is also reported to decrease the plasma catecholamine concentration in normal subjects and inhibit neurohumoral indices of the stress response (9,10). However, Housmans (12) reported that DEX had no intrinsic myocardial contractile effects except for a slight increase in maximal isotonic relaxation. The discrepancy of effects on LV function may have been the result of the involvement of indirect effects of DEX in the in vivo study, such as a decrease in sympathetic outflow from the central nervous system and the increase in afterload. The direct effects of {alpha} 2-adrenergic stimulation on coronary circulation in the normal state, ischemic state and in the presence of abnormal (e.g., atherosclerotic) endothelium are also controversial.

This study was conducted to test the following hypotheses. 1) DEX can exert a direct protective effect on the LV dysfunction caused by hypoxia-reoxygenation. 2) The protective effect is related to the dose and timing of administration. 3) The protective effect of DEX is mediated via {alpha} 2-adrenergic stimulation. We used an isolated buffer-perfused heart model to assess the direct myocardial effects of DEX on LV function, coronary flow (CF), and oxygen consumption during hypoxia and reoxygenation without systemic hemodynamic and humoral effects.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
All experimental procedures and protocols were approved by the Animal Care and Use Committee of Nagasaki University School of Medicine. In each experiment, male Sprague-Dawley rats weighing 350–400 g were anesthetized with diethyl ether and sodium pentobarbital (100 mg/kg IP) and then heparinized (2000 U/kg IP). A midline sternotomy was performed, and the heart was rapidly excised, submerged into the oxygenated perfusate (37°C, composition provided below), and immediately perfused via the ascending aorta in a Langendorff coronary perfusion system (13). Coronary perfusion pressure (CPP) was kept at 80 mm Hg throughout the experiment. LV apex was punctured with a thin piece of Tygon tubing to discharge the Thebesian drainage (13). Another piece of soft silicone tubing with a fenestrated tip was advanced into the right ventricle via the main pulmonary artery and then held in place by suturing it securely at its base. The opposite end of this tube was placed 5 cm below the position of the heart, and the collected fluid (all perfusate through the coronary sinus and the right ventricular Thebesian veins) was passed down the tube by siphoning. Then, a thin latex balloon attached to the end of a piece of stiff polyethylene tubing was inserted into the LV cavity through the mitral valve. The balloon was held in place by suture around the mitral annulus, ensuring that the circumflex coronary artery was not damaged. The balloon and tubing were filled with water and connected to a pressure transducer (blood pressure monitor link sck-9082 Becton Dickinson, Franklin Lakes, NJ) for measurement of the isovolumic LV pressure. A bipolar pacing catheter was inserted into the right ventricle through the right atrium and connected to an electronic stimulator (SEN-7203; Nihon-Kohden, Tokyo, Japan) that was paced at 5 Hz (300 bpm). The heart was submerged into the heat-jacketed KH buffer, which was gassed by nitrogen at 37°C. CPP was kept constant by an adjustable-speed rotary pump (Masterflex model 7520–50; Cole-Parmer Instruments, Vernon Hills, IL) and continuously monitored from the sidearm of the perfusion line near the aortic root that was attached to another pressure transducer. The perfusate was composed of (in mmol/L) NaCl 120, KCl 5.8, NaHCO3 25, NaH2PO4 1.2, MgCl2 1.2, CaCl2 1.0, and dextrose 10. The pH was adjusted to 7.40–7.45 at 37°C with HCL and monitored by a Cyber scan pH 510 device (Kagaku Kyoeisha Ltd., Tokyo, Japan). Perfusion buffer was continuously bubbled with 95% O2 + 5% CO2 to achieve Po2 (450–550 mm Hg) and Pco2 (30–40 mm Hg) in the normoxia condition. During the hypoxic state, buffer was bubbled with mixed gas, 95% O2 + 5% CO2, and 95% N and 5% CO2 to achieve Po2 (70–100 mm Hg) and Pco2 (30–40 mm Hg). A filter (0.45 µm, Millipore, Billerica, MA) was used for the buffer before it perfused the coronary circulation. After the instrumentation was completed, all hearts were allowed to stabilize for at least 10 min before baseline measurement, and hearts in which LV developed pressure (LVDP) was less than 80 mm Hg at the baseline were excluded.

