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Ann Thorac Surg 2001;71:1931-1938
© 2001 The Society of Thoracic Surgeons

Original article: cardiovascular

Antiinflammatory effects of colforsin daropate hydrochloride, a novel water-soluble forskolin derivative

Nobuhiko Hayashida, MDa, Shingo Chihara, MDa, Eiki Tayama, MDa, Tohru Takaseya, MDa, Naofumi Enomoto, MDa, Takemi Kawara, MDa, Shigeaki Aoyagi, MDa

a Department of Surgery, Kurume University, Fukuoka, Japan

Accepted for publication February 4, 2001.

Address reprint requests to Dr Hayashida, Department of Surgery, Kurume University, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan
e-mail: nobuhiko{at}med.kurume-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. To evaluate the effects of colforsin daropate hydrochloride (colforsin), a water-soluble forskolin derivative, on hemodynamics and systemic inflammatory response after cardiopulmonary bypass, we conducted a prospective randomized study.

Methods. Twenty-nine patients undergoing coronary artery bypass grafting were randomized to receive either colforsin treatment (colforsin; n = 14) or no colforsin treatment (control; n = 15). Administration of colforsin (0.5 µg · kg-1 · min-1) was started after induction of anesthesia and was continued for 6 hours. Perioperative cytokine and cyclic adenosine monophosphate levels, hemodynamics, and respiratory function were measured serially.

Results. Marked positive inotropic and vasodilatory effects were observed in patients receiving colforsin. Interleukin 1ß, interleukin 6, and interleukin 8 levels after cardiopulmonary bypass were significantly (p < 0.05) lower in the colforsin group. Plasma levels of cyclic adenosine monophosphate increased significantly (p < 0.05) in the colforsin group, and the levels correlated inversely (r = -0.56, p = 0.002) with the respiratory index after cardiopulmonary bypass.

Conclusions. Intraoperative administration of colforsin daropate hydrochloride had potent inotropic and vasodilatory activity and attenuated cytokine production and respiratory dysfunction after cardiopulmonary bypass. The results indicate that the technique can be a novel therapeutic strategy for the systemic inflammatory response associated with cardiopulmonary bypass.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Forskolin, a diterpene derivative of the Indian plant Coleus forskohlli, has been shown to have potent positive inotropic and vasodilatory effects by increasing intracellular cyclic adenosine monophosphate (cAMP) through an activation of adenylate cyclase [1]. Because the action has been reported not to be associated with ß-adrenoceptor-mediated mechanism, administration of the drug is considered to be beneficial in patients with chronic heart failure [2]. Despite the potent cardiotonic effect, clinical use of forskolin is limited by its properties of insolubility in water and low oral activity. Recently, colforsin daropate hydrochloride, 6-(3-dimethylaminopropyonil) forskolin hydrochloride (Fig 1), has been developed as a water-soluble derivative of forskolin [3]. Several reports have shown that the regimen has potent positive inotropic and vasodilatory effects in vitro and in vivo [3–5]. The mechanism of action of the agent, like forskolin, has been reported to be mediated by an increase in intracellular cAMP, resulting in an increase in intracellular calcium concentration and acceleration of its kinetics [3]. In a clinical study, the regimen has also been shown to improve hemodynamics in patients with chronic congestive heart failure, especially when patients are insensitive to ß-adrenoceptor stimulants or to phosphodiesterase (PDE) inhibitors [5].



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  		Fig 1. Chemical structures of forskolin and colforsin daropate hydrochloride.

 
It is now well recognized that cardiac operations using cardiopulmonary bypass (CPB) cause a systemic inflammatory response and that the degree of the response is associated with the incidence of postoperative organ failure, such as left ventricular dysfunction and adult respiratory distress syndrome [6, 7]. To reduce the deleterious effects and improve the clinical results after CPB, numerous therapeutic interventions have been investigated. In a recent report, it has been suggested that cAMP-elevating agents, such as xanthine derivatives and specific PDE inhibitors, suppressed cytokine production in lipopolysaccharide-stimulated mononuclear cells [8]. We also have shown that milrinone, a type III PDE inhibitor, inhibited cytokine production by elevating cAMP levels in patients undergoing coronary artery bypass grafting [9]. Therefore, one could hypothesize that colforsin daropate hydrochloride also suppresses the production of proinflammatory cytokine by an increase in intracellular cAMP level in patients undergoing CPB. However, to date, effects of colforsin daropate hydrochloride on hemodynamics and inflammatory response have not been investigated in patients undergoing cardiac operations with CPB.

