(Circulation. 2001;103:2382.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Paradoxically Enhanced Endothelin-B Receptor–Mediated Vasoconstriction in Conscious Old Monkeys
From the Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, and Hackensack University Medical Center, Hackensack, NJ.
Correspondence to Stephen F. Vatner, MD, Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, MSB-I576, 185 S Orange Ave, Newark, NJ 07103. E-mail svatner{at}humed.com
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Abstract |
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Background—We investigated the effects of aging on the responses to endothelin (ET) in conscious old (19.8±0.6 years) and young adult (6.8±0.3 years) monkeys and compared these results with those of other vasoconstrictors, eg, phenylephrine (PE) and angiotensin II (Ang II).
Methods and Results—The monkeys (Macaca fascicularis) were chronically instrumented. Baseline total peripheral resistance (TPR) was not different between the 2 groups. As expected, TPR rose less (P<0.05) with PE (5 µg/kg) in old monkeys (34±3%) than in young monkeys (57±6%); TPR also rose less with Ang II. Surprisingly, TPR rose more (P<0.05) with endothelin-1 (ET-1, 25 ng · kg-1 · min-1) in old monkeys (36±6%) than in young monkeys (10±2%). An ETB receptor agonist, sarafotoxin (S6c, 30 ng · kg-1 · min-1) was administered in the presence of an ETA receptor antagonist, BQ-123 (1 mg/kg). Under these conditions, TPR increased more (P<0.05) in old monkeys (59±10%) than in young monkeys (31±4%). In the presence of nitric oxide synthase (NOS) inhibition with NW-nitro-L-arginine methyl ester (60 mg/kg), vasoconstriction induced by S6c no longer differed with age, because it was enhanced in young monkeys (P<0.05) (68±9% versus 31±4%) but not in old monkeys (58±6% versus 59±10%). Thus, after NOS inhibition, vasoconstrictor responses to ET were no longer enhanced in old monkeys.
Conclusions—Peripheral vasoconstriction (PE and Ang II) is reduced in old monkeys, as expected. Paradoxically, vasoconstriction induced by ET-1 was actually enhanced in old monkeys, which appears to be a result of impaired endothelium-dependent vasodilation, which with ET-1 should involve the ETB receptor.
Key Words: aging • endothelin • receptors • nitric oxide synthase • vasoconstriction
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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It is generally thought that vascular responses to vasoconstrictors are depressed in older animals1 2 3 4 5 6 and humans.7 8 The effects of aging on the vascular responses to endothelin-1 (ET-1), however, are more controversial.9 10 11 12 13 14 15 16 17 18 19 Although it would be predicted that ET-1–induced vasoconstriction would also be attenuated with age, it is conceivable that vascular responses to ET-1 are affected differently with age compared with other vasoconstrictors, eg, phenylephrine and angiotensin II (Ang II). Although all these vasoconstrictors may elicit endothelium-mediated vasodilation, ETB receptors are actually located on endothelial cells, which mediate vasodilation through the release of endothelium-derived relaxing factors such as nitric oxide (NO) and prostacyclin.20 21 22 23 Conversely, ETA receptors, located on smooth muscle cells, mediate vasoconstriction via activation of phospholipase C.20 24 ETB receptors are also located on smooth muscle cells, which also elicit vasoconstriction.25 Although ETB receptor–mediated vasodilation has been observed in adult healthy humans,26 the relative contribution of ETB receptors appears to be dependent on vessels and species.27 More importantly, the effects of aging on each ET receptor subtype have not yet been clarified.
A monkey aging model has the advantage of being phylogenetically closer to humans but exhibits fewer of the complicating effects of the diseases associated with aging, eg, diabetes and atherosclerosis.28 A recent study in this model from our laboratory indicated that with advancing age, vascular responsiveness to endothelium-dependent vasodilation was reduced in the absence of changes in baseline function.28 Therefore, it would be particularly interesting to determine the effects of ET-1 in this aging monkey model, in which endothelial vasodilation is known to be impaired.
Accordingly, the first goal of the present investigation
was to determine whether peripheral vascular responses to
vasoconstrictors, eg, phenylephrine and Ang II, and ET-1
are altered in conscious aging monkeys. To address this goal,
peripheral vascular responses (total peripheral
resistance, TPR) to ET-1 were compared with those to
phenylephrine and Ang II. The effects of ET-1, as noted
above, are more complex. Therefore, it is conceivable that a change in
vasoconstriction with ET-1 could be due to either a change in smooth
muscle vasoconstrictor activity or endothelial
vasodilator activity. To address this goal, vascular responses to an
ETB receptor agonist, sarafotoxin S6c (S6c),
were examined in the presence of an ETA receptor
antagonist, BQ-123. ETA blockade was
administered to allow full expression of ETB
activity. Furthermore, to address the question of whether
ETB receptor function was NO-dependent, the
vascular responses to S6c were also examined in the presence of NO
synthase inhibition with
N
-nitro-L-arginine
methyl ester (L-NAME).
