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Growth Hormone Increases Regional Coronary Blood Flow and Capillary Density in Aged Rats

^a Departments of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
^b Departments of Cardiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
^c Departments of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina

William E. Sonntag, Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1083. E-mail:wsonntag@wfubmc.edu

Decision Editor: John Faulkner, PhD

	Abstract

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In this study, we examined the effects of age and growth hormone replacement on both coronary blood flow and capillary density. Blood flow was measured by using [¹⁴C]-iodoantipyrine in three groups of anesthetized Brown Norway x Fischer 344 rats: young vehicle-treated animals (6 months; n = 13), old vehicle treated animals (30 months; n = 9), and old animals treated with bovine growth hormone (200 µg/kg) twice a day for 30 days (30 months; n = 7). Capillary density was measured by color segmentation analysis of sections stained for platelet endothelial cell adhesion molecule-1. In all regions examined, coronary blood flow decreased with age, and growth hormone administration resulted in an increase in flow compared to vehicle-treated animals. Capillary density decreased with age in the apex and the left ventricular middle segment. In response to growth hormone administration, capillary density increased significantly in the apex but not in other regions of the heart. Our results demonstrate that growth hormone enhances regional myocardial blood flow in the aged heart and suggest that part of this effect could be due to an increase in capillary density.

WITH advancing age, substantial changes in both the structure and function of the cardiovascular system have been observed. The changes in heart structure include an increase in left ventricular wall thickness ⁽¹⁾, a decrease in the number of cardiac myocytes ⁽²⁾, a rarefaction of coronary arterioles ⁽³⁾, and an increase in fibrosis ⁽⁴⁾ and collagen ⁽⁵⁾. It is well known that decreases in left ventricle diastolic filling ⁽⁶⁾, stress response ⁽⁷⁾, myocardial oxygen consumption ⁽⁸⁾, catecholamine responsiveness ⁽⁹⁾, and coronary flow ⁽¹⁰⁾ also occur with increasing age. These and other age-related changes lead to a deterioration in cardiovascular function, which contributes to an overall decline in physical condition and quality of life of the elderly population.

Although the specific etiology of the general functional deficits associated with aging are unclear, recent studies have associated these impairments with alterations in the endocrine system. One of the most robust events that occur with age in rodents, nonhuman primates, and humans is an attenuation of growth hormone pulse amplitude ^(11)(12). The decline in growth hormone secretory dynamics results in a reduction of insulin-like growth factor 1 (IGF-1), and these changes have been hypothesized to contribute to the decline in tissue growth, maintenance, and repair that occurs in aged animals. In some cases, growth hormone replacement therapy has been shown to prevent the age-related decline in tissue function in growth hormone deficient animals and humans. Growth hormone administration to aged animals and humans increases skeletal muscle protein synthesis ⁽¹³⁾, immune function ⁽¹⁴⁾, and lean body mass and skin thickness ⁽¹⁵⁾. Recent data also suggest that a decline in growth hormone and IGF-1 may also have a critical role in the functional decline of the aging myocardium.

Both growth hormone and IGF-1 receptors have been reported to be present in rat hearts ^(16)(17)(18), and recent evidence has shown that growth hormone administration improves cardiovascular function of rodents after left coronary artery ligation ⁽¹⁹⁾ or in animals with left ventricular failure ⁽²⁰⁾. However, these and other studies utilized high doses of growth hormone, which could induce left ventricular hypertrophy, and other deleterious effects, if these doses are administered long term in humans. Other investigators have shown that lower doses of growth hormone can improve cardiac performance in growth hormone deficient children ⁽²¹⁾ and adults ⁽²²⁾. Therefore, we hypothesized that lower, more physiological doses of growth hormone could also ameliorate age-related deficits in myocardial structure and function.

The primary focus of this study was to investigate the effects of growth hormone replacement on regional coronary blood flow and coronary capillary density in aged rats. Using [¹⁴C]-iodoantipyrine to measure regional coronary blood flow ⁽²³⁾, we confirmed the previous reports of an age-related decrease in coronary blood flow and demonstrated that growth hormone replacement increases coronary blood flow compared with that of age-matched controls. Furthermore, we found that an age-related, regional rarefaction occurs in myocardial capillary density, which is partially reversed by growth hormone replacement.