LV end-diastolic pressure (LVEDP), LV peak systolic pressure (LVSP), and the peak rates of positive and negative changes in LV pressure (dP/dtmax and dP/dtmin) were measured by AP-641G blood pressure amplifier (Nihon-Kohden) and shown on the Polygraph system (Nihon-Kohden). CF was determined by the volume collected per minute through the tube in the main pulmonary artery. The hemodynamic measurements and CF were recorded at baseline, prehypoxia, 10, 30, and 60 min after hypoxia, and every 10 min after reoxygenation. We also collected the perfused buffer from the sidearm of the perfusion line near the aortic root and tube in the main pulmonary artery aerobically at baseline, prehypoxia, 30 and 60 min after hypoxia, and 30 min after reoxygenation to measure Po2 and Pco2 using the ABL-625 device (Radiometer, Copenhagen, Denmark); myocardial oxygen consumption (MVo2) was also determined. LVDP and MVo2 were calculated as follows:



{4MMU1}



{4MMU2}

MVo2 was calculated according to the Fick principle with the use of the Bunsen absorption coefficient ({alpha}' = 0.036 µL/mm Hg/mL) at 37°C.

In all preparations, hemodynamic measurements, CF, and MVo2 were studied. The pacing rate, CPP and the initiating volume of the balloon in the LV were maintained constant. The experimental protocol is shown in Figure 1. Group A (n = 7) served as a time control experiment without any intervention. In other groups, isolated rat hearts underwent 60 min hypoxia followed by 30 min reoxygenation. The period of hypoxia, Po2 level 70–100 mm Hg, was chosen to decrease LVDP approximately 50% of baseline after 10 min reoxygenation, and LVDP beyond 30 min reoxygenation was little changed in our preliminary study. In a first experiment, group B, C, or D (n = 7 each group) received 0, 10, or 100 nM DEX from 5 min before hypoxia to the end of experiment. The dose of DEX was set on the basis of a previous study that showed that stroke volume was unchanged until approximately 10 nM DEX using 0.3–62.3 nM DEX in volunteers (11), and these concentrations of DEX corresponded to 2 and 20 times clinical plasma concentrations for sedation in the intensive care unit. In a second experiment, Group E (n = 7) received 100 nM DEX only after hypoxia. In a third experiment, an {alpha} 2 antagonist, yohimbine, was given with and without 100 nM DEX prehypoxia administration to block the presumed {alpha} 2-adrenergic agonist effect of DEX. Group F (n = 7) received 1 µM yohimbine 10 min before hypoxia to the end of the experiment. Group G (n = 7) received 1 µM yohimbine 10 min before hypoxia to the end of the experiment and 100 nM DEX from 5 min before hypoxia to the end of the experiment. The dose of yohimbine was chosen on the basis of the previous study using an isolated rat heart model (14).



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  		Figure 1. Experimental protocol. DEX = dexmedetomidine.

 

DEX was supplied by Orion Corporation (Espoo, Finland) and directly added to the KH buffer. Yohimbine was purchased from Sigma Chemical Company (St. Louis, MO). It was prepared as solution (1 mM in water) on the day of experiment and added to the KH buffer directly. The other drugs were obtained from Wako Pure Chemical Company (Osaka, Japan).

All values were expressed as mean ± sd. Data within and among groups were analyzed with analysis of variance for repeated measures followed by Turkey-Kramer test. A P value <0.05 was considered statistically significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
There were no significant differences in any measurement at baseline among the groups (Table 1 and figures). LVDP in group A was more than group B, and in group D more than groups B, C, E, and G (Figs. 2 and 3). LVEDP in group C was less than group B, and in group D less than groups B and E (Figs. 4 and 5).


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  		Table 1. Baseline Left Ventricular Function and Oxygen Consumption in Each Group

 


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  		Figure 2. The dose and timing effects of dexmedetomidine on left ventricular developed pressure during hypoxia and reoxygenation. Values are mean ± sd (n = 7 each group). DEX = dexmedetomidine. * Significantly (P < 0.05) different from group B. {dagger}Significantly (P < 0.05) different between group C and D. {ddagger}Significantly (P < 0.05) different between group D and E.

 


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  		Figure 4. The dose and timing effects of dexmedetomidine on left ventricular end-diastolic pressure during hypoxia and reoxygenation. Values are mean ± sd (n = 7 each group). DEX = dexmedetomidine. *Significantly (P < 0.05) different from group B. {ddagger}Significantly (P < 0.05) different between group D and E.

 



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  		Figure 3. The effects of yohimbine on left ventricular developed pressure during hypoxia and reoxygenation. Values are mean ± sd (n = 7 each group). DEX = dexmedetomidine. *Significantly (P < 0.05) different from group B. #Significantly (P < 0.05) different between group D and G. $Significantly (P < 0.05) different between group F and G.

 



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  		Figure 5. The effects of yohimbine on left ventricular developed pressure during hypoxia and reoxygenation. Values are mean ± sd (n = 7 each group). DEX = dexmedetomidine. *Significantly (P < 0.05) different from group B. $Significantly (P < 0.05) different between group F and G.

