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Am J Physiol Heart Circ Physiol 278: H168-H174, 2000;
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Vol. 278, Issue 1, H168-H174, January 2000

Impaired endothelium-mediated vasodilation is not the principal cause of vasoconstriction in heart failure

Carlos E. Negrao1, Michele A. Hamilton2, Gregg C. Fonarow2, Antoine Hage2, Jaime D. Moriguchi2, and Holly R. Middlekauff2

2 Division of Cardiology, Department of Medicine, University of California School of Medicine, Los Angeles, California 90095; and 1 Laboratory of Cardiovascular Physiology in Exercise, Heart Institute, University of Sao Paulo, School of Medicine, Sao Paulo, 05403-000, Brazil


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The extent to which abnormal endothelium-dependent vasodilator mechanisms contribute to abnormal resting vasoconstriction and blunted reflex vasodilation seen in heart failure is unknown. The purpose of this study was to test the hypothesis that the resting and reflex abnormalities in vascular tone that characterize heart failure are mediated by abnormal endothelium-mediated mechanisms. Thirteen advanced heart-failure patients (New York Heart Association III-IV) and 13 age-matched normal controls were studied. Saline, acetylcholine (20 µg/min), or L-arginine (10 mg/min) was infused into the brachial artery, and forearm blood flow was measured by venous plethysmography at rest and during mental stress. At rest, acetylcholine decreased forearm vascular resistance in normal subjects, but this response was blunted in heart failure. During mental stress with intra-arterial acetylcholine or L-arginine, the decrease in forearm vascular resistance was not greater than during saline control in heart failure [saline control vs. acetylcholine (7 ± 3 vs. 6 ± 3, P = NS) or vs. L-arginine (9 ± 2 units, P = NS)]. The increase in forearm blood flow was not greater than during saline control in heart failure [saline control vs. acetylcholine (1.2 ± 0.3 vs. 1.3 ± 0.3, P = NS), or vs. L-arginine (1.2 ± 0.2 ml · min-1 · 100 ml-1, P = NS)]. Furthermore, during mental stress with nitroprusside, the decrease in forearm vascular resistance was not greater than during saline control [saline control vs. nitroprusside (7 ± 3 vs. 5 ± 4 ml · min-1 · 100 g-1, P = NS)], and the increase in forearm blood flow was not greater than during saline control [saline control vs. nitroprusside (1.2 ± 0.3 vs. 1.3 ± 0.5 ml · min-1 · 100 g-1, P = NS)]. Because the endothelial-independent agent nitroprusside was unable to restore resting and reflex vasodilation to normal in heart failure, we conclude that impaired endothelium-mediated vasodilation with acetylholine-nitric oxide cannot be the principal cause of the attenuated resting- or reflex-mediated vasodilation in heart failure.

nitric oxide; mental stress


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

HEART FAILURE is characterized by resting vasoconstriction and abnormal vasodilatory responses during mental and physical stress (4, 6, 7, 10, 16, 17). This abnormal vasomotor tone may be due to increased vasoconstrictor influences and/or decreased vasodilator influences. In this study we investigated the contribution of the vasodilatory mechanisms to the abnormal resting and reflex vascular tone in heart failure. There is pharmacological evidence for impaired endothelial-dependent vasodilatation in heart failure, mediated by endothelium-dependent cholinergic and nitric oxide mechanisms (4, 6, 7). Furthermore, actual physiological reflex vasodilator responses, which depend on nitric oxide, are blunted in heart failure (10). Kubo and colleagues (7) administered intra-arterial methacholine, a muscarinic agent, and nitroprusside, an endothelium-independent vasodilator, in heart-failure patients and normal controls. The vasodilatory responses to methacholine were significantly more blunted compared with vasodilatory responses to nitroprusside in heart-failure patients compared with normal controls, consistent with abnormal cholinergic vasodilatory mechanisms in heart failure (7). Hirooka and colleagues (4) administered intra-arterial L-arginine, a precursor of endothelium-derived nitric oxide, in heart-failure patients during simultaneous acetylcholine infusion and found the attenuated cholinergic vasodilation was improved. Both of these studies in humans with heart failure are consistent with abnormal endothelium-dependent vasodilation, mediated by acetylcholine-nitric oxide mechanisms.

