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Effects of acute intravenous iloprost on right ventricular hemodynamics in rats with chronic pulmonary hypertension Author(s): Nabil S. Zeineh, Timothy N. Bachman, Hazim El-Haddad and Hunter C. Champion Source: Pulmonary Circulation, (-Not available-), p. 000 Published by: The University of Chicago Press on behalf of Pulmonary Vascular Research Institute Stable URL: http://www.jstor.org/stable/10.1086/677358 . Accessed: 20/11/2014 02:10 Your use of the JSTOR archive indicates your acceptance of the Terms & Conditions of Use, available at . http://www.jstor.org/page/info/about/policies/terms.jsp . JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range of content in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new forms of scholarship. For more information about JSTOR, please contact [email protected]. . The University of Chicago Press and Pulmonary Vascular Research Institute are collaborating with JSTOR to digitize, preserve and extend access to Pulmonary Circulation. http://www.jstor.org This content downloaded from 213.41.170.64 on Thu, 20 Nov 2014 02:10:31 AM All use subject to JSTOR Terms and Conditions ORIGINAL RESEARCH Effects of acute intravenous iloprost on right ventricular hemodynamics in rats with chronic pulmonary hypertension Nabil S. Zeineh,1 Timothy N. Bachman,1 Hazim El-Haddad,2 Hunter C. Champion1 1 Vascular Medicine Institute, Pulmonary Allergy and Critical Care Medicine, Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA; 2Department of Internal Medicine, Wake Forest University Medical Center, Winston-Salem, North Carolina, USA Abstract: The inotropic effects of prostacyclins in chronic pulmonary arterial hypertension (PAH) are unclear and may be important in directing patient management in the acute setting. We sought to study the effects of an acute intravenous (IV) infusion of iloprost on right ventricular (RV) contractility in a rat model of chronic PAH. Rats were treated with monocrotaline, 60 mg/kg intraperitoneally, to induce PAH. Six weeks later, baseline hemodynamic assessment was performed with pressure-volume and Doppler flow measurements. In one group of animals, measurements were repeated 10–15 minutes after IV infusion of a fixed dose of iloprost (20 μg/kg). A separate group of rats underwent dose-response assessment. RV contractility and RV–pulmonary artery coupling were assessed by the end-systolic pressure-volume relationship (ESPVR) and end-systolic elastance/effective arterial elastance (Ees/Ea). RV cardiomyocytes were isolated, and intracellular cAMP (cyclic adenosine monophosphate) concentration was measured with a cAMP-specific enzyme immunoassay kit. Animals had evidence of PAH and RV hypertrophy. Right ventricle/(left ventricle þ septum) weight was 0.40 0.03. RV systolic pressure (RVSP) was 39.83 1.62 mmHg. Administration of iloprost demonstrated an increase in the slope of the ESPVR from 0.29 0.02 to 0.42 0.05 (P < .05). Ees/Ea increased from 0.63 0.07 to 0.82 0.06 (P < .05). The RV contractility index (max dP/dt normalized for instantaneous pressure) increased from 94.11 to 114.5/s (P < .05), as did the RV ejection fraction, from 48.0% to 52.5% (P < .05). This study suggests a positive inotropic effect of iloprost on a rat model of chronic PAH. Keywords: prostacyclin, contractility, right ventricle. Pulm Circ 2014;4(4):000-000. DOI: 10.1086/677358. I NT RO D UCT I ON Pulmonary hypertension is a syndrome of increased pulmonary vascular resistance (PVR) that ultimately leads to right ventricular (RV) failure.1-3 The treatment of patients presenting with acute worsening of RV function in the context of chronic pulmonary arterial hypertension (PAH) is a poorly tackled clinical issue and involves management of preload, afterload, and coronary perfusion pressure and often involves addition of positive inotropes.4,5 For enhancing RV myocardial contractility, dobutamine or dopamine6 has been traditionally favored