The purpose of this study was to evaluate the effects of intraoperative administration of colforsin daropate hydrochloride on perioperative hemodynamics and cytokine production after CPB in patients undergoing coronary artery bypass grafting.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Patients and grouping
Between October 18, 1999, and May 15, 2000, a prospective randomized study was performed on 29 consecutive patients undergoing primary isolated coronary artery bypass grafting by one surgeon (T.K.). All patients signed a consent form approved by the Human Experimental Committee of Kurume University. Exclusion criteria for the study were impaired organ function other than myocardial ischemia, the presence of active inflammatory disease, and acute myocardial infarction. Fifteen patients were receiving aspirin or a nonsteroidal antiinflammatory drug before the operation. Administration of these platelet-active drugs was stopped at least 7 days before the operation. None of the patients was receiving corticosteroids preoperatively. The patients were randomized into two groups by means of a computer-generated randomization table. The control group received no colforsin daropate hydrochloride treatment (n = 15); the colforsin group (n = 14) received continuous infusion of colforsin daropate hydrochloride (Nihon Kayaku, Tokyo, Japan) immediately after anesthesia induction at a rate of 0.5 mg · kg-1 · min-1 for 6 hours. The dose was determined in accordance with a previous study that investigated the optimal clinical dose of the agent [10]. The administration protocol was determined in order to achieve and maintain its therapeutic serum concentration (10 ng/mL within 1 hour) during and shortly after CPB [11]. As a result of this protocol, the duration of administration of the drug after CPB varied from patient to patient (ranging from 105 minutes to 140 minutes). The pharmacology and pharmacokinetics of the drug have been described previously [11]. The demographic data are shown in Table 1.


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  		Table 1. Clinical and Operative Dataa

 
Technique of operation
All patients were premedicated with 1 mg flunitrazepam orally 1 hour before operation. Induction and maintenance of anesthesia were standardized. Anesthesia was induced with fentanyl (2 mg/kg intravenously) and midazolam (0.2 mg/kg intravenously). Muscle relaxation was induced with vecuronium bromide (0.1 mg/kg intravenously). Anesthesia was maintained with inhalation of 1.0% sevoflurane, continuous infusion of propofol (3 mg · kg-1 · hr-1 intravenously), and intermittent administration of fentanyl (2 mg/kg intravenously). The components of the extracorporeal perfusion circuit consisted of a capillary membrane oxygenator, a hard-shell cardiotomy reservoir, an arterial filter (CAPIOX SX (HP); Terumo, Tokyo, Japan), an arterial cannula, a two-staged venous cannula, and a cardiotomy suction (Duraflo II; Baxter Healthcare, Irvine, CA). These components were interconnected by polyvinylchloride tubing (HEPAFACE; Terumo). The circuit was primed with 1,000 mL electrolyte solution (Hespander; Kyorin Pharmaceutical, Tokyo, Japan), 450 mL D-mannitol, albumin (50 gm), sodium bicarbonate (45 mEq), and cefazolin sodium (1.0 g). All patients received 1 x 106 Kallikrein inactivator units (KIU) aprotinin (Trasylol) in the CPB priming solution. Before CPB was initiated, heparin sodium was administered at an initial dose of 300 IU/kg. Additional heparin was administered if the celite-activated clotting time (Hemochron 401; International Technidyne, Edison, NJ) became less than 500 seconds. During CPB, the hematocrit was maintained between 18% and 25%, nonpulsatile perfusion flows were kept between 2.4 and 2.6 L · min-1 · m-2, and mean arterial pressure was maintained between 50 and 60 mm Hg. Systemic temperature was maintained at 31 ± 1°C. During aortic cross-clamping, the myocardium was protected with intermittent antegrade cold blood cardioplegia given at approximately 15-minute intervals. Distal and proximal anastomoses were constructed in an alternating manner during a single period of aortic cross-clamping. Rewarming of all patients was commenced during construction of the last anastomosis. A left internal mammary artery graft was anastomosed to the left anterior descending coronary artery as the last graft in all patients. Cardiopulmonary bypass was terminated at a rectal temperature of 36°C. Heparin was neutralized by continuous intravenous administration of protamine sulfate over a 5-minute period. A minimal dose of catecholamines (dopamine, dobutamine, or both) was used to maintain a cardiac index of greater than 2.1 L · min-1 · m-2 and systolic blood pressure of greater than 80 mm Hg after CPB. Postoperative volume repletion and intensive care unit care followed the standard protocol of this institute.