	Materials and Methods

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Animals
Male Brown Norway x Fischer 344 rats were obtained from the Harlan Aging Colony (Indianapolis, IN). Young animals (6 months) and old animals (30 months of age) were housed in an animal satellite facility that is fully accredited by the American Association for Accreditation of Laboratory Animal Care. Rats were maintained on a 12-hour light, 12-hour dark cycle with rat chow (Purina Mills, Richmond, IN) and water available ad libitum. Body weights were monitored and animals that demonstrated external evidence of disease or significant weight loss during the study were eliminated from the experiment. All experimental procedures were approved by the Institutional Animal Care and Use Committee of Wake Forest University School of Medicine.

Animals were divided into three groups: young saline (YSAL; n = 13), old saline (OSAL; n = 9), and old growth hormone (OGH; n = 7; bovine growth hormone 200 µg/kg twice a day for 30 days). This dose of bovine growth hormone has been previously shown to increase plasma IGF-1 in old animals to levels observed in 4-month-old animals (William Sonntag, unpublished data, 1998).

Regional Coronary Blood Flow
General..-- Regional coronary blood flow was measured by a modification to the procedure of Sakurada and colleagues ⁽²⁴⁾ and has been previously described in detail ⁽²⁵⁾. Animals were anesthetized intramuscularly with a mixture of ketamine hydrochloride and xylazine (6 mg/100 g and 0.8 mg/100 g of body weight, respectively). Polyethylene catheters (Clay-Adams PE 50; i.d., 0.58 mm; o.d., 0.965 mm) were inserted in the femoral artery and vein. Immediately before coronary blood flow measurement, body weight and body temperature were recorded and a sample of arterial blood was removed for an analysis of plasma IGF-1.

Procedure..-- [¹⁴C]-iodoantipyrine concentrations were measured from precisely timed samples of arterial blood. The period of measurement of regional coronary blood flow was 1 minute, during which a ramp infusion of [¹⁴C]-iodoantipyrine (50 µCi/ml) in physiological saline was administered through the femoral vein. Throughout the infusion, arterial blood samples were collected every 5 seconds from the freely flowing femoral arterial catheter. The blood drops were collected on preweighed filter paper in scintillation vials. Immediately after collection, the filter paper and vials were weighed to determine the volume of blood, assuming a specific gravity of 1.05 g/ml. The filter paper was then suspended in 5 ml of scintillation cocktail (ScintiSafe 30%, Fischer Scientific, Raleigh, NC), shaken overnight to elute the [¹⁴C]-iodoantipyrine, and assayed by liquid scintillation counting (1217 Rackbeta, LKB Wallac, Finland). The concentration of [¹⁴C]-iodoantipyrine per unit volume of blood in each sample was calculated from the measured amount of ¹⁴C and the volume of blood.

At the end of the 1-minute [¹⁴C]-iodoantipyrine infusion, rats were decapitated and the hearts were rapidly removed (within 60 seconds), weighed, frozen in isopentane on dry ice, and stored at -80°C until sectioning. Sections (20 µm) were cut on a cryostat (2800 Frigocut, Leica Instruments, Germany) at -20°C, mounted on glass slides, dried on a warming plate at 60°C, and apposed to Kodak Min-R film for 21 days. Sections were taken from the apex, middle, and basal areas of the heart, according to specifications in Kuchinsky and colleagues ⁽²³⁾. Adjacent sections from each area were saved for immunostaining. A set of autoradiographic [¹⁴C]-microscales (Amersham Pharmacia Biotech, Inc., Piscataway, NJ) was included on each film as standard.

Data Analysis.-- Autoradiograms were analyzed by quantitative densitometry after images were captured from a Northern Light Box (Imaging Research, Ontario, Canada) with a Nikon micro-Nikor 55-mm camera (Nikon, Mel-ville, NY) and Image software (NIH Image 1.44), using a Macintosh computer. Optical density measurements for each structure were made by using a minimum of three heart sections from each animal. Measurements of blood flow were taken from apex, left ventricular (LV) middle, and LV base areas. Blood flow in the right ventricle was assessed from middle and base areas, whereas papillary muscle blood flow was analyzed at the base. Tissue [¹⁴C]-concentrations were determined from the optical densities and a calibration curve obtained by densitometric analysis of the autoradiograms using the calibrated standards after correcting for non-uniform illumination. Rates of blood flow were calculated from the local [¹⁴C]-iodoantipyrine tissue concentrations, the concentration curve of blood [¹⁴C]-iodoantipyrine, and the appropriate constants according to the operational equation of the method given by Sakurada and colleagues ⁽²⁴⁾.

