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Cardiovascular Research 1997 36(3):453-459; doi:10.1016/S0008-6363(97)00204-6
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Copyright © 1997, European Society of Cardiology

Reduced myocardial cyclic GMP increases myocardial O2 consumption in control but not renal hypertension-induced cardiac hypertrophy

John D. Sadoff, Peter M. Scholz, James Tse and Harvey R. Weiss*

Heart and Brain Circulation Laboratory, Departments of Physiology and Biophysics, Anesthesia and Surgery, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854-5635, USA

* Corresponding author. Tel. (+1-732) 2354552; Fax (+1-732) 2355038.

Received 25 September 1996; accepted 18 July 1997


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objectives: We tested the hypothesis that a reduction in myocardial cyclic GMP would increase myocardial O2 consumption and that renal hypertension (One Kidney-One Clip, 1K1C)-induced cardiac hypertrophy would change this relationship. Methods: Either vehicle or LY83583 (10–3 M, a guanylate cyclase inhibitor) was topically applied to the left ventricular surface of control or 1K1C anesthetized open-chest New Zealand white rabbits (N = 38). Coronary blood flow (radioactive microspheres) and O2 extraction (microspectrophotometry) were used to determine subepicardial (EPI) and subendocardial (ENDO) O2 consumption and myocardial cyclic GMP was determined by radioimmunoassay. Results: The heart weight/body weight ratio was greater in the 1K1C rabbits (3.16±0.20) than controls (2.58±0.08 g/kg). Systolic blood pressure was higher in 1K1C rabbits (116±8 mm Hg) than controls (80±6), but topical LY83583 had no significant hemodynamic effects. LY83583 significantly and similarly decreased EPI cyclic GMP in both control (7.9±1.2 to 6.0±1.0 pmol/g) and 1K1C (7.7±1.2 to 5.3±0.9) hearts and control ENDO (8.7±1.7 to 7.2±1.2) but not 1K1C ENDO (6.7±0.5 to 5.7±1.1). Myocardial O2 consumption was significantly increased in control with LY83583 (EPI 6.6±1.1 to 15.6±1.4 and ENDO 7.2±0.9 to 14.2±0.7 ml O2/min/100 g), but not in 1K1C hearts (EPI 12.1±1.0 to 12.9±1.2 or ENDO 11.4±0.7 to 12.9±0.9). Conclusions: Thus myocardial O2 consumption was only increased by LY83583 in control hearts, but LY83583 decreased cyclic GMP similarly in both the control and 1K1C EPI. This indicated, at least in the EPI, a dissociation of the inverse relationship between the myocardial level of cyclic GMP and O2 consumption in the 1K1C rabbit heart.

KEYWORDS Renal hypertension; Cardiac hypertrophy; Guanylate cyclase inhibition; Cyclic GMP; Coronary blood flow; Myocardial O2 consumption; Rabbit


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
The second messenger, cyclic GMP, exerts an important influence on myocardial cells [1, 2]. It causes reductions in local myocardial metabolism, inotropy, force development and contractile duration, basically through reductions in cytosolic calcium [1–3]. These effects have been found both in vivo and in vitro in a variety of species including man [1, 4, 5]. In the rabbit heart, increases in the level of myocardial cyclic GMP lead to reduced myocardial O2 consumption [6, 7]. In vascular smooth muscle, increases in cyclic GMP cause vasodilation [2]. There have been few reports on the effects of lowering the basal intrinsic level of myocardial cyclic GMP. Some positive functional effects of lowering cyclic GMP have been reported in isolated papillary muscle [8]. Positive inotropic effects caused by inhibition of guanylate cyclase have also been observed in the intact dog heart [9]. In vascular smooth muscle, reduction in cyclic GMP levels may induce vasoconstriction [2, 10]. It is not clear how important the basal myocardial level of cyclic GMP is in controlling myocardial O2 consumption.

During cardiac hypertrophy, there are often changes in the myocardial level and/or effect of the second messenger, cyclic AMP [11, 12]. Changes in cyclic GMP levels and its effects have been less studied in cardiac hypertrophy. Myocardial cyclic GMP levels have been reported to be elevated in some types of pressure-load hypertrophy [5, 13]. Cyclic GMP levels may also increase during some forms of heart failure [14, 15]. However in the rat, myocardial cyclic GMP levels are normal after aortic constriction [16]. In the rabbit, basal levels of myocardial cyclic GMP were not altered in thyroxine-induced hypertrophy [7]. Cardiac hypertrophy will develop as a basic response of the heart to persistent increases in blood pressure [12, 17]. The effects of pressure-load cardiac hypertrophy on myocardial cyclic GMP levels and cyclic GMP's relationship to the control of myocardial O2 consumption have not been fully elucidated.