Cytokine and cyclic adenosine monophosphate levels
Blood was collected from the patient’s peripheral arterial lines or the arterial side of CPB circuit immediately after induction of anesthesia; at 5 minutes after initiation of CPB; at the end of CPB; and at 1 hour, 3 hours, and 18 hours after completion of CPB. All blood samples were drawn in precooled red-top vacuum tubes for determination of cytokines and in precooled vacuum tubes containing disodium ethylenediaminetetraacetic acid (1.5 mg/mL) for determination of cAMP. The samples were immediately centrifuged (1,500 g for 10 minutes) at -4°C. The plasma was transferred to a sterile polypropylene test tube and stored at -80°C until assayed. Interleukin 8 (IL-8) was measured in plasma by means of enzyme-linked immunosorbent assays (Human IL-8 ELISA kit; Toray, Tokyo, Japan). Interleukin 1ß (IL-1ß) was measured in plasma by means of radio immunoassay (Human IL-1 IRMA kit; Medgenix Diagnostics, Fleurus, Belgium). Interleukin 6 (IL-6) was measured in plasma by means of chemiluminescent enzyme immunoassay (Human IL-6 CLEIA kit; Fuji Rebio, Tokyo, Japan). Cyclic adenosine monophosphate was measured in plasma by means of radio immunoassay (YAMASA RIA kit; YAMASA Shoyu, Choshi, Japan). No adjustment was made for hemodilution. The sensitivity was 5 pg/mL for IL-1ß, 4 pg/mL for IL-6, and 12.5 pg/mL for IL-8. Reference range of plasma cAMP was 11 to 21 pmol/mL.

C-reactive protein and MB isoenzyme of creatinine kinase levels
Blood samples for the determination of C-reactive protein and MB isoenzyme of creatinine kinase (CK-MB) levels were also collected from the patient’s peripheral arterial lines immediately after induction of anesthesia and at 1 hour, 3 hours, 12 hours, 24 hours, and 48 hours after completion of CPB. C-reactive protein levels were measured with a turbidimetric immunoassay, and the reference range was 0 to 0.4 mg/dL. Creatinine kinase-MB levels were measured with a chemiluminescent immunoassay, and the reference range was 6 to 28 IU/L. Integration of the area under the time-concentration curve for CK-MB within the first 48 hours postoperatively allowed calculation of the total CK-MB release, expressed as international units times hours per liter.

Hemodynamic measurements
Heart rate (HR), mean arterial blood pressure (MAP), mean pulmonary artery pressure (MPA), mean right atrial pressure (RAP), and pulmonary capillary wedge pressure (PCWP) were measured. Cardiac output (CO) was measured in triplicate by the thermodilution technique (Edwards Swan-Ganz Model 744H-7.5F; Baxter Healthcare). Derived hemodynamic indices were calculated as follows: rate-pressure product = HR x systolic blood pressure (mm Hg/min); cardiac index (CI) = CO/body surface area (L · min-1 · m-2); stroke index (SI) = CI/HR (mL · min-1 · m-2); left ventricular stroke work index = SI x (MAP - PCWP) x 0.0136 (g · m · m-2); right ventricular stroke work index = SI x (MPA - RAP) x 0.0136 (g · m · m-2); pulmonary vascular resistance = (MPA - PCWP)/CI x 80 (dyne · s-1 · cm-5); and systemic vascular resistance = (MAP - RAP)/CI x 80 (dyne · s-1 · cm-5). These hemodynamic variables were measured immediately after induction of anesthesia; 5 minutes before CPB; and at 1 hour, 3 hours, 6 hours, and 18 hours after cessation of CPB. Postoperative volume repletion and intensive care unit care followed the standard protocol of this institute.