over milrinone because of the latter’s smaller impact on systemic vascular resistance.7 Inhaled nitric oxide8,9 and traditional vasodilator therapies such as prostacyclins10 and intravenous phosphodiesterase- 5 inhibitors have been evaluated11 in their ability to reduce pulmonary artery (PA) pressure and vascular resistance. It has been shown that prostacyclin analogs (iloprost, epoprostenol) improve ventriculoarterial coupling in animal models of acute rise in RV afterload.12,13 There have been some conflicting reports regarding the inotropic effect of these agents on the right and left ventricles (RV and LV, respectively), both in controls and in animal models of acute RV failure but not chronic RV failure. The effect of intravenous prostacyclin administration on RV contractility has not been studied in models of chronic pulmonary hypertension. We therefore sought to study the effects of an acute intravenous infusion of a prostacyclin Address correspondence to Dr. Hunter C. Champion. E-mail: [email protected]. Submitted January 14, 2014; Accepted February 18, 2014; Electronically published October 29, 2014. © 2014 by the Pulmonary Vascular Research Institute. All rights reserved. 2045-8932/2014/0404-00XX$15.00. This content downloaded from 213.41.170.64 on Thu, 20 Nov 2014 02:10:31 AM All use subject to JSTOR Terms and Conditions 000 | Iloprost and RV contractility Zeineh et al. analog on RV contractility in a frequently used model of chronic pulmonary hypertension. METHODS All experiments were approved by the University of Pittsburgh Institutional Animal Care and Use Committee. Ten Sprague-Dawley rats weighing 250–350 g were treated with monocrotaline (MCT) 60 mg/kg intraperitoneally (IP). Six weeks later, they were brought to the animal physiology laboratory for hemodynamic assessment and iloprost infusion. Central venous access was obtained via internal jugular venous cannulation using sterile PE-50 tubing. To obtain in vivo hemodynamic measurements, rats were anesthetized with an IP injection of ketamine (100 mg/kg) and acepromazine (5 mg/kg). The rats were then ventilated by the insertion of a tracheal cannula attached to a rodent ventilator (Harvard Apparatus, South Natick, MA) set to 90 breaths/min, with a tidal volume of 8 mL/kg body weight. The chest was opened with a midline incision, and then a 4-electrode pressure-volume catheter (Scisence, London, Ontario, Canada) was placed through the RV apex to record chamber volume by admittance and pressure micromanometry, as described previously.14,15 Data were acquired with IOX 2.0 (EMKA, Falls Church, VA). Direct Doppler velocities of the pulmonary arterial flow were obtained with a 20-MHz ultrasound probe (Indus Instruments, Houston, TX). A silk tie was loosely placed around the inferior vena cava (IVC), and a transient decrease in preload was achieved by a gentle constriction of the tie. PA flow velocities and stroke distance were obtained. A family of pressure-volume loops can thus be generated that allows evaluation of the slope of the RV endsystolic pressure-volume relationship (ESPVR). In addition, single-beat estimates of pulmonary arterial elastance (Ea) and end-systolic elastance (Ees) allow for measurement of ventricular-arterial coupling (Ees/Ea).16,17 After baseline hemodynamics had been obtained, iloprost (10 μg/mL) was infused to a total dose of 20 μg/kg body weight over 5 minutes. Hemodynamic measurements were repeated 10–15 minutes after completion of the infusion. In a separate group of rats similarly treated with MCT for 6 weeks (n ¼ 3), a dose-response relationship to intravenous iloprost was evaluated. The rats were first given a volume of drug-free vehicle as control, followed by iloprost 10 μg/kg, and this was followed by a second bolus of iloprost 10 μg/kg. Hemodynamic measurements were obtained with a pressure-volume catheter at baseline and 10–15 minutes after each infusion (4 acquisitions in total per animal). Isolation of rat RV