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(Circulation. 1996;93:646-651.)
© 1996 American Heart Association, Inc.

Articles

Enhanced Coronary Vasoconstriction to Endothelin-BReceptor Activation in Experimental Congestive Heart Failure

Charles R. Cannan, MB, CHB; John C. Burnett, Jr, MD; Amir Lerman, MD

From the Division of Cardiovascular Diseases and Internal Medicine, Department of Internal Medicine and Physiology, Mayo Clinic/Foundation, Rochester, Minn.

Correspondence to Amir Lerman, MD, Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905.

	Abstract

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Background Endothelin (ET), a coronary vasoconstrictor, mediates its activity through the specific receptors ET-A and ET-B, which may demonstrate different activity under pathophysiological conditions. Thoracic inferior vena cava constriction (TIVCC) is an experimental model of congestive heart failure that is characterized by a decrease in cardiac output and an increase in circulating ET concentrations. The present study was designed to test the hypothesis that experimental heart failure altered coronary vascular responsiveness to ET-A– and ET-B–receptor stimulation in vivo.

Methods and Results ET-1 was infused at a rate of 2 ng/kg per minute into the left circumflex coronary artery in normal dogs (n=5) and in dogs subjected to TIVCC (TIVCC dogs, n=6). Similarly, sarafotoxin, an ET-B–receptor agonist, was infused at the same dosage in normal (n=5) and TIVCC (n=6) dogs. Intracoronary infusion of ET-1 significantly decreased coronary blood flow and increased coronary vascular resistance in normal dogs; this effect was significantly attenuated in TIVCC compared with normal dogs. The percent changes in coronary blood flow and coronary vascular resistance in the TIVCC compared with the normal dogs was -11±8% versus -48±7% (P<.01) and 29±10% versus 105±23% (P<.01), respectively. There was no significant effect on coronary blood flow, coronary vascular resistance, or coronary artery diameter in normal dogs that received an intracoronary infusion of sarafotoxin. In contrast, the administration of intracoronary sarafotoxin in TIVCC compared with normal dogs resulted in significant percent changes in coronary blood flow and coronary vascular resistance (-31±4% versus -7±3% [P<.001] and 53±12% versus 12±8% [P<.02], respectively).

Conclusions The present study demonstrates an attenuated coronary vasoconstrictor response to ET-1 with an enhanced vasoconstrictor response to sarafotoxin and suggests an alteration in coronary ET receptor sensitivity in experimental heart failure.

Key Words: endothelin • receptors • arteries • heart failure • vasoconstriction

	Introduction

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Congestive heart failure (CHF) is characterized by tissue hypoperfusion and diminished cardiac output. These changes are caused in part by a shift in the neurohormonal balance, which may, in turn, result in changes in receptor activity responsiveness and sensitivity, such as that seen in the downregulation of cardiac ß-adrenergic receptors in heart failure.¹ Recent studies have demonstrated elevated levels of plasma ET in heart failure both in animal models² and humans.³ Moreover, a functional role for the elevation of ET in the vasoconstriction that characterizes CHF is suggested by studies in which regional and systemic vasodilation and hypotension to ET receptor blockade in CHF were observed.^{4 5}

One important system in CHF is the coronary circulation, in which the coronary endothelium regulates its own vascular tone by the release of vasodilator substances such as EDRF and vasoconstrictor substances such as ET.⁶ However, one characteristic of CHF is an alteration of coronary endothelial function in which vasodilatory responses to endothelium-dependent vasodilation are reduced.⁷ ET produces potent coronary vasoconstriction at pharmacological and pathophysiological concentrations^{8 9} by binding to specific receptors on vascular smooth muscle¹⁰ and directly activating voltage-operated calcium channels in vascular smooth muscle membrane.^{11 12} Two distinct cDNAs of ET receptors recently were identified. The ET-A receptor is expressed in vascular smooth muscle cells, whereas the ET-B receptor is localized to the endothelial and smooth muscle cells.¹³ Coronary vasoconstriction is thought to be mediated predominantly via the ET-A receptors.^{14 15} Recent in vitro studies demonstrated downregulation of ET-1 receptors in the heart¹⁶ and desensitization of ET-1 transmembrane signaling pathways in the coronary arteries in heart failure.¹⁷ The functional significance of ET-A and ET-B receptors in the setting of heart failure is unknown. Therefore, the present study was designed to test the hypothesis that experimental CHF is characterized by differential responsiveness of ET-A and ET-B receptors in its presence and absence.