Respiratory function
Arterial blood gas analysis was determined by standard techniques using an automated analyzer (860 and 800 CHIRON blood gas system; Chiron Diagnostics, East Walpole, MA). The alveolar-arterial oxygen tension difference (A-aDO2) and respiratory index were calculated as follows: A-aDO2 = [FiO2 x 713 - (PaCO2/0.8)] - PaO2; and respiratory index = A-aDO2/PaO2. These variables were measured at anesthesia induction; at 1, 3, and 6 hours after cessation of CPB; and before extubation.

Statistical analysis
Statistical analysis was performed with StatView 5.0 software (SAS Institute, Cary, NC). All data are expressed as a mean ± standard error of the mean. One-way or two-way repeated measures analysis of variance was used to test the effect of group and time on the levels of cytokines, cAMP, C-reactive protein, CK-MB, and hemodynamic measurements. When analysis of variance indicated a significant effect of group or time (p < 0.05), the differences were specified with Sheffé’s test for within-group comparison and unpaired Student’s t test for between-groups comparison. The Pearson’s correlation coefficient test was used to explore the correlation between cytokine levels and cAMP levels and between respiratory function and cAMP levels. Unpaired Student’s t test was used to compare other continuous variables. Categoric data were analyzed using the {chi}2 test or Fisher’s exact test where appropriate. Statistical significance was assumed at a probability level of less than 0.05.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Clinical and operative data for the two patient groups are shown in Table 1. No significant differences were noted in the clinical and operative data.

Cytokines and cAMP levels
The levels of cytokines and cAMP are shown in Figure 2. Interleukin 1ß levels at the end of CPB in the colforsin group were significantly (p < 0.05) lower than those in the control group. Interleukin 6 levels were significantly (p < 0.05) lower in the colforsin group than those in the control group 5 minutes after initiation of CPB, at the end of CPB, 1 hour after CPB, and 3 hours after CPB. Interleukin 8 levels in the colforsin group were significantly lower than those in the control group at the end of CPB. A marked increase (p < 0.05) in plasma cAMP levels was found in patients receiving colforsin daropate hydrochloride, and the levels were significantly (p < 0.05) greater than those in the control group 5 minutes after initiation of CPB, at the end of CPB, 1 hour after CPB, and 3 hours after CPB. A significant inverse correlation was observed between the plasma cAMP levels at the end of CPB and the peak IL-6 levels after CPB (r = -0.57, p = 0.001).



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  		Fig 2. Cytokine and cyclic adenosine monophosphate (cAMP) levels. Interleukin-1ß (IL-1ß) levels were significantly lower at the end of cardiopulmonary bypass (CPB), and interleukin-6 (IL-6) levels were significantly lower at the end of CPB, at 1 hour after CPB, and at 3 hours after CPB in the colforsin group. Interleukin-8 (IL-8) levels in the colforsin group were also significantly lower than those in the control group at the end of CPB. Plasma cAMP levels in the colforsin group were significantly higher than those in the control group 5 minutes after initiation of CPB, at the end of CPB, at 1 hour after CPB, and at 3 hours after CPB. (Colforsin = colforsin group; Control = control group; Off = at the end of CPB; On = 5 minutes after initiation of CPB; start = induction of anesthesia.)

 
C-reactive protein and MB isoenzyme of creatinine kinase levels
The peak levels of C-reactive protein were significantly lower in the colforsin group than those in the control group (control group, 19.5 ± 1.5 mg/dL; colforsin group, 15.3 ± 1.2 mg/dL; p = 0.03). No significant difference was found in the total releases of CK-MB within the first 48 hours after CPB (control group, 1,306 ± 220 IU x h/L; colforsin group, 1,290 ± 184 IU x h/L; p = 0.96).