Immunohistochemistry
General..-- Platelet endothelial cell adhesion molecule-1 (PECAM-1) staining to estimate capillary density in aged rodents was performed as described by Rivard and colleagues ⁽²⁶⁾, with slight modifications. PECAM-1 was identified with a murine monoclonal antibody against rat PECAM-1 (Pharmingen, San Diego, CA), followed by donkey antimouse secondary antibody conjugated to peroxidase (Jackson Immunoresearch, West Grove, PA). Briefly, frozen sections were thawed and fixed in 10% formalin in ddH₂O for 10 minutes at room temperature (RT). After they were washed in ddH₂O, slides were incubated in a blocking solution consisting of 1% bovine serum albumin (BSA; Sigma, St. Louis, MO) in phosphate-buffered saline (PBS; pH 7.4) for 30 minutes at RT, and subsequently in primary antibody diluted to 2 µg/ml in the blocking solution for 60 minutes at RT. Slides were washed in PBS, incubated for 30 minutes at RT in secondary antibody diluted to 8 µg/ml in the blocking solution, washed again in PBS, and reacted with diaminobenzidine (Vector Labs, Burlingame, CA) for 5 minutes at RT. Slides were then dehydrated with a gradient of alcohol and xylene, and they were mounted with Permount (Fischer Scientific, Pittsburgh, PA) dissolved in xylene. Control slides were incubated with blocking solution in the absence of primary antibody.

Analysis..-- Bright field images of sections were captured by using a Zeiss Axioplan 2 microscope (Zeiss; Thornwood, NY) with a 40x (N.A. 1.3 plan; Neofluar oil immersion) objective and a SPOT digital camera (Diagnostic Instruments, Sterling Heights, MI). Four images were taken per section, three to four sections per area, resulting in the analysis of 12–16 images per area of the heart. A color segmentation analysis was performed to determine the density of PECAM-1 per high-power field (pixel counts/mm²) with Image Pro Plus Software (Media Cybernetics, Silver Spring, MD) with the analyzer blind to the treatment group. The results were averaged among groups.

IGF-1 Radioimmunoassay
IGF-1 concentrations were measured in plasma after extraction, as previously described ⁽²⁷⁾. IGF-1 antiserum was obtained from the National Pituitary Program, Dr. A. Parlow, and National Institute of Diabetes and Digestive and Kidney Diseases. Thr⁵⁹IGF-1 (Bachem, Torrance, CA) was radiolabeled with ¹²⁵I by using a lactoperoxidase, glucose oxidase procedure ⁽¹¹⁾. Data were expressed in relation to standards run in the same radioimmunoassay.

Statistics
Regional coronary blood flow, body weight, heart weight, plasma IGF-1, body temperature, and capillary density were analyzed by a multivariate analysis of variance (ANOVA), using the SAS program (SAS Institute, Cary, NC). Because the multivariate analysis indicated statistical significance (Wilks's lambda = .009, F(24,36) = 13.96, p < .0001), univariate ANOVAs were performed on individual dependent variables. Significant effects were further assessed by the Student Newman-Keuls or Fischer LSD post hoc tests, as appropriate if p < .05.

	Results

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General Animal Information
As shown in Table 1 , body weight increased 30% with age (p < .05) and increased 6% further in response to growth hormone administration (p < .05). Body temperatures were not different among the groups. Heart weight increased approximately 38% with age (p < .05) and was slightly higher in the OGH group than OSAL group; however, this latter effect did not reach statistical significance. Heart weights corrected for body weight were not different among the groups (data not shown). Plasma IGF-1 decreased approximately 28% with age (p < .05), and it increased 33% in response to the administration of growth hormone (p < .05).

View larger version (80K): [in this window] [in a new window]   Figure 1. Pseudocolor-enhanced photographs depicting blood flow in the base of the rat myocardium, using [14C]-iodoantipyrine. Sections (20 µm) are representative of the changes in blood flow seen with age and growth hormone treatment in A, young saline; B, old saline; and C, old growth hormone treated animals.