	Methods

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Short-term experiments were conducted among four groups of mongrel dogs (18 to 22 kg) after such experiments were approved by the Mayo Clinic Institutional Animal Care and Use Committee. One week before these experiments were performed, dogs in two of the four groups underwent TIVCC to create an experimental model of heart failure (see Reference 18). Each dog was administered sodium pentobarbital anesthesia (30 mg/kg), and after the dogs received adequate exposure to the anesthesia, a band was placed around the thoracic inferior vena cava to create an 50% reduction in diameter via a right thoracotomy.¹⁸ Before and for the first 2 days after all surgical procedures, each dog was treated with the prophylactic antibiotics clindamycin and Combiotic (Pfizer).

Each dog was fasted overnight before the day of the short-term study but was allowed access to tap water ad libitum. Each animal initially was anesthetized with sodium pentobarbital (30 mg/kg IV), and additional anesthesia was given as needed to maintain a constant level. An endotracheal tube was inserted into the dog, and the dog then was ventilated with room air and supplemental oxygen at 4 L/min (Harvard Respiratory). The right external jugular vein was cannulated by use of a flow-directed thermodilution catheter (American Edwards Laboratories, Inc) for the measurement of right atrial pressure, pulmonary capillary wedge pressure, and cardiac output. The right femoral artery was cannulated with a polyethylene catheter to monitor mean arterial pressure, and the right femoral vein was cannulated for intravenous infusion of fluids.

Each dog underwent a left thoracotomy to expose the anterior wall of the left ventricle. One centimeter of the proximal left circumflex coronary artery was dissected free of the surrounding tissue. A calibrated, electromagnetic flow probe was positioned on the proximal circumflex coronary artery and connected to a flowmeter (model FM 5010, Carolina Medical Electronics, Inc) for measurement of CBF. A needle was positioned proximal to the flowmeter to allow for intracoronary infusions. Two piezoelectric crystals (5 MHz, 2.5 mm diameter) were placed distal to the flow probe on opposing surfaces of the dissected coronary artery segment to measure the segment diameter continually. The correct alignment was verified by on-line sonomicrometry (Sonomicrometer 120, Triton Technology) and oscilloscopic monitoring (Tektronix 2221).¹⁹ Cardiac output was averaged from three measurements. Continuous recordings of CBF, coronary diameter, mean arterial pressure, right atrial pressure, pulmonary arterial pressure, and left ventricular end-diastolic pressure were obtained with the use of a model 2200 Gould strip recorder.

After surgical instrumentation, each dog underwent a 60-minute equilibration period, during which each animal received an intravenous infusion of normal saline at 1 cm³/min. The equilibration period was followed by a 20-minute baseline period (P1). P1 was followed by a 15-minute lead-in period, during which saline vehicle was infused directly into the coronary artery. After the lead-in period there was a 20-minute experimental period (P2), which was followed by a second 15-minute lead-in period during which ET-1 (2 ng/kg per minute, Peninsula Laboratories) was infused directly into the coronary artery in normal dogs (n=5) and dogs that had undergone TIVCC (TIVCC dogs, n=6). Sarafotoxin (2 ng/kg per minute, Peninsula Laboratories) also was infused directly into the coronary artery in normal (n=5) and TIVCC (n=6) dogs. ET-1 2 ng/kg per minute was the lowest intracoronarily infused dose that caused a significant decrease in CBF in a normal pilot dog study.¹⁵ Sarafotoxin, a 21–amino acid peptide, is a highly selective ET-B–receptor agonist²⁰ of approximately the same molecular weight as ET-1. After the lead-in period there were two 20-minute experimental periods (P3 and P4). A total coronary infusion rate of 1 cm³/min was maintained throughout the experiment.

We measured mean arterial pressure, cardiac output (in triplicate), right atrial pressure, pulmonary capillary wedge pressure, CBF, and coronary artery diameter during each experimental period. At the midpoint of the first three periods, blood was sampled from the ascending aorta for the measurement of plasma ET. Measurements of CBF over each experimental period were averaged from the strip-chart recorder data. Coronary artery diameter was measured at the end of each clearance period. CVR was calculated by CVR (mm Hg/mL per minute)=(MAP-RAP)/CBF, where MAP indicates mean arterial pressure and RAP, right atrial pressure. Systemic vascular resistance (SVR) was calculated by SVR (mm Hg/L per minute)=(MAP-RAP)/CO, where CO indicates cardiac output.