In addition to abnormal resting vasoconstriction, reflex vasodilation in heart failure is attenuated. For example, during mental stress in heart failure, reflex forearm vasodilation is blunted (10). In animals and normal humans, this reflex vasodilation during mental stress has been shown to be mediated by the endothelium-dependent mechanisms, acetylcholine and nitric oxide (2, 8). The extent to which abnormal endothelium-dependent vasodilator mechanisms in heart failure contribute to the abnormal resting vasoconstriction and blunted reflex vasodilation is unknown. The purpose of this study was to test the hypothesis that the resting and reflex abnormalities in vasoconstriction that characterize heart failure are mediated by abnormal endothelium-mediated mechanisms. We studied the vasodilatory responses during intra-arterial administration of the endothelium-dependent agents acetylcholine and L-arginine and the endothelium-independent agent nitroprusside at rest and during mental stress, which activates endothelium-mediated mechanisms.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Study Population

After informed written consent, 13 advanced congestive heart-failure patients (mean age 49 ± 12 yr) and 13 age-matched normal controls (mean age 49 ± 15 yr, P = NS) participated in two of three drug protocols. Thirteen heart-failure patients and 13 normal controls were enrolled in the study of saline and acetylcholine. Eight heart-failure patients and eight normal controls were enrolled in the study of saline and L-arginine infusion during mental stress. Five heart-failure patients and five normal controls were enrolled in the study of saline and sodium nitroprusside. The study protocols were approved by the University of California Los Angeles (UCLA) Human Subject Protection Committee. Normal subjects were healthy as confirmed by medical history and physical examination and were not taking medications. In the heart-failure patients, the etiology of heart failure was coronary artery disease in eight and idiopathic dilated cardiomyopathy in five patients. Medications, including vasodilators, diuretics, and digoxin, were discontinued 24-36 h before the study protocol under medical supervision in the UCLA Clinical Research Center. All patients had advanced (New York Heart Association, functional class III-IV) congestive heart failure. As measured by echocardiography, quantified mean left ventricular ejection fraction was 0.20 ± 0.03 and peak oxygen consumption was 13.9 ± 1.5 ml/kg. Patients and normal controls abstained from caffeine for 24 h before the study. The studies were performed in the postabsorptive state.

Measurements and Procedures

Forearm blood flow. Forearm blood flow was measured by means of venous occlusion plethysmography. The nondominant arm was elevated just above heart level to ensure adequate venous drainage. A mercury-filled Silastic tube attached to a low-pressure transducer was placed around the forearm and connected to a plethysmograph (Hokanson, Bellevue, WA). Sphygmomanometer cuffs were placed around the wrist and upper arm. The wrist cuff was inflated to suprasystolic level for 1 min prior to the flow measurements. At 15-s intervals, the upper cuff inflated above venous pressure for 7-8 s. The rate of increase in strain reflected the rate of increase in forearm volume and arterial blood flow. Forearm vascular resistance (units) was calculated by dividing mean arterial pressure (mmHg) by forearm blood flow (ml · min-1 · 100 ml tissue-1).

Drug infusions. Acetylcholine (CIBA) was used under IND-50695 and diluted in normal saline (40 µg/ml) just before the study. L-Arginine (Pharmacia) was used under IND-50694 and diluted in normal saline (100 mg/ml). Sodium nitroprusside (Gensia Laboratories) was diluted in normal saline (0.8 µg/ml).

Mental stress testing. Mental stress was elicited by the Stroop color-word test and mental arithmetic (12, 13). During the Stroop color-word test, subjects were shown a series of names of colors written in a different color ink from the color specified. The subject was asked to identify the color of the ink, not read the word. In the verbally administered mental arithmetic test, subjects were asked to rapidly subtract a one- or two-digit number from a three- or four-digit number. The difficulty of the task was tailored to the ability of the subject. The subject was urged to proceed as rapidly as possible and was gently chastised for incorrect responses. The subject was asked to try his best, but the number of correct answers was not quantified. Each subject was asked to assess task difficulty on completion of the protocol, using a standard five-point scale (1): 0, not stressful; 1, somewhat stressful; 2, stressful; 3, very stressful; 4, very, very stressful.

