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CARDIOVASCULAR

A Growth Hormone Secretagogue Prevents Ischemic-Induced Mortality Independently of the Growth Hormone Pathway in Dogs with Chronic Dilated Cardiomyopathy

Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania

Received February 27, 2003; accepted May 7, 2003.

	Abstract

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To determine the functional role of growth hormone (GH) secretagogue in myocardium with ischemia, left ventricular (LV) pressure gauge, wall thickness crystals, coronary occluder, pacers, and catheters were implanted in 26 dogs. Beginning 1 week after ventricular pacing (240 beats/min) was initiated, dogs were treated (s.c.) with GH releasing peptide-6 (GHRP-6, n = 8, 0.2 mg/kg/day), GH (n = 7, 0.06 mg/kg/day), or vehicle (n = 11). Two weeks of pacing was associated with similar decreases in LV pressure, rate of change of LV pressure, systolic wall thickening (WT), and an increase in left atrial pressure in all groups. Coronary artery occlusion (CAO) resulted in a similar loss of WT in ischemic regions, which did not recover during reperfusion period in all groups. WT in nonischemic regions, however, was enhanced in the GHRP-6 group compared with the GH and vehicle groups, e.g., increase of WT after 1 h of reperfusion was greater (p <0.05) in the GHRP-6 (+53 ± 8%) than in the GH (+14 ± 12%) or (+14 ± 6%). There were no differences in myocardial blood flow, hemodynamics, or arrhythmic beats among all groups during CAO and reperfusion periods. Strikingly, no dogs in the GHRP-6 group died during CAO, whereas the survival rates for GH and vehicle groups were 57 and 55%, respectively. Our data demonstrate, for the first time, that chronic therapy with a GH secretagogue prevents sudden death in dogs with dilated cardiomyopathy subjected to acute ischemia. This seems to be related to an enhanced nonischemic compensatory mechanism mediated by the GH secretagogue receptors rather than via the GH/insulin growth factor-1 pathway.

The major goal of the present investigation was to determine whether modulation of GH secretagogue receptors in the myocardium would elicit salutary effects in an intact animal model of chronic heart disease. To achieve this goal, experiments were conducted using conscious dogs with rapid ventricular pacing-induced chronic dilated cardiomyopathy that were subjected to a prolonged period of coronary artery occlusion. The uniqueness of this model is that it not only mimics the process of human chronic heart disease but also allows left ventricular (LV) dysfunction-induced permanent myocardial injury to be studied. To differentiate the potential effects of GH secretagogues acting directly on the myocardium from the effects of GH secretagogues acting via the GH/insulin-like growth factor-1 (IGF-1) pathway, both GH-releasing peptide-6 (GHRP-6), a synthetic peptidyl GH secretagogue, and GH were studied. The dose of GH selected was based on our preliminary data and on results of other studies (Prahalada et al., 1998) in which IGF-1 levels were similar to those induced by the dose of GHRP-6 used in this study. All measurements were made by using chronically implanted instrumentation to directly and continuously measure LV regional myocardial function and systemic hemodynamics.

	Materials and Methods

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The animals used in this study were maintained in accordance with the Guide for the Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources (National Institutes of Health, 1996) and the Merck Research Laboratories Institutional Animal Care and Use Committee. Twenty-six adult dogs, i.e., seven young mongrel (1-year-old) and 19 elderly (9–11-year-old) beagles, weighing 9 to 17 kg, were anesthetized with pentothal (12–15 mg/kg i.v.). After tracheal intubation and ventilation, anesthesia was maintained with isoflurane (1.5–2.0 vol% in oxygen). A left thoracotomy was performed at the 5th intercostal space. Tygon catheters (Norton Plastics, Akron, OH) were implanted in the descending aorta and left atrium to measure their respective pressures and to administer radiolabeled microspheres. The left circumflex coronary artery was isolated, and a flow probe (Transonic Systems Inc., Ithaca, NY) and a hydraulic occluder were implanted to measure coronary blood flow and to temporally occlude the coronary artery, respectively. A solid-state miniature pressure gauge (Konigsberg, Pasadena, CA) was implanted in the LV cavity through the apex to measure LV pressure and the rate of change of LV pressure (LV dP/dt). Two pairs of piezoelectric ultrasonic dimension crystals were implanted transmurally across the LV anterior and posterior regions to measure their respective wall thicknesses. Proper alignment of the crystals was achieved during surgical implantation by positioning the crystals so as to obtain a signal with the greatest amplitude and shortest transit time. A pacing lead (Medtronic Inc., Minneapolis, MN) was attached to the right ventricular free wall, and stainless steel pacing leads were attached to the left atrial appendage. Catheters and electrical leads were externalized between the scapulae, and the chest was closed in layers.