cardiomyocytes Fifteen Sprague-Dawley rats (250–300 g) were treated with MCT 60 mg/kg IP. Six weeks later, the animals underwent deep anesthesia with ketamine 150 mg/kg IP, a thoracotomy was performed, and the hearts were rapidly excised. Cardiomyocytes were isolated via enzymatic dissociation, as previously described.18,19 In brief, hearts were retrogradely perfused with a buffer solution in a Langendorff apparatus at 37°C via the aorta, followed by enzymatic dissociation. RV free walls were carefully separated from the LV and septum before mechanical dissociation. RV cardiomyocytes were then plated in culture dishes containing antibiotic-free bicarbonate-buffered medium (Gibco, Gaithersurg, MD; pH 7.40 in 5% CO2–95% air at 37°C) for 24 hours. Measurement of intracellular cyclic guanosine monophosphate content Cell-containing culture plates were exposed for 30 minutes to control medium (n ¼ 3), [iloprost-1] (10 μg/mL; n ¼ 4), [iloprost-2] (20 μg/mL; n ¼ 4), and [iloprost-3] (30 μg/mL; n ¼ 4) at 37°C. RV cardiomyocytes were then centrifuged at 100 g for 10 minutes at 4°C; the pellets were resuspended in 250 μL lysis reagent and shaken for 10 minutes at room temperature. After centrifugation at 1,000 g for 3 minutes at 4°C to remove the debris, part of the cell lysate was used to determine protein concentration via the Bradford method (Bio-Rad, Hercules, CA), with bovine serum album as the standard. The rest of cell lysate was used for the adenosine monophosphate concentration measurement with a cyclic adenosine monophosphate (cAMP) enzyme-immunoassay (EIA) kit (GE Health Care–Amersham, Piscataway, NJ), according to manufacturer’s instructions. Intracellular cAMP concentration was expressed in optical density (OD)−1/μg protein. Data and statistical analysis All values are reported as means SEM. Paired and unpaired analyses were performed with Student’s t test. Oneway ANOVA was used for multiple group comparisons in the group of animals that underwent control drug-free infusion and dose-response assessment, as well as for comparing intracellular cAMP concentrations. All statistical analysis was performed with Prism (ver. 5.04; GraphPad Software, La Jolla, CA). RES ULTS MCT-induced changes Six weeks after MCT injection, pulmonary hypertension was confirmed: the RV systolic pressure (RVSP) was 39.83 This content downloaded from 213.41.170.64 on Thu, 20 Nov 2014 02:10:31 AM All use subject to JSTOR Terms and Conditions Pulmonary Circulation 1.62 mmHg, which was significantly higher than that for controls (18.67 1.202 mmHg, n ¼ 3). Cardiac output was 47.3 1.60 mL/min. The Fulton index, the ratio of the RV weight to that of the (LV þ septum), is a measure of RV hypertrophy and was measured in 9 animals. It was 0.40 0.03, the normal range being 0.2–0.25. Influence of intravenous iloprost on RV function under conditions of chronic PAH Results from single-dose iloprost infusion are summarized in Table 1. Ten to 15 minutes after completion of iloprost infusion, there was a non–statistically significant increase in cardiac output, from 47.3 to 51.1 mL/min (P ¼ .07), and the heart rate remained unchanged. There was a nonsignificant decrease in peak RVSP, from 42.3 1.62 to 39.2 1.19 mmHg. Several measures of RV systolic function were significantly improved. The RV con- Table 1. Parameters of global cardiovascular function after single-dose iloprost infusion (20 μg/kg) Parameter Heart rate, bpm RVSP, mmHg RV contractility index, 1/sb Cardiac output, μL/min Stroke volume, μL RVEDV, μL Ejection fraction, % ESPVR slope, mmHg/mL Ees, mmHg/mL Ea, mmHg/mL Ees/Ea ESPVR slope/ Ea PVR, Wood units PA flow mean velocity, cm/s Stroke distance, cm Baseline After infusiona 325 11 42.30 1.47 94.11 11.23 332 10 39.20 1.19 114.5 12.06* 47,341 1,596 146.0 3.5 318.0 21.0 47.98 3.73 0.292 0.017 0.205 0.012 0.330 0.019 0.633 0.067 0.897 0.090 0.502 0.025 13.91 4.229 51,129 2,395 153.8 5.2 298.1 20.4* 52.53 2.88* 0.424 0.026* 0.209 0.011 0.256 0.018* 0.827 