Miscellaneous measurements. Arterial pressure was monitored noninvasively by an automatic blood pressure cuff. Heart rate was monitored continuously through lead II of the electrocardiogram.

Experimental Protocol

The subject was positioned, and electrocardiogram leads were placed on the chest (Fig. 1). An intra-arterial line was placed into the brachial artery of the nondominant arm. The catheter was attached to a three-way stopcock for ease of intra-arterial drug infusion. Cuffs for forearm blood flow measurements were placed on the nondominant arm. After a 15-min rest period, saline was infused (0.8 ml/min, saline control) and baseline values for forearm blood flow, arterial pressure, and heart rate were recorded for 2 min. Four minutes of mental stress testing were then begun. After the mental stress test, the recovery values were recorded for 4 min followed by a rest period to allow hemodynamics to return to baseline. After a 15-min rest period, intra-arterial infusion of acetylcholine (20 µg/min), L-arginine (10 mg/min), or nitroprusside (0.8 µg/min) was started. After 4 min, a new baseline forearm blood flow, arterial pressure, and heart rate were recorded. Mental stress testing for 4 min using the same mental stress test as in the saline-control study was performed. Following the mental stress test, the recovery values were recorded for 4 min simultaneously with drug infusion and then hemodynamics were allowed to return to baseline. Saline was then infused intra-arterially (0.8 ml/min), and using a different mental stress test (Stroop color word if mental arithmetic had been used first) 4 min of mental stress testing was performed. Finally, a second drug was infused, and after 4 min, mental stress testing was repeated. All subjects underwent mental stress testing with acetylcholine, and either L-arginine or nitroprusside, each preceded by saline-control mental stress test.


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  		Fig. 1.   Timeline of experimental protocol (see Experimental Protocol for explanation). IA, intra-arterial; FBF, forearm blood flow; BP, blood pressure; HR, heart rate.

Statistical Analysis

Statistical analysis was performed by using paired and unpaired Student's t-tests and two-group repeated measure ANOVA. The data are presented as means ± SE, mean absolute change, or mean absolute value unless otherwise stated. Probability values of <0.05 were considered statistically significant.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Basal Measurements

The baseline data before mental stress testing are shown in Table 1. Heart rate was significantly greater in heart-failure patients when compared with normal controls, but mean arterial pressure was not significantly different between the two groups. Baseline forearm blood flow was significantly lower and baseline forearm vascular resistance was significantly greater in patients with heart failure when compared with normal controls.

                              
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  		Table 1.   Baseline hemodynamics

Perceived Difficulty of Mental Stress Testing

The perceived difficulty of each saline-control mental stress test was not different from that of the mental stress test performed during drug infusion in either heart-failure patients [1.8 ± 0.2 vs. 1.9 ± 0.2 (P = NS)] or normal controls (1.9 ± 0.2 vs. 2.2 ± 0.3, P = NS). Similarly, perceived difficulty of mental stress testing was not different between normal subjects and heart-failure subjects (1.9 ± 0.2 vs. 1.8 ± 0.2, P = NS).

Hemodynamic Responses to Mental Stress With Saline Infusion

Forearm blood flow increased significantly in both normal controls and heart-failure patients, although the increase was significantly greater in normal controls (Table 2). During mental stress forearm vascular resistance decreased in both normal controls and heart-failure patients.

                              
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  		Table 2.   Peak changes in hemodynamic responses to mental stress

Hemodynamic Responses to Acetylcholine, L-Arginine, and Sodium Nitroprusside at Rest

Resting heart rate and arterial pressure were not changed by acetylcholine, L-arginine, or sodium nitroprusside. Acetylcholine infusion significantly increased resting values of forearm blood flow in both normal controls and heart-failure patients, although the increase was significantly blunted in heart-failure patients (Fig. 2A). Acetylcholine infusion significantly decreased resting forearm vascular resistance in normal controls, but this decrease was blunted in heart-failure patients (Fig. 2B). L-Arginine infusion did not change resting values of forearm blood flow and forearm vascular resistance in normal controls or heart-failure patients (Fig. 2, A and B). During sodium nitroprusside at rest, the increase in forearm blood flow was significantly blunted in heart-failure patients compared with normal subjects (Fig. 2A). Similarly, during sodium nitroprusside, the decrease in forearm vascular resistance was significantly blunted in heart-failure patients compared with normal subjects (Fig. 2B).