Hemodynamic recordings were made using a data tape recorder and a multiple-channel oscillograph (Gould, Cleveland, OH). Aortic and left atrial pressures were measured using strain gauge manometers (Argon, Athens, TX) that had been calibrated using a mercury manometer connected to the fluid-filled catheters. The solid-state LV pressure gauge was cross-calibrated with aortic and left atrial pressure measurements. LV dP/dt was obtained by electronically differentiating the LV pressure signal. A triangular wave signal was substituted for the pressure signals to directly calibrate the differentiator (Triton Inc., San Diego, CA). Anterior and posterior LV wall thicknesses were measured using an ultrasonic transit-time dimension gauge (Triton Inc.). LV end-diastolic dimension for both regions was measured at the time that coincided with beginning of the upstroke of the LV dP/dt signal. LV end-systolic dimension was measured at minimum LV dP/dt. Systolic wall thickening was calculated as end-diastolic dimension – end-systolic dimension. A cardiotachometer triggered by the LV pressure pulse provided instantaneous and continuous records of heart rate.

Regional myocardial blood flow was measured by using the radioactive microsphere technique. Microspheres (15 ± 1 µm) labeled with Nb⁹⁵, Ce¹⁴¹, Sn¹¹³, Ru¹⁰³, or Sc⁴⁶ (PerkinElmer Life Sciences, Boston, MA) were suspended by placing them in an ultrasonic water bath for 30 min. Each injection of microsphere suspension, which contained approximately 1 million microspheres, was administered through the left atrial catheter and flushed with saline. An arterial blood reference sample was withdrawn at a rate of 7.75 ml/min for 120 s. Regional tissue samples were collected at the end of the study and radioactivity was measured using a gamma counter with appropriately selected energy windows. After correcting the radioactive counts for background and crossover, regional blood flow was calculated and expressed as milliliters per minute per gram of tissue.

The experiments were initiated 10 to 14 days after surgery. One week before surgery and during the postoperative recovery period, the dogs were trained to lie quietly in the right lateral position. After obtaining hemodynamic recordings for baseline measurements of LV systolic pressure, LV dP/dt, mean arterial pressure, left atrial pressure, LV wall thickness and systolic wall thickening in the anterior and posterior regions, and heart rate while the dogs were conscious, rapid (240 beats/min) right ventricular pacing was initiated and continued for 4 weeks using a programmable external cardiac pacemaker (model EV4543; Pace Medical, Waltham, MA). The dogs were treated subcutaneously with either GHRP-6 at a dose of 0.2 mg/kg (n = 8), porcine GH at a dose of 0.06 mg/kg (n = 7), or vehicle (n = 11) once daily for 3 weeks beginning on the 7th day of ventricular pacing. There were four and three young dogs in the GHRP-6- and vehicle-treated groups, respectively. The dose of GH selected for the present study was determined by a preliminary study. In that study, we found that administration of GHRP-6 at a dose of 0.2 mg/kg/day for 2 weeks increased plasma IGF-1 by 94 ± 18 ng/ml from a baseline level of 103 ± 15 ng/ml. Administrations of GH increased plasma IGF-1 by 78, 90, and 183 ng/ml at doses of 0.03, 0.06, and 0.10 mg/kg/day, respectively. After the 1st week of treatment (i.e., 2 weeks after rapid ventricular pacing was initiated), the pacing was temporarily stopped and the dogs were administered morphine sulfate (0.3 mg/kg s.c.). While the dogs were conscious and hemodynamic status continuously monitored, the left circumflex coronary artery was occluded for 90-min duration for the young dogs and 60-min duration for the elderly dogs by inflating the implanted hydraulic occluder. Our feasibility data showed that elderly dogs were more vulnerable to myocardial ischemia compared with young dogs. Based upon our initial results, the myocardial infarct size developed after 60 min of coronary artery occlusion and 4 days of reperfusion in the elderly dogs was similar to that induced by 90 min of occlusion and 4 days of reperfusion in young dogs. Immediately before coronary artery reperfusion, a 1.5-ml bolus injection of lidocaine (2%) was administered via the left atrial catheter. Microspheres were given before coronary artery occlusion, 3 to 5 min after coronary artery occlusion, and approximately 5 min after coronary artery reperfusion. Hemodynamic recordings were made continuously for up to 3 h after coronary artery reperfusion and then rapid ventricular pacing was resumed. Four days later, the dogs were euthanized with an overdose of pentobarbital sodium and their hearts were excised and placed on a dual perfusion apparatus as described previously (Shen et al., 1996). Briefly, the ascending aorta was cannulated (distal to the sinus of Valsalva) and perfused retrogradely with Monastral blue dye (0.2% solution; Sigma-Aldrich, St. Louis, MO). The left circumflex coronary artery was cannulated at the site of occlusion and perfused with saline. The driving pressure for the perfusion apparatus was maintained at approximately 120 mm Hg for both cannulas. After perfusion, the hearts were fixed in 5% formalin for 3 days and then sectioned at the atrioventricular junction. The LV was sliced into six to nine rings and both sides of the individual rings were photographed using a digital camera. The previously occluded vascular bed, i.e., the area at risk, was identified. The surface area of each ring was traced using computer-assisted planimetry to measure the area at risk and infarct size. After pathological analysis, the individual rings were sectioned to measure regional myocardial blood flow.