0.064* 1.682 0.152* 0.337 0.027* 16.15 6.167 2.763 0.795 3.173 1.166 Note: Data are reported as means SEM. N ¼ 4 –10 rats. Ea: arterial elastance; Ees: end-systolic elastance; ESPVR: endsystolic pressure-volume relationship; PA: pulmonary artery; PVR: pulmonary vascular resistance; RV: right ventricular; RVEDV: right ventricular end-diastolic volume; RVSP: right ventricular systolic pressure. a 10 –15 minutes after infusion of 20 μg/kg iloprost. b Maximum dP/dt normalized for instantaneous pressure. * P < .05. Volume 4 Number 4 December 2014 | 000 tractility index (max dP/dt normalized for instantaneous pressure) increased from 94.11/s to 114.5/s (P < .05), as did the RV ejection fraction, from 48.0% to 52.5% (P < .05). The true measure of ventricular contractility is made with the ESPVR, in which the slope of the ESPVR is measured during a reduction in ventricular preload. To achieve this, we obtained pressure-volume data during a transient IVC occlusion before and after iloprost administration. Administration of iloprost demonstrated a significant increase in the slope of the ESPVR, from 0.29 0.02 to 0.42 0.05 (P < .05), in addition to concomitant increases in ventricular-arterial coupling (using either single-beatderived Ees or the ESPVR slope), Ees/Ea, from 0.63 0.07 to 0.82 0.06 (P < .05), and in ESPVR slope/Ea, from 0.897 0.090 to 1.682 0.152 (P < .05). Moreover, PVR decreased from 0.50 0.05 to 0.33 0.05 Wood units (P < .05). There was nonsignificant trend toward increased cardiac output in response to intravenous iloprost infusion, as shown in Table 1. Direct cardiac output measurement, from admittance-derived data, as well as Doppler derived parameters (stroke distance, mean PA flow), were increased, while there was no significant change in heart rate after drug administration. Results of control and dose-response data are summarized in Table 2. Infusion of drug-free vehicle did not have any discernible effect on several indices of inotropy and systolic function, as shown in Figure 1. A trend toward a dose-response relationship was observed with increasing doses of the study drug. The ESPVR slope increased from 0.30 0.06 at baseline to 0.43 0.08 and 0.46 0.08 after infusion of iloprost at 10 and 20 μg/kg, respectively. Similarly, the contractility index increased from 154.0 13.53/s at baseline to 181.0 21.46 and 214.7 25.41/s on the same time line. Similar trends were observed for heart rate response, stroke volume, and cardiac output. There was a trend toward dose-response increase in ESPVR slope/Ea, reflecting improvement in ventricular-arterial coupling as well (Fig. 1d ). Influence of Iloprost on cAMP levels in isolated cardiac myocytes After isolation of RV cardiomyocytes, the level of cAMP, as measured by specific cAMP EIA, was 0.115 0.007 OD−1/μg protein. Iloprost induced a dose-dependent increase in cAMP in isolated RV cardiac myocytes. After 30 minutes of incubation in medium with a concentration of [iloprost-1], there was an approximately 25% increase in cAMP levels (0.145 0.019 OD−1/μg protein). Similarly, levels of cAMP after incubation in medium with This content downloaded from 213.41.170.64 on Thu, 20 Nov 2014 02:10:31 AM All use subject to JSTOR Terms and Conditions Table 2. Parameters of cardiovascular function after drug-free vehicle infusion and dose-response data Parameter Heart rate, bpm RVSP, mmHg RV contractility index, 1/sa Cardiac output, μL/min Stroke volume, μL ESPVR slope, mmHg/mL Ea, mmHg/mL ESPVR slope/Ea Baseline Vehicle Iloprost 10 μg/kg Iloprost 20 μg/kg 262 18 33.33 3.33 154.0 13.5 42,965 5,770* 165.3 23.1 0.3 0.06 0.16 0.01 1.87 0.32 248 22 31.67 0.88 140.3 3.76 39,753 641* 162.7 11.1 0.28 0.07 0.18 0.02 1.58 0.42 313 17 35.33 2.19 181.0 21.5 69,195 10,573* 218.7 25.0 0.43 0.08 0.20 0.05 2.25 0.32 384 10 42 2.52 214.7 25.4 72,015 6,515* 187.0 13.1 0.46 0.08 0.18 0.04 2.63 0.39 Note: Data are reported as means SEM. N ¼ 3 rats. Ea: arterial elastance; ESPVR: end-systolic