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Ann Thorac Surg 2001;71:265-269
© 2001 The Society of Thoracic Surgeons
a Department of Thoracic Surgery, Karolinska Hospital, Stockholm, Sweden
Accepted for publication June 9, 2000.
Address reprint requests to Dr Lockowandt, Department of Thoracic Surgery, Karolinska Hospital, SE-171 76 Stockholm, Sweden
e-mail: ulf.lockowandt{at}ks.se
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Abstract |
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Methods. The left anterior descending coronary artery in anesthetized pigs was occluded for 10 or 60 minutes followed by 120 minutes reperfusion. Thereafter, the flow changes in the left anterior descending coronary artery were studied after intracoronary infusion of ACh, ADO, and ET.
Results. Short-term ischemia (10 minutes) caused a decrease in vasodilatation, but not the vasoconstriction response to ACh. Prolonged ischemia (60 minutes) impaired ADO induced vasodilatation and aggravated ET evoked vasoconstriction.
Conclusions. The present findings suggest that a short period of ischemia (10 minutes) causes disturbances of the endothelial regulation of coronary vascular tone and that this endothelial regulation is more sensitive, and precedes changes in vascular smooth muscle function after ischemia and reperfusion.
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Introduction |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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Acetylcholine (ACh) relaxes vascular smooth muscle cells by binding to muscarinic receptors on the endothelial cell causing release of nitric oxide (NO). Nitric oxide then diffuses from the endothelium to the adjacent smooth muscle cell and produces relaxation by activation of guanylate cyclase and increased intracellular cyclic guanosine monophosphate (cGMP). This vasodilator response is abolished or even reversed to vasoconstriction in conditions with impaired endothelial function, including arteriosclerosis, congestive heart failure and hypertension [1]. In the pig coronary circulation ACh elicits constriction by a direct action on smooth muscle cells which is counteracted by release of NO from the endothelium [2].
In preliminary experiments we could observe a clear cut dilatation of the porcine coronary vessels after infusion of ACh in vivo. The dilatation occurred after a short lasting vascular contraction. This finding is partly inconsistent with other published works regarding porcine coronary vessels reacting to ACh where only a constriction was observed [3, 4]. However, in these publications the vessels were examined in vitro.
Adenosine (ADO), an endogenous nucleoside, is a breakdown product of adenosine triphosphate and has been suggested to be involved in cardiac ischemic preconditioning and also seems to have an infarct limiting capacity during myocardial ischemia [5]. Adenosine exerts its endothelium-independent coronary vasodilator effect through activation of purinergic receptors coupled to adenylate cyclase and generation of cyclic adenosine monophosphate (cAMP).
Endothelin-1 (ET-1) is an endothelially-derived polypeptide with multiple actions including both coronary endothelium-dependent vasodilatation (mainly mediated through release of prostacyclin and NO) and endothelium-independent vasoconstriction [6, 7]. A number of studies have revealed plasma ET levels to be increased in myocardial ischemia [8] and an increase in postischemic sensitivity to ET-1 in the coronary circulation has been demonstrated in vitro [9, 10]. The possible role of ET in cardiac ischemia and reperfusion damage has gained considerable interest. Data on the involvement in the development of myocardial infarction is conflicting however, with no effects, as well as very marked reduction by use of ET-antagonists in experimental myocardial ischemia [8, 10].
Previous studies have suggested that coronary vascular injury is observed only after prolonged ischemia when significant myocardial damage has occurred [11, 12], as assessed by impaired tissue reperfusion and increased coronary vascular resistance. Increased permeability (ie, myocardial accumulation of macromolecules) has been demonstrated in vitro after short-term myocardial ischemia and reperfusion, although the interpretation of these findings has been diverging [12]. In this study we have evaluated the coronary vasoreactivity to ACh, ADO and ET in the pig myocardial circulation in vivo after a brief ischemic period (10 minutes) and an extended ischemic period (60 minutes) followed by reperfusion.