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  		Fig. 2.   Resting FBF (A) and forearm vascular resistance (FVR; B) during acetylcholine, L-arginine, and nitroprusside administration in normal controls and heart-failure patients. Acetylcholine increased FBF and decreased FVR in normal controls and heart failure, although this response was significantly blunted in heart failure. L-Arginine did not increase FBF or decrease FVR in normal controls or heart-failure patients. During nitroprusside, the increase in FBF and decrease in FVR was blunted in heart-failure patients compared with normal controls. * P < 0.05 within group comparison and between group comparison.

Hemodynamic Responses to Acetylcholine, L-Arginine, and Sodium Nitroprusside During Mental Stress

In heart-failure patients during mental stress, acetylcholine did not change the increase in forearm blood flow compared with saline control (Fig. 3A). Similarly, in heart-failure patients, acetylcholine did not change the decrease in forearm vascular resistance in heart failure compared with saline control (Fig. 3B). When heart-failure patients were compared with normal controls during mental stress, forearm blood flow and forearm vascular resistance remained blunted during acetylcholine administration (Fig. 4, A and B).


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  		Fig. 3.   Absolute change in FBF and FVR in response to mental stress during intra-arterial acetylcholine, administration of L-arginine, or nitroprusside compared with saline control in heart-failure patients. FBF during mental stress was not increased above saline control during administration of endothelial-dependent (A and C) or endothelial-independent (E) agents. Similarly, FVR during mental stress was not decreased from saline control during administration of endothelial-dependent (B and D) or endothelial-independent (F) agents.



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  		Fig. 4.   FBF and FVR during mental stress in heart-failure patients compared with normal controls during intra-arterial administration of acetylcholine (A and B), L-arginine (C and D), and nitroprusside (E and F). FBF and FVR remained blunted in response to endothelial-dependent (A-D) and -independent (E and F) agents.

During mental stress in heart-failure patients, L-arginine did not change the increase in forearm blood flow compared with saline control (Fig. 3C). Similarly, in heart failure, L-arginine did not change the decrease in forearm vascular resistance compared with saline control (Fig. 3D). When heart-failure patients were compared with normal controls during mental stress, forearm blood flow and forearm vascular resistance remained blunted during L-arginine administration (Fig. 4, C and D).

During mental stress in heart-failure patients, nitroprusside did not change the increase in forearm blood flow compared with saline control (Fig. 3E). Similarly, in heart failure, nitroprusside did not change the decrease in forearm vascular resistance compared with saline control (Fig. 3F). When heart-failure patients were compared with normal controls during mental stress, forearm blood flow and forearm vascular resistance remained blunted during nitroprusside administration (Fig. 4, E and F).


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Abnormal resting vasoconstriction and blunted reflex vasodilation in heart failure may be due to increased vasoconstrictor mechanisms, decreased vasodilatory mechanisms, or both. In this study we focused on the vasodilatory mechanisms. The main findings of the present investigation are that 1) at rest vasodilation during administration of endothelium-dependent and -independent agents acetylcholine and nitroprusside is blunted in heart-failure patients compared with controls; 2) in heart-failure patients reflex vasodilatation during mental stress, which is normally mediated by endothelial-dependent mechanisms, is not restored by the endothelium-dependent agent acetylcholine; 3) L-arginine, the substrate for nitric oxide production, does not restore reflex vasodilation during mental stress; and 4) reflex vasodilation during mental stress in heart-failure patients is not restored by the administration of the endothelium-independent agent sodium nitroprusside. Based on these findings, we conclude that impaired acetylcholine-nitric oxide mechanisms are not the principal cause of the attenuated resting or reflex-mediated vasodilation in heart failure. These findings support the concept that heightened vasoconstrictor influences, such as increased central sympathetic neural outflow, angiotensin, and endothelin activity, underlie the abnormalities of resting and reflex vascular tone in heart failure (9, 15).