Blood for ET analysis was collected into EDTA-treated tubes, immediately placed on ice, and then centrifuged at 2500 rpm, 4°C. The level of plasma ET was determined by use of an ET-1 assay system (Amersham).²

Statistical Analysis
Data from each period are expressed as mean±SEM. Within each group, repeated measurements were analyzed by ANOVA for overall period differences and by paired Student's t test for comparison of active periods with baseline. Between-group comparisons were analyzed by ANOVA and unpaired Student's t test. Significance was achieved with a value of P<.05.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Table 1 illustrates baseline systemic and coronary hemodynamic parameters and plasma ET levels in normal and TIVCC dogs. TIVCC dogs had lower baseline levels of cardiac output and mean arterial pressure and a higher baseline level of plasma ET-1. Table 2 illustrates the systemic and coronary effects of intracoronarily infused vehicle, ET-1, and sarafotoxin. There were no significant differences in systemic and coronary parameters at baseline within groups compared with vehicle (P2). There were no significant changes in systemic hemodynamics during the intracoronary infusion of ET-1 (P3 and P4) in normal dogs, which is in contrast with the decrease in cardiac output and increase in systemic vascular resistance seen in TIVCC dogs. In normal and TIVCC dogs, intracoronary infusion of sarafotoxin resulted in a decrease in cardiac output that was associated with a rise in systemic vascular resistance. Among the groups that received ET or sarafotoxin, no significant changes in plasma ET concentrations were observed compared with baseline.

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics of Normal Dogs (n=10) and Dogs Subjected to TIVCC (n=16)

View this table: [in this window] [in a new window]   Table 2. Systemic and Coronary Effects of Intracoronary Infusion of ET-1 and Sarafotoxin in Normal Dogs and Dogs Subjected to TIVCC

In normal dogs, intracoronary infusion of ET significantly decreased CBF and coronary artery diameter in association with an increase in CVR. In TIVCC dogs, these effects were markedly attenuated, and no significant changes were seen in the coronary artery diameter. The percent decreases in CBF in normal compared with TIVCC dogs were -48±7% and -11±8% (P<.01), respectively (Fig 1). This effect was associated with an increase in CVR of 105±23% in normal dogs compared with 29±10% in TIVCC dogs (Fig 1, P<.01). In normal dogs receiving intracoronary sarafotoxin, no significant effect on CBF, CVR, or coronary artery diameter was seen. This phenomenon was in sharp contrast to the significant decrease in CBF and the increase in CVR without a significant change in coronary artery diameter that were seen in TIVCC dogs. Fig 2 compares the percent change in CBF and CVR between normal and TIVCC dog groups that received intracoronary sarafotoxin. There were significant differences in the percent changes for CBF (-7±8% versus -31±4% [P<.001]) and CVR (12±8% versus 53±12% [P<.02]) between normal and TIVCC dogs, respectively. There was no significant difference in the percent change for coronary artery diameter in response to infusion of sarafotoxin between the two groups (1.9±0.7% versus 2.1±1.9%). We noted a significant difference between the effects of ET-1 and sarafotoxin on CBF and CVR in normal dogs. There was a -48±7% versus -7±3% (P<.01) change in CBF and a 105±24% versus 9±7% (P<.01) change in CVR with the infusion of ET-1 and sarafotoxin, respectively, in normal dogs. No significant difference was noted between the effects of ET-1 and sarafotoxin in TIVCC dogs. There was a -14±9% versus -31±13% (P=NS) change in CBF and a 20±14% versus 53±13% (P=NS) change in CVR with the administration of ET-1 and sarafotoxin, respectively, in TIVCC dogs.

View larger version (16K): [in this window] [in a new window]   Figure 1. The percent change in CBF and CVR in response to intracoronary ET compared with baseline in normal () and TIVCC () dogs. P3 and P4 indicate experimental periods of 20 minutes each during which ET was infused into the coronary artery. *P.01 between groups.

View larger version (22K): [in this window] [in a new window]   Figure 2. The percent change in CBF and CVR in response to intracoronary sarafotoxin compared with baseline in normal () and TIVCC () dogs. P3 and P4 indicate experimental periods of 20 minutes each during which sarafotoxin was infused into the coronary artery. *P.01 between groups.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The present study, in which low concentrations of intracoronary ET-1 and sarafotoxin were exogenously administered, demonstrates an enhanced response to sarafotoxin and an attenuated response to ET in the coronary circulation of dogs with experimentally induced heart failure (TIVCC dogs) compared with normal dogs. Such alterations in coronary vascular responsiveness occurred in the setting of long-term elevation of the level of ET-1. This study supports the importance of both the ET-A and ET-B receptors in the control of coronary vascular tone in the presence and absence of CHF.