pressure-volume relationship; RV: right ventricular; RVSP: right ventricular systolic pressure. a Maximum dP/dt normalized for instantaneous pressure. * P < .05. by ANOVA. Figure 1. In rats with chronic pulmonary arterial hypertension, the right ventricular end-systolic pressure-volume relationship (ESPVR) slope, contractility index, and ESPVR slope/Ea showed a trend toward improvement after intravenous iloprost infusion. Cardiac output was significantly improved. N ¼ 3 rats. Ea: arterial elastance. This content downloaded from 213.41.170.64 on Thu, 20 Nov 2014 02:10:31 AM All use subject to JSTOR Terms and Conditions Pulmonary Circulation Figure 2. Cyclic adenosine monophosphate (cAMP) levels in isolated rats cardiomyocytes, measured by enzyme immunoassay (EIA). Dose-response relationship with increasing concentrations of iloprost (1–3) in the cell culture plates. OD: optical density; 1: 10 μg/mL; 2: 20 μg/mL; 3: 30 μg/mL. [iloprost-2] and [iloprost-3] were increased by 56% (0.179 0.015 OD−1/μg protein) and 107% (0.238 0.108 OD−1/μg protein), respectively (Fig. 2). D I S CU S S I O N A number of studies have been published that tackled the question of the direct inotropic effect of prostacyclins on the myocardium.12,13,20-22 The importance of this issue is due to the fact that prostacyclins are often used empirically in the acute setting of PAH decompensation, as well as chronically 23,24 (with proven benefits on quality of life and, sometimes, improved survival). It is unclear whether inotropic effects play a role in the phenotypic responses to treatment. The effects on contractility have been studied in various animal species, with different experimental protocols. Older studies involving isolated atrial and ventricular cardiomyocytes have suggested a positive inotropic effect of prostacyclins, thought to be related to alterations in cAMP metabolism.25,26 In general, in vivo results have been mixed. Studies involving dogs12 and pigs20,22 with acute pulmonary hypertension demonstrated a negative RV inotropic effect of prostacyclins, albeit with improvement in global hemodynamics. These favorable effects have been ascribed to improved ventriculoarterial coupling as well as to a known decrease in afterload. However, acute infusion of prostacyclins in healthy pigs resulted in an increase in left ventricular contractility.13 Similarly, results from a study in 1998 among a cohort of patients with LV failure and secondary pulmonary hypertension showed Volume 4 Number 4 December 2014 | 000 evidence of a positive LV inotropic effect during an infusion of epoprostenol.21 The conflicting nature of previously published results seems to point toward a differential effect of prostacyclins on inotropy, depending on the clinical scenario and disease conditions. To our knowledge, the effect of an acute infusion of prostacyclin on an animal model of chronic PAH with RV hypertrophy has not yet been reported. This model is a closer analog of human PAH as encountered in clinical practice, since patients are typically diagnosed at a fairly advanced stage in the natural history of their disease.27 In this study, we show that iloprost infused at a conventional dosing regimen of 20 μg/kg and a low total infused volume (200–300 μL) improves RV hemodynamics, with evidence of a direct inotropic effect, in addition to a drop in PVR. The ESPVR, as obtained from a transient decrease in venous return, has been previously shown to be an index of contractility that is relatively independent from preload and afterload conditions. In addition, other indices of contractility, such as ejection fraction and the maximal change in pressure/change in time (dP/dt max) normalized for instantaneous pressure, show an increase after infusion of prostacyclin. Afterload (PVR) decreased as well, a finding that correlates with the known pharmacology of iloprost. Finally, we also show that iloprost improves right ventriculoarterial coupling (by measuring both Ees/Ea and