Because both baseline hemodynamics and hemodynamic responses to all treatments were similar for young versus elderly dogs, data for both groups of animals were combined and presented in all tables and figures. Data obtained before and after rapid ventricular pacing and in response to coronary artery occlusion and reperfusion were compared using Student's t test for paired data with a Bonferroni correction. Comparisons among the GHRP-6-, GH-, and vehicle-treated groups were conducted using an unpaired Student's t test. Survival rates for the groups were compared using Fisher's exact test. All values are expressed as the mean ± S.E. Statistical significance was accepted at the p < 0.05 level.

	Results

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Hemodynamics before and after Rapid Ventricular Pacing. The values for LV systolic pressure, LV dP/dt, mean arterial pressure, mean left atrial pressure, systolic wall thickening in the nonischemic and potentially ischemic regions, and heart rate in conscious dogs before and after 2 weeks of rapid ventricular pacing and 1 week of treatment with vehicle, GHRP-6, or GH are shown in Table 1. There were no differences among the three treatment groups in any of these indices before initiation of rapid ventricular pacing. After 2 weeks of pacing and 1 week of treatment, LV systolic pressure, LV dP/dt, and mean arterial pressure had decreased (p < 0.05), whereas mean left atrial pressure had increased (p < 0.05) similarly in all three groups. In addition, systolic wall thickening in the nonischemic and potentially ischemic regions was reduced in the three groups. However, not all of the reductions in regional function were significantly different from the control values, and there were no differences among the three groups.

Effects of Coronary Artery Occlusion (CAO) and Coronary Artery Reperfusion (CAR). There were no differences in LV systolic pressure, LV dP/dt, mean arterial pressure, heart rate, or systolic wall thickening in the nonischemic and ischemic zones among the groups treated with vehicle, GHRP-6, and GH before CAO. The changes in LV systolic pressure, LV dP/dt, mean arterial pressure, wall thickening in the nonischemic and ischemic zone, and heart rate during CAO and CAR are shown in Fig. 1. During CAO, there was either no wall thickening or wall thinning in the ischemic zone in all three groups, and systolic wall thickening did not recover during the 3-h monitoring period after CAR (Fig. 1). However, systolic wall thickening in the nonischemic zone during CAO was significantly (p < 0.05) increased by 37 ± 8% in the group treated with GHRP-6, whereas systolic wall thickening was increased by only 14 ± 8 and 7 ± 14% from the baseline levels in the groups treated with vehicle and GH, respectively. Mean left atrial pressure was increased (p < 0.05) similarly in the groups treated with vehicle (15 ± 4 mm Hg), GHRP-6 (15 ± 3 mm Hg), or GH (15 ± 4 mm Hg) during CAO. After CAR, the increase in systolic wall thickening in the nonischemic zone was significantly (p < 0.05) greater in the group treated with the GHRP-6 compared with the vehicle- and GH-treated groups. For example, systolic wall thickening in the nonischemic zone was increased (p < 0.05) by 53 ± 8% 1 h after CAR in the GHRP-6-treated group, which was significantly (p < 0.05) greater than in the vehicle-(14 ± 6%) and GH-treated (14 ± 12%) groups.