Hemodynamic measurements
The hemodynamic measurements are shown in Figure 3. There were no significant differences in mean arterial pressure, mean pulmonary artery pressure, right atrial pressure, heart rate, rate-pressure product and pulmonary vascular resistance between the groups at any time. A marked decrease was observed in pulmonary capillary wedge pressure in the colforsin group 5 minutes before CPB. Cardiac index, right ventricular stroke work index, and left ventricular stroke work index were significantly (p < 0.05) greater in the colforsin group than in the control group 5 minutes before CPB and 1 hour after CPB. Systemic vascular resistance was significantly (p < 0.05) lower in the colforsin group than in the control group 5 minutes before CPB and 1 hour after CPB.



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  		Fig 3. Hemodynamic measurements. A marked decrease was observed in pulmonary capillary wedge pressure (PCWP) in the colforsin group 5 minutes before cardiopulmonary bypass (CPB). Cardiac index (CI), right ventricular stroke work index (RVSWI), and left ventricular stroke work index (LVSWI) were significantly greater in the colforsin group than in the control group 5 minutes before CPB and 1 hour after CPB. Systemic vascular resistance (SVR) was significantly lower in the colforsin group than in the control group 5 minutes before CPB and 1 hour after CPB. (Colforsin = colforsin group; Control = control group; Ind = induction of anesthesia; pre = 5 minutes before CPB; RAP = right atrial pressure; RPP = rate-pressure product.)

 
Respiratory function
Respiratory function measurements are shown in Table 2. The A-aDO2 value was significantly greater in the control group before extubation (p = 0.003). The respiratory index was also significantly greater in the control group 6 hours after CPB (p = 0.03) and before extubation (p = 0.005). Plasma cAMP levels at the end of CPB correlated inversely (r = -0.56, p = 0.002) with the respiratory index before extubation (Fig 4).


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  		Table 2. Perioperative Respiratory Functiona

 


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  		Fig 4. Relationship between the plasma cyclic adenosine monophosphate (cAMP) and respiratory index. Plasma cAMP levels at the end of cardiopulmonary bypass correlated inversely (r = -0.56, p = 0.002) with the respiratory index before extubation. (Colforsin = colforsin group; Control = control group.)

 
Clinical outcome
No serious adverse effects, including hypotension, tachycardia, and arrhythmias, were observed in patients receiving colforsin daropate hydrochloride. No significant difference was found in the lowest platelet level after CPB (control group, 9.4 ± 0.8 x 104/µL; colforsin group, 8.3 ± 0.7 x 104/µL; p = 0.33). The colforsin group experienced significantly shorter intensive care unit stays (control group, 3.0 ± 0.3 days; colforsin group, 2.2 ± 0.1 days; p = 0.03) and duration of intubation (control group, 16.6 ± 2.7 hours; colforsin group, 10.3 ± 1.0 hours; p = 0.04). None of the patients died in this series of 29 patients, nor did any of the patients have perioperative myocardial infarction (defined as the appearance of new Q waves or ischemic ST segment changes with a concomitant rise in CK-MB) or a low-output syndrome postoperatively (defined as a requirement for inotropic medication, balloon pump support, or both because of a cardiac index of less than 2.1 L · min-1 · m-2 and systolic blood pressure less than 80 mm Hg, despite an adequate preload and correction of any electrolyte disorders).


   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
Colforsin daropate hydrochloride, a water-soluble forskolin derivative, has been recently introduced as a positive inotropic and vasodilatory agent [3]. The mechanism of action of the regimen, like forskolin, has been shown to directly activate adenylate cyclase, resulting in an increase in intracellular cAMP [3]. In an experimental study, it has been shown that the regimen increased left ventricular dp/dt, cardiac output, and coronary blood flow and decreased peripheral vascular resistance in a dose-related manner without influencing the balance of myocardial oxygen supply and demand [3]. To date, however, hemodynamic effects of the agent have not been studied in patients undergoing cardiac operations. In the present study, we found a marked increase in plasma cAMP levels during the administration of the drug, with resulting marked increases in cardiac index and left ventricular stroke work index, and decreases in pulmonary capillary wedge pressure and systemic vascular resistance without any effect on the rate-pressure product. Thus, the present study confirms the theoretic action of colforsin daropate hydrochloride that the drug has potent positive inotropic and systemic vasodilatory actions through an increase in cAMP level in patients undergoing cardiac surgery.