In this study, we tested the hypothesis that decreasing the basal endogenous myocardial level of cyclic GMP would increase myocardial O2 consumption in the rabbit heart and that renal hypertension-induced cardiac hypertrophy would alter this relationship. We used topical application of 6-phenylamino-5,8-quinolinedione (LY83583), a guanylate cyclase inhibitor, which can directly affect the heart to decrease the myocardial level of cyclic GMP. This agent was applied directly to the left ventricular surface of control and renal hypertensive (one kidney-one clip, 1K1C) hearts in order to avoid systemic effects in anesthetized open chest rabbits.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
Male New Zealand white rabbits (2–3 kg) (Davidson Mill Farm, Jamesburg, NJ) were used in these experiments. Animals were prepared as a one-kidney one-clip (1K1C) renal hypertensive model [17, 18]under sterile, anesthetized conditions (30 mg/kg sodium pentobarbital, iv). A left flank incision exposed the left kidney and the renal artery was dissected free. A Sterling silver clip (0.5 mm gap opening) was threaded around the artery and folded over itself, securing it in place. This incision was closed and the contralateral kidney exposed. The ureter, renal artery and vein were ligated and the kidney removed. Animals were administered 60 ml of normal saline and kept warm overnight. The rabbits were monitored and antibiotics and/or additional fluid was administered as required. Animals were allowed to recover for thirty-five days. All experiments were conducted in accordance with the Guide for the Care of Laboratory Animals (DHHS Publication No. 85–23, revised 1985) and were approved by our Institutional Animal Care and Use Committee.

In the terminal experiments, nineteen 1K1C and nineteen control rabbits were used. All animals were anesthetized with sodium pentobarbital (30 mg/kg) in the circumflex ear vein, which was supplemented as needed. Polyethylene catheters were introduced into a femoral artery and vein. The arterial cannula was used for measurement of blood pressure, anaerobic collection of arterial blood samples, and withdrawal of blood for blood flow measurements. The venous cannula was used for administration of additional anesthetic. A tracheostomy was performed and an endotracheal tube was inserted to allow artificial respiration using a Harvard respirator. The chest was opened at the fourth intercostal space, the pericardium was opened, and a cannula was inserted through a stab wound in the left atrium to allow injection of radioactive microspheres for coronary blood flow measurements. A 5-French catheter-tip transducer (Millar Inst., Houston, TX) was introduced into the left ventricle through a stab wound in the apex. A multichannel recorder (Beckman Inst., Allendale, NJ) was employed to record the following parameters continuously and simultaneously: heart rate, aortic blood pressure, left ventricular blood pressure and dP/dt. A computer and an A/D converter performed the data acquisition. Arterial blood gases were measured using a Radiometer ABL 330 Blood Gas Analyzer (Radiometer America, Westlake, OH). Eucapnia was maintained by adjustment of the respirator and supplementary oxygen was added to maintain PO2 above 80 mm Hg.

After the surgical preparation was completed, the animals were allowed to stabilize for 15 min after which arterial blood gases, heart rate, blood pressures and dP/dt were measured in preparation for a control coronary blood flow measurement. A dose of approximately 5·105 Formula or Formula -labeled microspheres (Dupont NEN, Boston MA, 15±3 µm diameter) was agitated for approximately 2 min and then slowly injected as a 0.2 ml bolus into the atrial cannula, which was then flushed with 1 ml of saline over the next 20 s. A 3 min timed-reference blood sample, beginning 30 s before the injection of radioactive microspheres, was obtained from the femoral artery using a pump set at approximately 2 ml/min. No changes in hemodynamic parameters occurred during this procedure. The reference-sample method was used to calculate the coronary blood flow of the left ventricular free wall.

Animals received either a guanylate cyclase inhibitor, 6-phenylamino-5,8-quinolinedione (LY83583, RBI, Natick, MA), or vehicle (30% ethanol in saline). The animals were divided into four groups: control-vehicle (N = 9), control-LY83583 (N = 10), 1K1C-vehicle (N = 9) and 1K1C-LY83583 (N = 10). A cotton gauze sponge soaked with either vehicle or LY83583 (10–3 M) was applied to the surface of the left ventricular free wall. The fluid was replaced every 5 min with fresh solution for 15 min. Blood pressures and heart rate were monitored continuously during this period, after which arterial blood gases were again measured. Another blood flow measurement was performed at this point as previously described, using either Formula - or Formula -labeled microspheres.