View larger version (27K): [in this window] [in a new window]   Fig. 1. Effects of GHRP-6, GH, and vehicle on LV systolic pressure, LV dP/dt, mean arterial pressure, systolic wall thickening in the nonischemic and ischemic zones, and heart rate in conscious dogs during CAO and 3 h of reperfusion. Values are percentages of change from control (C) baseline levels. During CAO and reperfusion, systolic wall thickening in the ischemic zone was reduced similarly in the GHRP-6-, GH-, and vehicle-treated groups. In contrast, systolic wall thickening in the nonischemic zone was increased significantly (p < 0.05) in the GHRP-6-treated group compared with the GH- and vehicle-treated groups. There were no differences in any of the other indices among the three groups.

The effects of CAO and CAR on regional myocardial blood flow in the non- and ischemic zones are shown in Table 2. Blood flow in the endo-, mid-, and epimyocardial layers before CAO was similar among the three groups. Both early (i.e., 5 min) and late (i.e., just before CAR) during CAO, blood flow in the ischemic zone had decreased more in the endomyocardium than in the epimyocardium. However, there were no differences among the three groups studied, suggesting that the functional collateral blood flow was developed similarly. After CAR, blood flow in all of the layers was increased slightly more than the baseline level, suggesting that a reactive hyperemic response had occurred. The changes in blood flow in the endo-, mid-, and epimyocardium did not differ among the three groups at any of the time points. The pathology data for the infarct size are summarized in Fig. 2. There were no differences among the vehicle-, GHRP-6-, and GH-treated groups with respect to LV, area at risk, or infarct weights. Thus, the infarct size, expressed as a percentage of the area at risk, was similar among the groups treated with vehicle (36 ± 5%), GHRP-6 (42 ± 3%), or GH (44 ± 5%).

View larger version (18K): [in this window] [in a new window]   Fig. 2. LV, area at risk (AAR), and infarct (IF) weights for dogs treated with GHRP-6, GH, and vehicle. IF is normalized as percentage of AAR. Coronary artery occlusion did not result in any statistical difference in the AAR, IF, or IF/AAR among the three groups.

There were no differences in the number of ventricular arrhythmic beats among the vehicle-, GHRP-6-, and GH-treated groups either before or during 5, 15, 30, or 60 min after CAO as shown in Fig. 3. Two dogs in the vehicle-treated group developed ventricular tachycardia, one 7 min and one 40 min after CAO. Two dogs in the GHRP-6-treated group developed ventricular tachycardia, one 3 min and one 16 min after CAO. One dog in the GH-treated group developed ventricular tachycardia 18 min after CAO. The survival rates for the vehicle-, GHRP-6-, and GH-treated groups during prolonged CAO are shown in Fig. 4. The survival rate was 55% (i.e., 6 of 11 dogs) and 57% (i.e., four of seven dogs) for the vehicle-treated and GH-treated groups, respectively. Interestingly, none of the dogs (total n = 8) in the GHRP-6-treated group died during CAO. In the subgroup of elderly animals, the survival rate was 43 and 57% in the groups treated with vehicle and GH, respectively.

View larger version (14K): [in this window] [in a new window]   Fig. 3. Effects of CAO on the occurrence of ventricular arrhythmic beats in conscious dogs treated with GHRP-6, GH, or vehicle. Values are the average number of arrhythmic beats within each of monitored time period that occurred during CAO with no difference among the three groups.

View larger version (14K): [in this window] [in a new window]   Fig. 4. Effects of GHRP-6, GH, and vehicle on survival rate during coronary artery occlusion. Clearly, both the GH- and vehicle-treated groups had similar mortality rates. In contrast, no animals in the GHRP-treated group died.

	Discussion

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We have demonstrated that chronic treatment with GHRP-6, a peptidyl GH secretagogue, prevented sudden death in dogs with moderately dilated cardiomyopathy subjected to acute myocardial ischemia. To our knowledge, this is the first time that this effect of a GH secretagogue has been reported. We also found that GHRP-6 considerably enhanced regional myocardial function in the nonischemic zone when myocardial contraction was depressed in the ischemic zone after coronary artery occlusion. This compensatory phenomenon may explain how GHRP-6 prevented acute cardiac failure-induced death during coronary artery occlusion.