Acetylcholine may be released by activation of "cholinergic nerves" or by flow-induced activation of endothelial cells. In normal subjects during mental stress, sympathetic withdrawal at the initiation of mental stress has been described, thereby leading to flow-induced acetylcholine release and nitric oxide activation (3). In heart failure, which is characterized by heightened sympathetic nerve activity, sympathetic nerve withdrawal may not occur during mental stress or may be inadequate to activate flow-induced acetylcholine-nitric oxide release.

In our study, we administered exogenous acetylcholine to determine whether, in the presence of vasodilatory concentrations of acetylcholine, vasodilatory mechanisms would be restored in heart failure. Acetylcholine administration at rest significantly increased baseline forearm blood flow in both heart-failure patients and normal controls, but this increase was blunted in heart-failure patients. Blunted muscle vasodilatory responses to acetylcholine in patients with dilated cardiomyopathy at rest has been observed by others as well (6). During mental stress, acetylcholine failed to restore the vasodilatory responses to normal in heart-failure patients. This blunted vasodilatory response to acetylcholine infusion suggests that the muscle vasodilatory dysfunction in heart-failure patients is not solely attributable to an impairment in the cholinergic activation. Other potential mechanisms of the impaired muscle vascular response to local intra-arterial infusion of acetylcholine may include muscarinic receptor dysfunction. The density of muscarinic receptors in the myocardium is reduced in dogs with chronic ventricular pressure overload (14) and may be reduced in the vasculature as well. Alternatively, abnormal endothelial synthesis of nitric oxide in response to cholinergic activation may underlie the abnormal vasodilatation during mental stress in heart failure. To further evaluate the contribution of insufficient nitric oxide synthesis at rest and during mental stress in heart failure, we infused L-arginine intra-arterially.

In humans with heart failure, acute intra-arterial administration of L-arginine (10 mg/min) has been shown to enhance vasodilation during acetylcholine-mediated vasodilation, consistent with defective endothelial function in heart failure (4). In our study, L-arginine (10 mg/min) had no effect on forearm blood flow responses at rest. Furthermore, L-arginine did not restore the vasodilatory responses during mental stress in heart-failure patients to normal. These findings suggest that the blunted muscle vasodilation at rest and in response to mental stress in heart-failure patients is not due to the lack of substrate for nitric oxide production. In heart failure, nitric oxide-mediated vasodilation may not be limited by substrate availability for enzymatic conversion to nitric oxide but may be limited by enzyme availability. Nitric oxide synthase expression is downregulated in low-flow states. This is likely the case in heart failure, in which blood flow is decreased (9, 15). Alternatively, abnormal end-organ response to nitric oxide release, in other words, endothelial-independent mechanisms, may underlie the abnormal vasodilatory response to mental stress in heart failure.

To assess the integrity of endothelial-independent vasodilation in these heart-failure patients, sodium nitroprusside was administered intra-arterially. The increase in resting forearm blood flow during administration of sodium nitroprusside was blunted in heart-failure patients compared with normal controls. Similar findings have been previously reported by other investigators (6) but not all (4). Nitroprusside failed to restore the vasodilatory response during mental stress to normal in heart-failure patients. These findings are consistent with heightened basal muscle vasoconstriction in heart-failure patients, which cannot be offset by the exogenous, endothelial-independent agent nitroprusside. Furthermore, because endothelial-independent vasodilatory mechanisms are abnormal in heart failure, we cannot implicate abnormalities of cholinergic neural activation or nitric oxide release as the principal mechanism of the abnormal vasodilation at rest or in response to mental stress in heart failure. The abnormal tonic vasoconstriction in heart failure is likely multifactorial, including endothelin, angiotensin, and sympathetic neural vasoconstrictor activity (9, 15), as well as structural vascular changes which limit vasodilatory capacity (16, 17).