The hearts were then excised below the atrioventricular ring and quickly frozen in liquid nitrogen. The hearts were weighed and the left ventricular free wall was removed using a band saw at –20°C. The free wall was divided into an inner subendocardial (ENDO) and outer subepicardial (EPI) half using a straight-edged razor blade on dry ice. Sections were then weighed and kept frozen on dry ice until blood flow was determined. The activity of the radioactive microspheres in each blood and tissue sample was determined using a Hewlett-Packard Auto Gamma Spectrometer. Arterial blood samples obtained from the timed-reference samples were weighed and placed in the spectrometer along with the tissue samples. The tissue samples were kept on dry ice and placed in the gamma counter singly, for one min each, to insure they remained frozen. No visible thawing occurred during this time period. Appropriate corrections were made for activity overlap. Blood flows were calculated from the formula Fu=Fk·Cu/Ck, where Fu is the flow to any organ, Fk is the flow to the reference organ, Cu is the radioactivity in any organ, and Ck is the radioactivity in the reference organ. Coronary blood flow was expressed in ml/min/100 g tissue. Cardiac output was determined using the equation: Cardiac output=Fk·Ci/Ck, where Ci is the radioactivity in the injected dose of microspheres.

Once coronary blood flow was determined, half of the tissue samples were used to measure cyclic GMP. The samples were warmed to 0°C and homogenized in ethanol using a Brinkmann Polytron placed in an ice bath. The homogenate was centrifuged at 30 000 g for 15 minutes in a Sorvall RC-5B centrifuge. The supernatant was recovered. The pellet was resuspended in 1 ml of 2:1 ethanol:water and centrifuged as before. The combined supernatants were evaporated to dryness in a 60°C bath under a stream of nitrogen gas. The final residue was dissolved in 1.5 ml of assay buffer (0.05 mol/l sodium acetate, pH 5.8, containing sodium azide). Cyclic GMP levels were determined using a radioimmunoassay (Amersham, Arlington Heights, IL). This assay measures the competitive binding of Formula -cyclic GMP to a cyclic GMP specific antibody. After construction of a standard curve, cyclic GMP levels were determined directly from the counts in picomoles/gram of tissue wet weight.

Arterial and venous O2 saturations were determined from half of the EPI and ENDO samples of the left ventricular free wall of each heart. Details of this technique have been published previously [19]. Briefly, the regions were mounted with an embedding medium in a microtome-cryostat. Twenty micra sections were obtained on the microtome-cryostat at –35°C under a N2 atmosphere. The sections were transferred to precooled glass slides and covered with degassed silicone oil and a coverslip. These slides were placed on a microspectrophotometer (Zeiss, Thornwood, NY) fitted with a N2-flushed cold stage to obtain readings of optical density at 568, 560 and 523 nm. This three-wavelength method corrects for the light scattering in the frozen blood. The size of the measuring spot was 8 µm. Only vessels in transverse section were studied so that the path of light only traversed the blood. Readings were obtained to determine O2 saturation in 5 arteries and 7 veins found in the EPI and ENDO. The O2 content of blood was determined by multiplying the percent O2 saturation by the hemoglobin concentration times 1.36 ml O2/g. The difference between the average arterial and venous O2 contents (regional O2 extraction) was then obtained. Using the Fick principle, the paired product of local O2 extraction and blood flow was used to determine O2 consumption.

An additional four animals, not used for other purposes, were studied to determine the absorption of LY83583 into the left ventricular free wall. LY83583 (10–3 M) was applied to the epicardial surface. This included Formula -LY83583 (ICN Biomedicals, Inc., Irvine, CA) at a specific activity of 10 µCi/µg. After 15 min, the hearts were removed and sectioned into the subepicardial and subendocardial regions of the left ventricular free wall as well as the septal wall. Aliquots of the stock solution and tissue samples were weighed and placed in a gamma spectrometer. Ratios of the activity of the stock and tissue samples were used to determine the concentration of LY83583 in each region.