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Material and methods |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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Functional experiments
Swedish farm pigs (25 to 36 kg, n = 15) of either sex were fasted overnight and premedicated with intramuscular ketamine hydrochloride (20 mg/kg; Parke-Davis, Morris Plains, NJ) and atropine sulfate (0.04 mg/kg; NM Pharma, Stockholm, Sweden). Anesthesia was induced by a bolus dose of intravenous sodium pentobarbitone (12 to 18 mg/kg; ACO, Ume
, Sweden) and was maintained by continuous infusion (6 to 15 mg/k/h) of sodium pentobarbitone and fentanyl (10 µg/kg/h; Janssen Pharmaceutica, Beerse, Belgium). Muscle relaxation was obtained by pancuronium bromide (100 µg/kg/h; Organon Teknika, Boxtel, Holland) through a catheter placed in the left femoral vein.
The animals were intubated and automatically ventilated with air and oxygen. Respiratory rate and tidal volume were adjusted to keep arterial blood pH, partial pressure of oxygen (PO2) and partial carbon dioxide pressure (PCO2) within the physiologic range. Body temperature was kept at 38°C to 39°C by means of a heating pad. Fluid was administered through a 7F catheter placed in the femoral vein. An electrocardiogram was connected to the pig for registration of heart rate (HR).
The heart was exposed through a left-sided thoracotomy and division of the sternum, which gives excellent access to the left anterior descending coronary artery (LAD). A vessel loop was passed around the LAD in a position from which approximately the distal two thirds of the artery would be occluded by tightening the snare. Left anterior descending coronary artery blood flow was monitored using an ultrasonic flow probe model PA 100021 (CardioMed AS, Oslo, Norway), which was placed around the artery just proximal to the snare, connected to a CM 1000 blood flow meter and recorded on a Gould ES 1000 (Gould Electronique, Longjenau, France). Proximal to the snare a thin catheter (0.6 mm diameter) was placed in the LAD for infusion of the vasoactive substances and for measurement of LAD blood pressure. The mean systemic blood pressure (MAP) was continuously recorded using Transducers Triplus 6023 (Peter v Berg Medizintechnik, Erlingharting, Germany).
After instrumentation and placement of catheters, the animals were allowed to stabilize for 30 minutes before base line (which equals preischemic) hemodynamic measurements were registered. The LAD was then randomly occluded for 0, 10, or 60 minutes in 5 pigs each. Occlusion was followed by 120 minutes of reperfusion in all pigs after which ACh (10 µg) was infused into the coronary vessel as a bolus injection. Changes in mean LAD flow (MLADF) and mean LAD pressure (MLADP) were registered. After this the MLADF was allowed to return to base line and stabilize for 10 minutes before infusion of ADO (18 µg). Once more, MLADF and MLADP were monitored until MLADF had returned to base line, and then again for a further 10 minutes before infusion of ET (1.2 µg). The MLADF and MLADP were monitored for a final 10 minutes. The doses were chosen based on preliminary experiments with consistent and reproducible flow changes in the LAD without any changes in MAP or HR. All substances were diluted with 2 ml of physiologic saline. Mean systemic blood pressure and HR were registered throughout the experiment.
Statistical evaluation
Values are given as mean ± the standard error of the mean. For statistical evaluation, ordinary or repeated measures of analysis of variance were used with Bonferroni multiple comparison test. (INSTAT software, version 2.01; GraphPad, CA). A p value less than 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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There were no significant hemodynamic changes in the 10 minutes group after 10 minutes of ischemia and 120 minutes of reperfusion. However, in the 60 minutes group after 60 minutes of ischemia and 120 minutes reperfusion there was a significant increase in HR (to 130 ± 4 beats/min; p < 0.01) and a decrease in MAP (to 78 ± 3 mm Hg; p < 0.05), as well as in MLADP (to 70 ± 3 mm Hg; p < 0.001), but no change in the MLADF (40 ± 4 ml/min; Fig 1).
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Acetylcholine infusion in the control pigs evoked a biphasic response consisting of a rapid decrease in MLADF (from 38 ± 5 mL/min to 0 mL/min at 12 ± 2 seconds) followed by a sustained increase in flow (to 105 ± 24 mL/min; p < 0.05 at 167 ± 28 seconds). This vasodilator response returned to normal at 362 ± 106 seconds. In the group subjected to 10 minutes ischemia, the vasoconstrictor response to ACh remained unchanged whereas the vasodilatation was markedly impaired (48 ± 15 mL/min; p < 0.05) without any influence on the time to peak (164 ± 46 seconds) or duration of the response (431 ± 94 seconds). The vasodilatation to ACh was completely abolished by 60 minutes ischemia, which, however, did not influence the vasoconstriction (Figs 2 and 3).