 
Hypoxia immediately impaired LV function in all groups. LVDP, dP/dtmax, dP/dtmin, and MVo2 decreased, and LVEDP increased significantly (Table 1 and figures). CF increased during the first 10 min and then gradually deceased (Table 1). LVDP in group C was more than group B, and in group D more than group G after 60 min hypoxia (Figs. 2 and 3). LVEDP in group D was less than group B, and in group G less than groups B and F (Figs. 4 and 5). The dP/dtmax and dP/dtmin in group D were more than group G, and dP/dtmin in group F less than group B (Table 1).

Reoxygenation resulted in poor recovery of LV function after 30-min reoxygenation (Table 1 and figures). As compared with group A (control), LVDP in groups B, C, E, F, and G were less, and LVEDP in groups B and F were more, and dP/dtmax in group B was less. LVDP in group C was more than group B, and in group D more than groups B, C, E, and G after 30 min reoxygenation (Figs. 2 and 3). LVEDP in groups C, D, E, and G were less than group B (Figs. 4 and 5). The dP/dtmax and dP/dtmin in group D were more than groups B, E, and G (Table 1). CF and MVo2 in group D were more than groups B and G (Table 1). These results showed that DEX administration prehypoxia, but not after hypoxia, improved recovery of the LVDP, dP/dtmax, dP/dtmin, and CF and also showed that the effect was antagonized by yohimbine. Only LVDP appears to be dose-dependent. Conversely, DEX administration not only prehypoxia but also after hypoxia improved recovery of the LVEDP, and the effect was not antagonized by yohimbine.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The present results show that hypoxia immediately impairs LV function and causes an immediate increase in CF followed by a gradual decrease, and reoxygenation results in poor recovery of LV function. DEX administration prehypoxia, but not after hypoxia, improves recovery of LV function and CF, and the effects are antagonized by yohimbine. These results suggested that this protective effect could be mediated via {alpha} 2-adrenergic stimulation mainly before and during the hypoxic period. Administration of DEX improves recovery of LVEDP not only prehypoxia but also after hypoxia administration, and the effect is not antagonized by yohimbine. The results suggested that DEX might have the property of decrease in LVEDP, albeit not via {alpha} 2-adrenergic stimulation. It has previously been reported that DEX increased maximal isotonic relaxation in isolated ventricular myocardium (12).

Although the mechanisms by which DEX exerts its protective effects against hypoxia-reoxygenation-induced LV dysfunction are not clear, there are several possible explanations. First, DEX might exert the protective effect against hypoxia-reoxygenation-induced LV dysfunction through inhibition of the release of norepinephrine (NE). Chen et al. (15) showed that the postischemic heart had a large amount of coronary NE overflow and that reduction in cardiac NE with reserpine significantly improved the recovery of postischemic LV function in an isolated working heart preparation. They suggested that acute reduction in cardiac NE might be of potential therapeutic importance for postischemic LV dysfunction. Ebert et al. (11) reported that DEX diminished the hemodynamic and NE response to the activation of cardiac sympathetic nerves by the cold pressor test. The release of NE from the isolated human papillary muscle was inhibited by xylazine, an {alpha} 2-adrenergic agonist (16). Clonidine and DEX could prevent a myocardial ischemia-induced NE release in anesthetized dogs (9,17). Thus it is likely that DEX could inhibit hypoxia-reoxygenation-induced NE release from cardiac sympathetic nerve endings and thus improve the recovery of LV function.

Second, DEX could increase the cyclic adenosine monophosphate (cAMP) level in the coronary artery. In the present study, hypoxia caused an immediate increase in CF followed by a gradual decease, similarly to the results of Karmazyn et al. (18), and reoxygenation resulted in poor recovery of CF. Pinsky et al. (19) reported that the graft vasculature stored with hypoxia impaired vascular function and decreased blood flow after transplantation. They also showed that hypoxia enhanced phosphodiesterase activity and caused a time-dependent decline in cAMP levels in the vascular smooth muscle cells. Our results also show that DEX prehypoxia administration significantly increases CF after reoxygenation. Kitakaze et al. (20) reported that an increase in cAMP level by stimulation of adenosine receptors was amplified by the {alpha} 2-adrenergic stimulation in the coronary artery. Thus it is possible that DEX could increase the cAMP level and attenuate coronary vascular damage and preserve CF. Third, DEX could ameliorate myocardial damage resulting from the enhancement of an adenosine-induced coronary vasodilative effect. Kitakaze et al. (20) provided evidence that {alpha} 2-adrenergic stimulation increased CF during ischemia as a result of enhancement of adenosine-induced coronary vasodilation, although {alpha} 2-adrenergic stimulation exerted prominent vasoconstriction in nonischemic hearts. However, DEX did not significantly improve the CF during hypoxia in the present study. Thus it is difficult to explain the protective effect of DEX by this hypothesis.

In conclusion, DEX exerts a direct protective effect against hypoxia-reoxygenation-induced LV dysfunction, and this effect is mediated mainly via {alpha} 2-adrenergic stimulation before and during the hypoxic period.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press