ESPVR slope/Ea), most likely reflecting the effect on the pulmonary vasculature as well as on intrinsic ventricular contractility. In both the systemic and the pulmonary arterial beds, ventriculoarterial coupling has been shown to reflect the system’s efficiency,28,29 with higher ratios indicating improved bioenergetics. In other terms, an increase in afterload and arterial system compliance (Ea) normally has to be met by a concomitant increase in contractility (as estimated by Ees and ESPVR slope), and vice versa. A decline in RV–pulmonary arterial Ees/Ea has been shown to be an indicator of developing RV failure and to portend a worse prognosis in both animal models30 and in patients.31 In addition to the inotropic responses observed in fixed-dose experiments, there was a trend toward a dose-response relationship when using subsequently higher doses of iloprost. On a molecular level, and using RV cardiomyocytes from rats with chronic PAH, we have observed a dosedependent increase in intracellular cAMP concentration after exposure to iloprost. The presence of prostacyclin receptors in ventricular tissue has been shown in previous studies,32 and cAMP is a known second messenger in This content downloaded from 213.41.170.64 on Thu, 20 Nov 2014 02:10:31 AM All use subject to JSTOR Terms and Conditions 000 | Iloprost and RV contractility Zeineh et al. the prostacyclin signaling pathway.32-35 Commonly used positive inotropes, such as catecholamines, stimulate adenylate cyclase, production of cAMP, and increased contractility via Ca2þ-mediated facilitation in actin-myosin complex binding with troponin C.36 We hypothesize that the increase in cAMP in RV cardiomyocytes exposed to iloprost might play a mechanistic role in the observed increased inotropy in the model we used here. However, further elucidating the molecular mechanisms underlying these observations is the subject of ongoing studies. We think that our results do not contradict prior published works but rather complement the knowledge in the field. The physiology of hypertrophied ventricles is probably different from that of models in which acute disease is induced or that when healthy control animals are used. Our study model had evidence of RV hypertrophy, as demonstrated by a substantial increase in the Fulton index, and therefore in principle should have exhibited hemodynamic and morphologic changes similar to those that occur in patients diagnosed with PAH. As stated above, iloprost has been shown to have negative effects on contractility in models of acute pulmonary hypertension, and the reasons underlying these different responses are unclear at this time. As with all studies, this study has some limitations. It should be noted that we have not examined the effects of iloprost on RV contractility in a model of acute decompensation in the setting of chronic PAH. Therefore, we cannot infer that positive inotropy will occur in that setting, despite our findings here. Future studies will evaluate the effect of acute on chronic right heart failure in the setting of pulmonary hypertension. The practical clinical implications of these preliminary findings are not clear at this time, given the lack of clinical end points assessed in our animal model (such as mortality). Further studies will be needed to determine the role of iloprost as adjunct inotropic support. Whether the modest increase in various indices of myocardial contractility and systolic function may play a significant role in the acute treatment of human PAH remains to be determined. In conclusion, we report that in a model of chronic PAH with RV hypertrophy, acute iloprost infusion exhibits positive inotropic effects. The evaluation of iloprost or other prostacyclin analogs in the treatment algorithm of acute PAH decompensation merits further study in the clinical setting. Source of Support: Nil. Conflict of Interest: None declared. REF ERE NC ES 1. 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