Analysis of variance (ANOVA) using a repeated measure design was used to determine whether there were differences in hemodynamic or blood gas variables between treatments and groups. This analysis was also used to determine differences between groups, regions and treatments for myocardial O2 consumption, cardiac function, cyclic GMP, and coronary blood flow indices. Analysis was also performed using the Wilcoxon rank sum test. Regional data are presented for both the subepicardium and the subendocardium. In all cases, a value of P<0.05 was accepted as significant. All values are expressed as the mean±standard error of the mean.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
The results obtained from the hemodynamic recordings and blood gas data both before and during treatments for the four groups are presented in Table 1. The 1K1C rabbits had significantly higher systolic, diastolic and mean arterial blood pressure compared to the control rabbits. Cardiac output was greater in the 1K1C-vehicle treated compared to control-vehicle group prior to vehicle. Other hemodynamic parameters were not significantly different in comparisons between control and 1K1C rabbits. Topical application of LY83583 to the surface of the left ventricular free wall had no significant hemodynamic effects. The 24% greater dP/dtmax in the control-LY83583 compared to the control-vehicle group did not achieve statistical significance. The vehicle produced no significant hemodynamic effects. The arterial blood gas and pH values were similar in all groups and were within the physiologically normal range in the four groups. The heart weights (10.0±0.7 g) and heart weight/body weight ratios (3.16±0.20 g/kg) of the 1K1C rabbits were significantly greater than the heart weights (6.7±0.3) and heart weight/body weight ratios (2.58±0.08) of the controls.


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  		Table 1 Hemodynamic and blood gas data for control and 1K1C rabbits prior to and after treatment with vehicle or LY83583

 
The myocardial cyclic GMP data for the four groups are shown in Fig. 1. The endogenous basal EPI and ENDO cyclic GMP levels were similar in the control and 1K1C rabbit hearts of the vehicle treated animals. The EPI cyclic GMP level decreased significantly by 24% in controls and by 31% in the hypertrophied hearts in the groups treated with LY83583. There was no significant difference between the 1K1C and control EPI cyclic GMP levels after LY83583 treatment. In the control group, the ENDO cyclic GMP level was significantly decreased by 17% (1.5 pmol/g) in the LY83583 treated animals compared to that in the vehicle treated hearts. The 15% lower cyclic GMP level in the LY83583 treated ENDO was not statistically different from the vehicle treated ENDO in the 1K1C rabbits.


Figure 1
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  		Fig. 1 Myocardial cyclic GMP levels (pmol/g) of the subepicardial and suendocardial regions of the left ventricular free wall. Data are presented for the control and lKlC rabbits administered either vehicle or LY83583. *, different from comparable vehicle group, p<0.05.

 
Coronary blood flow data are presented in Table 2. Prior to treatment, there were no statistical differences in EPI or ENDO blood flow among the four experimental groups. Application of vehicle to the left ventricular surface produced no changes in EPI blood flow. In the control rabbits, LY83583 significantly increased EPI blood flow by 39% from its value prior to treatment. This blood flow value was also higher than that of the control-vehicle group. Treatment with LY83583 had no significant effects on EPI blood flow in the 1K1C rabbit heart in comparisons to the preexisting level or to the 1K1C-vehicle group value. ENDO blood flow was higher with LY83583 than the vehicle treated group in control, but not from the pre-application value. The hypertrophied hearts had no differences in ENDO blood flow. Myocardial O2 extraction data for the EPI and ENDO after application of the gauze sponge for the four groups are also presented in Table 2. There were no statistically significant differences in either the EPI or ENDO O2 extraction between the two control or two 1K1C groups.


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  		Table 2 Coronary blood flow (before and during treatment with vehicle or LY83583) and myocardial O2 extraction (during) for control and 1K1C rabbits with and without LY83583

 
Regional myocardial O2 consumption data are shown in Fig. 2. In the vehicle-treated hearts, average EPI O2 consumption was significantly higher in the 1K1C-vehicle group (+94%) than the control-vehicle group. Topical treatment with LY83583 significantly increased EPI O2 consumption in the control hearts by 136% compared to that of the control-vehicle group. EPI O2 consumption was not significantly affected by LY83583 in the 1K1C hearts. The ENDO O2 consumption was greater in the LY83583 treated compared to the vehicle treated control hearts, but not hypertrophied hearts. ENDO O2 consumption was greater in the vehicle treated hypertrophied hearts than in the control group. Thus, despite similar decreases in the level of EPI cyclic GMP in control and hypertrophied hearts, EPI O2 consumption did not increase in the hypertrophied hearts.


Figure 2
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  		Fig. 2 Myocardial O2 consumption (ml O2/min/100 g) of the subepicardial and subendocardial regions of the left ventricular free wall. Data are presented for the control and lKlC rabbits administered either vehicle or LY83583. *, different from comparable vehicle group, p<0.05. + different from comparable control group, p<0.05.