View larger version (18K): [in this window] [in a new window]   Figure 2. Regional coronary blood flow decreases with age and was restored by growth hormone treatment in A, apex; B, right ventricle; C, left ventricular (LV) middle; D, LV base; and E, papillary muscle. *Indicates a significant effect when comparing YSAL and OSAL (p < .05). Indicates a significant effect when comparing OSAL and OGH (p < .05). YSAL = young saline; OSAL = old saline; OGH = old growth hormone.

View larger version (146K): [in this window] [in a new window]   Figure 3. Representative images (40x) indicating capillary density as assessed by immunostaining for platelet endothelial cell adhesion molecule-1 in the left ventricular middle from A, young saline; B, old saline; C, old growth hormone; and D, secondary antibody-only control animals.

View larger version (11K): [in this window] [in a new window]   Figure 4. Effects of age and growth hormone administration on capillary density in different areas of the heart. Capillary density (pixel counts/mm2) measurements in the A, apex, indicate a significant decrease with age and an increase with growth hormone treatment. In B, the left ventricular middle, there is a significant decrease in capillary density with age and no effect of growth hormone. In C, the left ventricular base, there was no effect of either age or growth hormone. YSAL = young saline; OSAL = old saline; OGH = old growth hormone. *Indicates a significant effect when comparing YSAL and OSAL (p < .05). Indicates a significant effect when comparing OSAL and OGH (p < .05).

	Discussion

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Although previous studies have used radioactive microspheres and Doppler flow techniques to assess blood flow, we chose to use [¹⁴C]-iodoantipyrine, which has been used extensively in both murine and rodent models ^(24)(29)(30) and has been found to be a sensitive and reliable measure of blood flow in several tissues. A recent study indicated the usefulness of [¹⁴C]-iodoantipyrine in measuring regional coronary blood flow ⁽²³⁾. The use of this chemically inert, diffusable, and slowly metabolized compound to measure regional blood flow allows greater sensitivity to detect changes within different areas of the heart. Because the tissue concentrations of [¹⁴C]-iodoantipyrine are not limited by diffusion, but rather by perfusion, an accurate estimation of blood flow was calculated and determined to be in close agreement with previous studies, both by using radioactive microspheres ^(10)(31) and [¹⁴C]-iodoantipyrine ⁽²³⁾. Regional coronary blood flow was measured solely under basal conditions because the use of vasodilators such as dipyridamole or adenosine decrease mean arterial pressure and thus compromise the analysis of coronary blood flow. Nevertheless, our results indicate that [¹⁴C]-iodoantipyrine can be used to measure basal coronary blood flow in aged animals and that growth hormone increases basal coronary blood flow in aged rats.

We investigated whether the increases in coronary flow with growth hormone administration are due to a reversal of age-related rarefaction of coronary vasculature. Treatment with growth hormone resulted in an increased number of capillary endothelial cells in the apex, an indication that growth hormone stimulated apical angiogenesis. Interestingly, the apex, which contains the terminal branches of the coronary tree, presented both the greatest degree of rarefaction and the most robust increase in capillary density in response to growth hormone. Previous studies indicate that growth hormone stimulates angiogenesis in chorioallantoic membranes of the chick embryo ⁽³²⁾, and replacement with growth factors including IGF-1 has been shown to induce angiogenesis in aged microvessels in vitro ⁽³³⁾. Other investigators have shown that IGF-1 has angiogenic effects on carotid artery cells in vitro ⁽³⁴⁾ and in vivo in the retina ⁽³⁵⁾. Consequently, our results, together with previous reports in the literature, support the conclusion that decreases in growth factors such as IGF-1 contribute to the rarefaction that occurs in different vascular beds with age.