It has been postulated that GH secretagogues target cardiac receptors, which potentially mediate their actions independent of GH release. To determine whether the observed effects of GHRP-6 were related to GH/IGF-1 release rather than a specific GH secretagogue pathway, an additional group of dogs treated with GH alone was included. The dose of GH that was selected was based on our preliminary data and on results of other studies (Prahalada et al., 1998) in which IGF-1 levels were similar to those induced by the dose of GHRP-6 used in this study. Interestingly, both mortality and regional myocardial function in the nonischemic zone in the GH-treated group were similar to those in the vehicle-treated group, but different from those in the GHRP-6-treated group, suggesting that the observed salutary effects of GHRP-6 were most likely mediated by GH secretagogue receptors rather than by the GH/IGF-1 pathway. Recently, a gastric-derived peptide, ghrelin, has been proposed as the natural ligand of the GH secretagogues receptors (Cassoni et al., 2001; Katugampola et al., 2001). It also has been shown that administration of ghrelin enhanced cardiac function both in rats with heart failure (Nagaya et al., 2001b) and in healthy volunteers' (Nagaya et al., 2001a), further supporting the potential GH secretagogues to affect myocardial function.

In our study, none of the dogs in the GHRP-6-treated group died during coronary artery occlusion. In contrast, the mortality rates for the vehicle- and GH-treated groups were comparable, i.e., about 50%. Although the precise mechanism that is responsible for this unexpected finding is unclear, it is apparently unrelated to ventricular arrhythmia/tachycardia leading to ventricular fibrillation-induced sudden death, because the frequency of ventricular arrhythmia and tachycardia in each group was similar during sustained coronary artery occlusion. In addition, there were no differences in global hemodynamics between these three groups at baseline or during coronary artery occlusion or reperfusion, which excludes the possibility that hemodynamic changes were responsible for the enhanced regional myocardial function induced by the GHRP-6. Also, we did not observe any differences among the three groups in the area at risk, infarct size, or hemodynamics, including systolic wall thickening in the ischemic zone, regional myocardial blood flow, and collateral blood flow within the entire risk area in any layers of the myocardium early or late during the prolonged coronary artery occlusion.

It is conceivable that despite a significant loss of myocardial contractile function in the ischemic zone, the GHRP-6-induced increase in contractile function in the nonischemic zone facilitated overall cardiac function, thereby effectively preventing acute cardiac failure leading to death. Importantly, unlike other inotropic responses, the enhanced regional myocardial contractile function induced by GHRP-6 was not accompanied by a substantial increase in myocardial blood flow. The change in myocardial blood flow in any layer of myocardium in the nonischemic zone was minimal in the GHRP-6-treated group early and near the end of the period of coronary artery occlusion, whereas systolic wall thickening was increased by approximately 40%.

In conclusion, chronic therapy with GHRP-6, a GH secretagogue, prevents sudden death in dogs with moderately dilated cardiomyopathy subjected to acute myocardial ischemia. This effect seems to be related to an enhanced nonischemic compensatory mechanism and mediated via specific GH secretagogue receptors rather than via the GH/IGF-1 pathway.

	Acknowledgements

 
We acknowledge the technical assistant from Laboratory Animal Resources (Merck Research Laboratories).

	Footnotes

 
DOI: 10.1124/jpet.103.050997.

ABBREVIATIONS: GH, growth hormone; LV, left ventricular; IGF-1, insulin-like growth factor-1; GHRP-6, growth hormone releasing peptide-6; LV dP/dt, rate of change of LV pressure; CAO, coronary artery occlusion; CAR, coronary artery reperfusion.

Address correspondence to: Dr. Y.-T. Shen, Department of Pharmacology, Merck Research Laboratories, WP46-200, West Point, PA 19486. E-mail: you-tang_shen{at}merck.com

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This Article Abstract Full Text (PDF) All Versions of this Article: jpet.103.050997v1 306/2/815    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shen, Y.-T. Articles by Gould, R. J. Search for Related Content PubMed PubMed Citation Articles by Shen, Y.-T. Articles by Gould, R. J.