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Comment |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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The vascular endothelium plays an important role in maintaning homeostasis of the blood vessels. Although a number of in vitro studies have demonstrated that vascular injury can occur after brief ischemia, in vivo studies have previously failed to demonstrate endothelial damage following short-term ischemia. Signs of vascular injury, such as changes in myocardial albumin content, altered blood flow distribution, or increased coronary vascular resistance, were not found to be present in vivo until 60 minutes of coronary occlusion [12]. Furthermore, in another in vivo model morphologic changes that were thought to be a prerequisite for endothelial dysfunction were not found to appear within 15 minutes of ischemia [13].
The response to ACh is dependent on the vascular bed studied, thus in the porcine coronary circulation ACh causes vasoconstriction, which is attenuated by endothelin-dependent release of NO [2]. The extent to which the vasodilator portion of the response in our study represents activation of muscarinic receptors with release of NO or as an NO-mediated reactive hyperemia [14] cannot be determined from the present experimental set-up. We observed a short-lasting vasoconstriction to ACh in the control group. This vasoconstriction was not aggravated by ischemia and reperfusion in the 10 minutes group and 60 minutes group suggesting involvement of mechanisms independent of the vascular endothelium in the vasoconstriction evoked by ACh, whereas the vasodilatation after ACh induced constriction was impaired after only 10 minutes ischemia. The present findings, with changes in the response to ACh, before any influence on the response to ADO or ET could be detected, thus supports a hierarchy of ischemia-reperfusion impairment of coronary vascular reactivity. Increased postischemic sensitivity of the coronary vascular bed to ET has been demonstrated in vitro [9], whereas the vasoconstrictor response to ET was augmented after 60 minutes ischemia. This could be due to either an upregulation of vasoconstrictor ETA-receptors during ischemia [15] or diminished release of prostacyclin/NO from endothelial ETB-receptors [16]; however, the latter effect seems less likely since the response to ET in our study remained unchanged after 10 minutes of ischemia when the response to ACh was markedly reduced.
We did not detect any changes in cardiac function (assessed by HR, MAP, MLADP and MLADF) during short-term ischemia (10 minutes), and no changes were detected in this group upon reperfusion in spite of decreased endothelial vasodilator capacity. This suggests that mechanisms other than the functional state of the myocardium or coronary blood flow, as such, participate in the recovery of the endothelium. It has been shown in vitro that the endothelial dysfunction after 15 minutes ischemia persists for at least 60 minutes [12], and it has also been shown that after a 60-minute ischemic period and 12 weeks of reperfusion in vivo, there is still a selective impairment of endothelium-dependent vasodilatation [17].
Endothelial ischemia-induced dysfunction may have important clinical implications with possibilities of altered vasoreactivity and coronary vasospasm, permeability changes and development of edema, adherence of neutrophils and platelets, all leading to recurrent ischemia eventually resulting in further vascular damage and infarction. Therefore, protection of the endothelium could prove to be of great therapeutic value in ischemic events.
Possible endothelial damage is not only the consequence of clinical conditions with decreased myocardial perfusion but also may be caused by interventional procedures such as angioplasty and coronary bypass operations. Coronary revascularization operations are usually performed with cardiopulmonary bypass (ie, a heart-lung machine). However, bypass operations without the use of a heart-lung machine, have recently gained increasing attention [18]. In these operations [18], the blood flow in the vessels to be grafted has to be interrupted for an average of 23 minutes. Quite contrary to what was believed, this constitutes a clear-cut ischemic insult to the heart [19]. Although the long-term effects on the vascular endothelial function have not been assessed in the present study, it seems clear that short-term interruption of the coronary blood flow causes marked effects on the vasodilator capacity of the coronary vessels. It should be emphasized though that stenotic or occluded coronary arteries being the target for coronary bypass operations may adjust to decreased or interrupted flow and respond differently compared to the present experimental setup in which the flow to healthy arteries was investigated.
To what extent off bypass operations are superior to the use of heart-lung machines in trying to attenuate postsurgical impairment of endothelial function remains to be established.
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Acknowledgments |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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References |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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p less than 0.05, 
= infusion of ACh (10 µg).