An attenuated systemic and regional vascular response of exogenous ET-1 in CHF previously was demonstrated.²² The changes in plasma ET were speculated to reflect changes in the tissue ET binding. Recent in vitro studies demonstrated both downregulation of ET-1 receptors in the heart¹⁶ and desensitization of the ET-1 transmembrane signaling pathway in the coronary arteries in heart failure.¹⁷ Löffler and colleagues¹⁶ demonstrated in rabbits with heart failure that plasma ET was elevated but that the density of ET-1 receptors in the heart and the kidney was decreased. Although the heart has a high content of mRNA-encoding ET-A receptors, this study did not differentiate between receptor subtypes. In a pacing-overdrive model of heart failure, Calderone and colleagues¹⁷ demonstrated that agonist-induced desensitization of ET-1 mediated phosphatidylinositol turnover and suggested that this was one possible mechanism contributing to desensitization of the ET-1 transmembrane signaling pathway in heart failure. Indeed, these in vitro observations may account for the attenuated response seen in the peripheral vasculature to exogenous ET-1.²¹ Fu and colleagues²² demonstrated a blunting of the functional ET-A receptor–mediated pressor response and downregulation of ET receptors in the mesenteric arteries in rats with chronic, ischemic heart failure. Our findings in the coronary circulation concur with those of the previously mentioned studies. Intracoronary infusion of ET-1 resulted in significant coronary vasoconstriction in normal dogs, and a marked attenuation of this effect was seen in heart failure. This suggests, as discussed above, a downregulation of the ET-A receptors and possible agonist-induced desensitization secondary to the increased levels of circulating ET that occur in the TIVCC model of heart failure¹⁸ and in heart failure in general.^{2 3} Although minimal effect on the coronary circulation was seen with the specific ET-B agonist sarafotoxin, a significant vasoconstrictor response was seen in dogs with heart failure. Moreover, since the decrease in CBF and the increase in CVR occurred without a significant change in CAD, we speculate that these changes were chiefly localized to the microcirculation. In fact, there was no significant difference in the percent changes in CBF and CVR between the two groups of TIVCC dogs receiving ET-1 and sarafotoxin, which suggests that most of the effect of intracoronary ET-1 was due to activation of the ET-B receptor.

The finding of an enhanced response to sarafotoxin in the coronary circulation in heart failure is less clear. The ET-B receptor found on the endothelium mediates the release of EDRF and prostacyclin. Additionally, ET-B receptors are found on vascular smooth muscle cells and are thought to mediate vasoconstriction.¹³ Possible explanations for our findings are that, in the normal state, stimulation of the ET-B receptors results in a "balanced" effect of vasodilation and vasoconstriction with very little net effect on the coronary circulation, as was seen in the normal dogs in our study. However, in the setting of heart failure, this balance may be interrupted with a resultant predominant vasoconstrictive effect. Production of basal EDRF is increased in the coronary circulation in heart failure,²³ and thus the stimulation of the endothelial ET-B receptor may have little effect on production of EDRF relative to that caused by stimulation of the receptor on the vascular smooth muscle. Moreover, the attenuated response to ET-1 in heart failure also supports the hypothesis that the basal EDRF production is enhanced in heart failure, since the inhibition of EDRF production actually enhances the coronary vasoconstrictive response to ET-1, which was attenuated in the present study.²⁴ Another possible explanation is the upregulation of ET-B receptors. The results of the present study are further supported by a recent observation that ET-1 contributes to the vascular tone in heart failure in humans.²⁵

In conclusion, the present study demonstrates an alteration in coronary vascular responsiveness to ET-1 and sarafotoxin in the presence and absence of experimental CHF and chronically elevated ET. The enhanced coronary vasoconstrictive response to ET-B–receptor activation in heart failure underscores the importance of the ET-B receptors in the control of coronary vascular tone in this condition. The present study provides more biological insight into a novel target for therapeutic intervention, such as ET-receptor antagonists or specific ET-converting enzyme inhibitors.²⁶

	Selected Abbreviations and Acronyms

 

CBF = coronary blood flow CHF = congestive heart failure CVR = coronary vascular resistance EDRF = endothelium-derived relaxing factor ET = endothelin TIVCC = thoracic inferior vena cava constriction

	Acknowledgments

 
We thank Larry L. Aarhus for his technical expertise.

Received September 18, 1995; revision received December 4, 1995; accepted December 19, 1995.

	References

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