Limitations

Intra-arterial infusion of saline or drugs could alter the vasodilatory responses during mental stress in a volume-dependent manner. Previous studies (4, 5) have demonstrated that intra-arterial infusion of saline at 0.6-0.8 ml/min does not alter forearm blood flow. In the present study, the maximal volume infused for saline control or drugs was 0.8 ml/min. Therefore, the risk of volume-dependent changes in forearm blood flow was minimized.

We did not evaluate the changes in forearm blood flow at rest or during mental stress during simultaneous administration of acetylcholine and L-arginine. We reasoned that if both systems were abnormal, the simplest way to study the contribution of each was by separate infusions. Similarly, if only one system were abnormal, this would be easiest to determine during separate infusions. In our study, we found no effect with L-arginine alone in heart-failure patients. However, because we did not see any L-arginine effect in the normal controls, we are unable to invoke a role for abnormal nitric oxide synthesis in the blunted vasodilatory response to mental stress in heart failure.

Resting values of forearm vascular resistance were significantly higher in heart-failure patients compared with normal controls, which could complicate interpretation of changes in vasomotor tone during experimental protocols. In animal studies, the importance of the initial resistance on the magnitude of response to a vasodilator stimulus is significant (11). That is, an elevation in baseline vascular resistance may lead to a nonspecific enhancement of vasomotor responses to a vasodilator stimuli. Thus we would expect this difference in baseline forearm vascular resistance between heart-failure patients and normal subjects to lead to a nonspecific exaggeration in vasodilatory responses in heart failure. Of course, this did not occur, and in fact the vasodilatory responses in heart-failure patients were significantly blunted during drug infusions and mental stress testing.

It is possible that accelerated degradation, rather than inadequate production, of nitric oxide contributes to the increased vasoconstriction characteristic of heart failure. However, if this were the major cause of vasoconstriction in heart failure, we would have expected that the pharmacological dose of nitroprusside used in this study to have overcome degradation by endogenous substances and restore the vasodilatory response during mental stress to normal.

In summary, resting muscle blood flow is reduced and reflex vasodilatory responses during mental stress are blunted in patients with heart failure. Forearm intra-arterial administration of acetylcholine or L-arginine failed to restore to normal the vasomotor tone at rest or in response to mental stress in patients with heart failure. Sodium nitroprusside did not restore the vasomotor tone at rest or in response to mental stress in heart failure, consistent with a heightened basal vasoconstriction in heart failure. Altered cholinergic and/or nitric oxide pathways may be contributory, but are insufficient to explain the persistent resting vasoconstriction and blunted reflex vasodilatory responses in patients with heart failure.


    ACKNOWLEDGEMENTS

We are grateful to the nurses and staff of the UCLA Clinical Research Center for excellent patient care.


    FOOTNOTES

This work was supported in part by the National Institutes of Health Grants 1R29-HL-56796-01 and M01-RR-00865, and the Laubisch Fund (H. R. Middlekauff). C. E. Negrao was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo, Heart Institute Hospital das Clínicas da Faculdade de Medicinà da Universidade de São Paulo, and the University of Sao Paulo.

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Address for reprint requests and other correspondence: H. R. Middlekauff, UCLA Dept. of Medicine, Div. of Cardiology, 47-123 CHS, 10833 Le Conte Ave., Los Angeles, CA 90095 (E-mail: hmiddlekauff{at}mednet.ucla.edu).

Received 22 March 1999; accepted in final form 17 August 1999.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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4.   Hirooka, Y., T. Iamaizumi, T. Tagawa, M. Shiramoto, T. Endo, S. Ando, and A. Takeshita. Effects of L-arginine on impaired acetylcholine-induced and ischemic vasodilation of the forearm in patients with heart failure. Circulation 90: 658-668, 1994[Abstract/Free Full Text].

5.   Iamaizumi, T., A. Takeshita, S. Suzuki, M. Yoshida, S. Ando, and M. Nakamura. Age-independent forearm vasodilation by acetylcholine and adenosine 5'-triphosphate in humans. Clin. Sci. (Colch.) 78: 89-93, 1985.

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Am J Physiol Heart Circ Physiol 278(1):H168-H174
0363-6135/00 $5.00 Copyright © 2000 the American Physiological Society


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