In a previous report [3], colforsin daropate hydrochloride has been shown to increase coronary blood flow in an anesthetized dog model. The agent has also been reported to improve coronary circulation and contractility at subendocardium during coronary hypoperfusion [12]. Shafiq and colleagues [4] have demonstrated that the agent inhibited acetylcholine-induced contraction by both attenuating acetylcholine-induced Ca2+ mobilization and reducing the sensitivity of the contractile machinery to Ca2+ in endothelium-denuded porcine coronary artery. In patients with coronary artery sclerosis, endothelium-dependent vasodilation is very likely to be attenuated. Moreover, vasomotor regulation of the coronary circulations was reported to be altered after CPB and cardioplegia, perhaps because of ischemic cardioplegia-reperfusion–induced endothelial dysfunction [13]. Therefore, the endothelium-independent action of the agent, like that of nitroglycerin, is considered to be quite advantageous to the preservation of coronary circulation. Because the patients in this study received blood cardioplegia prepared by mixing four parts of oxygenated blood from CPB circuit with each part of crystalloid, it is probable that the myocardium was perfused with blood containing colforsin daropate hydrochloride during cardioplegic arrest. Therefore, the possibility exists that the improved left ventricular function after CPB in patients receiving colforsin daropate hydrochloride was attributable not only to the positive inotropic and systemic vasodilator activities but also to its cardioprotective effect during ischemia and reperfusion by optimizing the distribution of cardioplegia through the coronary vascular relaxation. In the present study, however, we assessed load-dependent factors (cardiac index, left ventricular stroke work index, and systemic vascular resistance) to compare hemodynamics between the groups. These factors are likely related to vasodilator action. Thus, the better cardiac function in the colforsin group may have been associated with vasodilator action of the agent. Preload independent measurements, after-load independent measurements, or both are required to confirm its pure inotropic effects.

It is well known that heart operations with CPB cause a systemic inflammatory response characterized by activation of complement, neutrophils, coagulation, fibrinolytic and kallikrein cascades, and the synthesis of proinflammatory cytokines, with resulting increases in the incidence of postoperative organ failure and mortality [6, 7]. The degree of the release of proinflammatory cytokines, such as tumor necrosis factor {alpha}, IL-6, and IL-8, has been reported to be associated with the depressed cardiac and pulmonary function after CPB [6, 7]. Therefore, if cytokine production could be reduced during and after CPB, some postoperative organ failure, such as cardiac dysfunction and respiratory distress syndrome, might be avoided.

In in vitro studies, it has been suggested that cAMP-elevating agents, such as xanthine derivatives and specific PDE inhibitors, suppressed cytokine production from lipopolysaccharide-stimulated human mononuclear cells [8, 14–17]. Although the mechanism of action is still not clear, the increase in intracellular cAMP levels has been reported to play an important role in modulating the cytokine production [8, 14–17]. Intracellular cAMP has been reported to depress the accumulation of tumor necrosis factor {alpha} mRNA by inhibiting the transcriptional processes [16]. The processes contrast with the action of glucocorticoids that block cytokine production at the translational level. Elevation of intracellular cAMP levels induced by PDE inhibitors, forskolin, prostaglandin E2, or cell-permeable cAMP analogue also inhibited the secretion of IL-1ß, whereas it increased IL-1ß mRNA levels from lipopolysaccharide-stimulated human monocytes [15, 16]. The present study also has shown that colforsin daropate hydrochloride resulted in a nearly twofold increase in cAMP levels compared to the control group, with a resulting suppression of IL-1ß production in patients undergoing CPB. The results were consistent with those in our previous study [9], in which effects of milrinone, a PDE III inhibitor, on cytokine production after CPB were investigated.