 
In the four animals in which Formula -LY83583 was placed on the epicardial surface, the concentration of LY83583 within the heart was determined after 15 min. The concentration of LY83583 in the EPI region under the applied patch was 7x10–6±1x10–6 M. In the ENDO region of the left ventricular free wall, the LY83583 concentration averaged 5x10–7±3x10–7 M. Some LY83583 was also measured in the septal region (2x10–8±1x10–8 M), which was not directly exposed to the bathing solution.


   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
The major finding of this study was that reducing the endogenous basal level of the second messenger cyclic GMP in the heart increased myocardial O2 consumption in the control rabbits, while similar reductions in subepicardial cyclic GMP in a renal hypertension-induced hypertrophic heart had no significant effect on local myocardial O2 consumption. This indicated a dissociation of the inverse relationship between the myocardial level of cyclic GMP and O2 consumption in the 1K1C rabbit heart. Thus, some of the metabolic alterations in renal hypertensive cardiac hypertrophy may be associated with a loss of cyclic GMP induced control, at least in the EPI.

In vascular smooth muscle, the level of cyclic GMP is a major controller of vascular smooth muscle tone [2]. Agents that elevate vascular cyclic GMP levels cause vasodilation [20, 21]. Inhibition of guanylate cyclase leads to vasoconstriction [2, 10]. LY83583 reduces vascular cyclic GMP levels and causes vascular smooth muscle to constrict [22].

In order to prevent significant vasoconstriction and other vascular effects of LY83583, we topically applied this agent to the left ventricular surface. This approach led to alterations in both local O2 consumption and cyclic GMP levels, but we did not observe any systemic effects of this guanylate cyclase inhibitor. Topical application causes a significant gradient in the delivery of LY83583. On the surface, we placed 10–3 M LY83583. This led to an approximately 7x10–6 M concentration in the EPI and a 5x10–7 M concentration in the ENDO. This dose range has been reported to alter cyclic GMP levels and function in cardiac myocytes [1–3, 23, 24]. These also appeared to be some minor delivery to the septal wall, possibly through the coronary arterial system. We did not determine the delivery of LY83583 into the 1K1C left ventricular free wall. We found that the application of LY83583 led to significant decreases in cyclic GMP in the left ventricular free wall of control hearts and the EPI region of the 1K1C rabbits. This was similar to previous reports using this type of application for different agents [6, 7]. In the hypertrophied heart, subepicardial cyclic GMP levels were decreased to a similar extent as in both the subepicardium and subendocardium of the nonhypertrophied hearts, but the decrease in subendocardial cyclic GMP was not statistically significant in the 1K1C rabbit heart.

In cardiac myocytes, the effects of cyclic GMP are less well studied than in vascular smooth muscle. The amount of the second messenger cyclic GMP is about 100 times less than cyclic AMP in the heart [1, 7]. Nevertheless, it exerts a significant influence on myocytes. Cyclic GMP is a major negative controller of cytosolic calcium [1, 2, 23]. Increases in cyclic GMP lead to negative functional and metabolic effects in the heart [1–3, 6].

Guanylate cyclase inhibition can reduce the level of myocyte cyclic GMP and increase calcium movement though the cardiac cell membrane [23, 25, 26]. Proposed mechanisms for the antagonistic effect of cyclic GMP on myocardial function include: (1) Reduction in action potential duration and intracellular calcium influx; [27](2) Direct activation of cyclic GMP-dependent protein kinase and phosphorylation of the calcium channel or an associated protein, which leads to the inhibition of L-type calcium channels; [1, 24](3) Stimulation of cyclic GMP dependent cyclic AMP phosphodiesterase activity, which in turn, indirectly reduces cyclic AMP levels and thereby also inhibits L-type calcium channels [2]. It is not clear which is the predominant mechanism in the rabbit heart.