An analysis of alterations in blood flow in the apex of the heart closely follows those found in other myocardial segments, but increased variance in this region prevented the effect from reaching statistical significance (p = .09). Nevertheless, the age-related rarefaction of coronary capillaries within the apex and the increase in capillary density in this area in response to growth hormone potentially could account, at least in part, for the regional increase in blood flow. Studies in our laboratory have previously demonstrated that age-related decreases in cerebral vasculature, specifically cortical arterioles, could be reversed by injections of growth hormone ⁽³⁶⁾. However, in the present study, the LV middle and LV basal segments showed increases in blood flow with growth hormone without a detectable increase in capillary density. It is unlikely that the regional increase in capillary density that was observed in the apical myocardium could account for a global increase in myocardial perfusion. Instead, it is likely that additional factors, such as an effect of growth hormone and/or IGF-1 on vascular resistance, resulted in an increased myocardial perfusion. Previous studies using IGF-1 have indicated that this hormone dilates iliac, renal, and superior mesenteric arteries when delivered as a bolus infusion ⁽³⁷⁾, and it increases blood flow in coronary vasculature beds ⁽³⁸⁾. Although the specific mechanisms for this increase are unclear, it has been proposed that the effects of IGF-1 on regional blood flow are mediated by an increase in nitric oxide activity ^(39)(40) and/or through activation of K⁺ channels ⁽³⁸⁾. However, most of these studies utilized supraphysiological, acute doses of IGF-1, and, as a result, the actions of physiologically elevated levels of the hormone on nitric oxide activity are unknown. Another possible mechanism for the actions of growth hormone and IGF-1 may be through an increase in basal metabolic rate (either directly or through an increase in thyroid hormone), which could subsequently increase myocardial metabolism and result in an increase in myocardial perfusion. However, we did not observe any evidence of increased metabolic rate in the whole animal. Rectal temperatures were taken immediately prior to blood flow measurement and no differences were observed among the groups. Finally, it is possible that growth hormone and IGF-1 regulate the release of other trophic factors, such as nitric oxide ⁽⁴⁰⁾ or matrix metalloproteases ⁽⁴¹⁾ from the vascular endothelial cells that may regulate blood flow and angiogenesis. Therefore, our studies suggest that growth hormone increases both angiogenesis and blood flow and that deficits in the growth hormone/IGF-1 axis with age are a contributing factor in vascular rarefaction and the decreases in coronary blood flow evident in aged animals. The specific mechanisms for the effect of growth hormone and IGF-1 remain to be determined.

We also considered that the lack of a uniform increase in myocardial capillary density in response to growth hormone may be due to age-associated pathologies. Animals were 29 months of age when growth hormone treatment was initiated, and consistent with previous studies, fibrosis ⁽⁴⁾ and collagen accumulation ⁽⁵⁾ were observed at necropsy and during the analysis of tissue sections from aged animals. These and other structural alterations that occur in the aging heart may not be reversible by a 30-day growth hormone treatment and may thus represent a pathological barrier to increasing capillary density in these areas.

Both growth hormone and IGF-1 have been shown to exert direct actions on cardiac function. In rodents, these hormones have been shown to increase stroke volume, cardiac output ⁽⁴²⁾, and systolic Ca²⁺ force responsiveness ⁽⁴³⁾, and to improve contractile performance after induction of heart failure by ligation of the left coronary artery ⁽¹⁹⁾. Chronic, high doses of growth hormone have been demonstrated to result in cardiac hypertrophy in humans ⁽⁴⁴⁾ and an increase in heart weight, contractility, and heart rate in mice ⁽⁴⁵⁾. Replacement therapy with physiologic doses of growth hormone can also increase stroke volume in growth hormone deficient adults ⁽⁴⁶⁾ and increase maximal oxygen uptake and exercise capacity in cardiomyopathic patients ⁽⁴⁷⁾. Therefore, growth hormone replacement appears to have beneficial effects on both rodent and human cardiovascular function.

In conclusion, this study demonstrates that growth hormone replacement to aged rats is able to reverse the age-related decline in regional myocardial blood flow and regional capillary density in cardiac tissue. At present, it is unclear whether these effects represent a direct action of growth hormone and/or IGF-1. Previous studies have demonstrated that growth hormone replacement to animals and humans can improve cardiac function, and this investigation suggests that these changes are associated with increases in basal myocardial blood flow and regional capillary density in the aged myocardium.

	Acknowledgments

 
This research was supported by Grant AG11370 from the National Institute on Aging to William E. Sonntag. Data from this manuscript were presented at the American College of Cardiology 49th Annual Scientific Session, March 2000. The bovine growth hormone was a generous gift of National Institute of Diabetes and Digestive and Kidney Diseases, Dr. A. Parlow, and the National Pituitary Program.

The authors wish to thank Dr. David Lyons and Dr. Linda Porrino for their guidance and training with the procedure for regional coronary blood flow, Kathie Barrett for her assistance with immunohistochemistry, as well as Dr. Ann Tallant, Sean Bennett, and Rhonda Ingram for editorial and technical assistance.

Received October 27, 2000

Accepted April 5, 2001

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