The inhibitory effect of increased intracellular cAMP by either forskolin or vesnarinone on IL-6 production in human tissues has also been reported [18, 19]. However, because these studies have concentrated on the effects of cAMP on cytokine production from certain isolated tissues, interactive tissue response and synergistic action of cytokine network in response to stress have not yet been elucidated in vivo. Moreover, little is known about whether cAMP-elevating agents modulate IL-6 production in patients undergoing cardiac surgery, which provokes multiple causative factors for cytokine production. Recently, we have reported that intraoperative administration of milrinone decreased IL-6 levels, which were inversely related to the cAMP levels after CPB [9]. The present study also has shown a marked reduction in IL-6 concentration after CPB in patients receiving colforsin daropate hydrochloride. Therefore, although the causative mechanisms are not known with certainty, the results of our studies indicate that the elevation in cAMP may be responsible for the inhibition of IL-6 production in patients undergoing cardiac surgery.

Although the regulatory modality of IL-8 production by cAMP is still unclear and depends on the cell type, enhanced cAMP appears to have favorable effects at least on airway cells by suppressing IL-8 production [20, 21]. Thus, the lower systemic IL-8 levels in patients receiving colforsin daropate hydrochloride in the present study can potentially be explained by the inhibitory effect of enhanced cAMP by the agent on IL-8 production from airway-related cells. However, because we measured cytokine levels only in peripheral arterial blood, the present study could not define the tissue source of cytokine. Therefore, further investigations are required to determine whether the inhibitory effects of increasing cAMP on airway inflammation are responsible for the lower systemic IL-8 levels. Very recently, it has been demonstrated that T-lymphocyte chemotaxis induced by IL-8 and platelet-activating factor, which are known to be induced by CPB, was inhibited by cAMP-elevating agents, including forskolin [22]. Enhanced cAMP levels by forskolin have also been recognized to reverse the increased pulmonary microvascular permeability associated with ischemia reperfusion [23]. Accordingly, the results in this study—that the better preserved indices of oxygen transport in the lung and the shorter duration of mechanical ventilation after CPB in patients receiving colforsin daropate hydrochloride—may be associated with the inhibitory effect of enhanced cAMP by the agent on CPB-related injuries in bronchoalveolar epithelial cells or pulmonary capillary.

In this study, cAMP levels were measured in plasma; consequently, the levels may not have directly reflected the intracellular levels. A previous study [24], however, demonstrated that cAMP can pass relatively freely across the cell membrane and that the released levels correlated strongly with cardiac function and coronary vasodilation, whereas intracellular levels did not. Therefore, we believe that the plasma levels are substantially relevant to its functional levels.

Because the patients involved in the present study did not have congestive heart failure and because cardiac function was relatively preserved preoperatively, down-regulation of ß-adrenoceptor may not have been prominent. Moreover, the number of patients was small; therefore, no differences, except for the intensive care unit stay and duration of intubation, were found in the clinical outcome. However, it is conceivable that patients with chronic congestive heart failure who are insensitive to ß-adrenoceptor stimulants or PDE inhibitors may benefit most from colforsin therapy because of improvements in cardiac performance. Moreover, because preoperative cytokine levels are already very likely to increase in such patients, the antiinflammatory effect of the agent may be quite beneficial.

No serious adverse effects were observed in patients receiving colforsin daropate hydrochloride. According to the report from the pharmaceutical company, however, adverse side effects of the agent, such as tachycardia (16.9%), ventricular premature contraction (10.8%), ventricular tachycardia (3.0%), and hypotension (3%), have been observed. The arrhythmogenicity of the agent was also reported to increase by simultaneous administration of catecholamines. Therefore, careful monitoring is required during its administration.

In conclusion, intraoperative administration of colforsin daropate hydrochloride, a novel water-soluble forskolin derivative, had potent positive inotropic and vasodilator activities in patients undergoing coronary artery bypass grafting. The technique also attenuated cytokine production and respiratory dysfunction after CPB. The results indicate that the technique can be a novel therapeutic strategy for the systemic inflammatory response associated with CPB.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
This work was supported in part by the Grant-in-Aid for Encouragement of Young Scientists, Japan Society for the Promotion of Science, Japan (grant A-11770753 and grant A-12770738).


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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