In the present study, we were able to show in control rabbit hearts that decreased endogenous cyclic GMP levels induced by topical myocardial application of LY83583 had a direct positive effect on myocardial O2 consumption. Metabolic vasodilation may explain the increase in coronary blood flow with this vasoconstrictor agent. Previous studies [25, 26, 28]with single cell preparations or tissue slices have shown that guanylate cyclase inhibition was only able to intensify the inotropic effect of the β-adrenergic agonist isoproterenol on adult rat ventricular myocytes but had no effect on basal contractility. The intrinsic sympathetic tone in the anesthetized rabbit may account for this difference. In the rabbit, the primary myocardial effects of alterations in cyclic GMP, due to local treatments, are metabolic rather than functional [6, 7]. In dogs, the primary effects appear functional [5]. This may be a species difference or it may be related to the limited area of application. We did see a nonsignificant increase in dP/dtmax in the present study, but did not make any measurements of local subepicardial function. Some positive functional effects of lowering cyclic GMP have been reported in isolated papillary muscle [8]. Local positive inotropic effects caused by inhibition of guanylate cyclase have also been observed in the intact dog heart [9]. Previous reports from our laboratory have established that raising myocardial cyclic GMP by various means lowers O2 consumption in the rabbit heart [6, 7].

Increases in work, pressure, flow, etc. or metabolism lead to increases in myocardial O2 consumption. This pressure load, if prolonged, can lead to cardiac hypertrophy. Renal hypertension induced cardiac hypertrophy occurs within one month in a variety of models [17, 29]. Elevated renin and increased sympathetic tone are implicated as contributing factors to the hypertrophy [30, 31]. Myocardial O2 supply/consumption balance is essentially normal in 1K1C rabbits, although myocardial O2 consumption is somewhat elevated [17], but not maximal [7, 17, 32]. This may indicate a lack of full adaptive compensation. The 1K1C rabbit heart is capable of significant increases in myocardial O2 consumption and function during atrial pacing or adrenergic stimulation [32]. During cardiac hypertrophy, there are often changes in the myocardial level and/or effect of the second messenger cyclic AMP [11, 12].

The myocardial level of cyclic GMP has been reported to be elevated in some types of pressure-load hypertrophy [5, 13]. Cyclic GMP levels may also increase during some forms of heart failure [14, 15]. However in the rat, myocardial cyclic GMP levels are normal after aortic constriction [16]. In the rabbit, basal levels of myocardial cyclic GMP were not altered in thyroxine-induced hypertrophy [7]. In the rabbit, renal hypertension-induced cardiac hypertrophy does not alter the endogenous basal level of cyclic GMP in the heart. The effect of pressure-load cardiac hypertrophy on myocardial cyclic GMP levels and cyclic GMP's relationship to the control of myocardial O2 consumption have not been fully elucidated.

In the subepicardium of the 1K1C rabbit heart, LY83583 decreased cyclic GMP levels to about the same extent as in control hearts. However, this did not cause an increase in EPI O2 consumption in the 1K1C heart. Myocardial O2 consumption can increase significantly in 1K1C rabbit hearts during atrial pacing or isoproterenol stimulation [32]. Basal cyclic GMP levels may not control metabolism in lKlC hypertrophic hearts. The reasons why the cyclic GMP decrement was not accompanied by an increase in myocardial O2 consumption have not been determined. There could be a shift in the sensitivity of the heart for cyclic GMP. There could also be some alterations in the cytoplasmic calcium levels or sensitivity controlled by cyclic GMP [2, 23]. Protein phosphorylation resulting from changes in cyclic GMP could also be affected [24]. The level of cyclic GMP was not significantly decreased by LY83583 in the ENDO of the 1K1C heart. This may possibly be related to the greater thickness of the hypertrophied heart. In a pressure overload hypertrophy model in the dog, cyclic GMP levels are elevated [5]. In thyroxine-induced hypertrophy in the rabbit, the heart requires less change in cyclic GMP to change metabolism [7]. Nitroprusside, which increases myocardial cyclic GMP, reduces local function in control dog hearts, but not in pressure overload induced hypertrophic dog hearts [5]. Further study is necessary to understand the importance of these changes in the role of myocardial cyclic GMP in cardiac hypertrophy.

In summary, we found that reducing the level of the second messenger cyclic GMP in both the subepicardial and subendocardial regions of the heart increased myocardial O2 consumption in the control rabbit heart, while similar reductions in subepicardial cyclic GMP in a renal hypertension-induced hypertrophic heart had no effect on local myocardial O2 consumption. There appears to be some dissociation of the inverse relationship between the myocardial level of cyclic GMP and O2 consumption in the 1K1C rabbit heart, at least in the subepicardium. Thus, renal hypertensive cardiac hypertrophy may be associated with a loss of myocardial cyclic GMP-induced control of cardiac metabolism.

Time for primary review 38 days.


   Acknowledgements
 
This study was supported, in part, by a Grant-in-aid from the American Heart Association, New Jersey Affiliate, and by USPHS grants HL 40320.


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 

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