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Methods |
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Animals
In the present study, the age of the old monkeys (Macaca fascicularis) averaged 19.8±0.6 years, and young adult monkeys (6.8±0.3 years old) were used as controls. The old monkeys were feral animals caught at the age of 5 to 7 years old and were maintained in captivity for 12 to 15 years. The original age was estimated on the basis of an eruption of dentition, general appearance, sexual development, and body weight. The monkeys were tranquilized with ketamine hydrochloride (2 to 3 mg/kg IM), anesthetized with thiamylal sodium (5 to 10 mg/kg IV), and maintained with isoflurane (0.5 to 1.5 vol% in oxygen) for the surgical procedure. Instrumentation was performed as previously described.28 29 In brief, an incision was made in the fourth left intercostal space under sterile surgical conditions. Tygon catheters (Norton Elastic and Synthetic Division) were implanted in the descending aorta and left atrium, and a solid-state pressure gauge (Konigsberg Instruments) was inserted into the left ventricle through the apex. A Transonic aortic flow probe (Transonic Systems) was implanted around the root of the ascending aorta to measure ascending aortic flow (cardiac output). The chest incision was closed in layers, and the thorax was evacuated of air. All animals were allowed to recover for 10 to 14 days before experimentation. The animals used in this study were maintained in accordance with guidelines of the Guide for the Care and Use of Laboratory Animals (Department of Health and Human Services publication [National Institutes of Health] No. 83-23, revised 1996).
Hemodynamic measurements were made with the monkeys fully awake, with a tether system to transmit the electronic signals and catheter pressures to the recording electronics.28 29 All monkeys were active and eating well in the tether. All hemodynamic measurements were recorded on a digital multiple recorder (PC216Ax, Sony Precision Technology Inc) and on a multiple-channel thermal strip chart (Astro-Med Inc). The fluid-filled catheter in the aorta was connected to a pressure transducer (Datex Ohmeda) for the measurement of arterial pressure. Left ventricular (LV) pressure and a first derivative of LV pressure (dP/dt) were measured with the solid- state pressure gauge. The Transonic flow probe was calibrated in vitro with timed saline collections in a gravity flow system. Zero aortic flow was assumed to occur during mid and late diastole. Cardiac index was calculated as cardiac output divided by body surface area. Body surface area was calculated as 71.84x(body weight)0.425x(height)0.725.30 TPR was calculated as the quotient of mean arterial pressure and cardiac index.
Protocol
Bolus injections of phenylephrine (1, 2,
5, and 10 µg/kg) and Ang II (0.01, 0.02, and 0.05 µg/kg) were
administered through the tether via the left atrial catheter, and
measurements of phasic and mean arterial pressure, LV
pressure, LV dP/dt, and cardiac output were recorded continuously
in the conscious monkeys. A steady state for
hemodynamic analysis was reached within the
first half minute. ET-1 could not be administered in a bolus because a
steady state could not be achieved. Accordingly, ET-1 (Peptide
Institute Inc) was administered as 3-minute graded infusions of 25, 50,
and 100 ng · kg-1 ·
min-1. The selective
ETB receptor agonist S6c (Sigma Chemical Co) was
administered in the presence of an ETA
antagonist, BQ-123 (1 mg/kg), as 5-minute graded
infusions of 5, 15, and 30
ng · kg-1 ·
min-1. After 30 to 45 minutes of recovery
after S6c infusion, the NO synthase inhibitor L-NAME (60
mg/kg) (Sigma) was administered, and after hemodynamics
were stabilized (20 to 30 minutes), S6c infusion was
repeated.
Blood Samples
Blood samples were obtained for determination of
plasma concentrations of blood urea nitrogen, creatinine,
fasting plasma glucose, total cholesterol, and
triglycerides by use of the tether system in the morning
before feeding. These levels were measured by standard laboratory
analyses.
Statistics
All data were reported as mean±SEM. The comparison
between the groups with young and old monkeys was made by unpaired
t test for grouped data. The
dose-response curves were analyzed by ANOVA for repeated
measurements. Values of peak response to each drug administration were
compared with baseline by the paired
t test. A value of
P<0.05 was taken as the
minimal level of
significance.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Characteristics of Body Weight, Height, and Surface Area and Blood Examinations in Young and Old Monkeys
There were no significant differences in body weight, height, and body surface area between the young and old monkeys. Lipid blood levels and plasma fasting glucose were also not different between the young and old monkeys.
Baseline Hemodynamics
There were no significant differences in heart rate
(young, 165±7 versus old, 154±8 bpm), mean arterial
pressure (young, 80±2 versus old, 79±3 mm Hg), LV dP/dt (young,
2882±208 versus old, 3000±203 mm Hg/s), cardiac index (young,
1.64±0.06 versus old, 1.59±0.14
L · min-1 · m-2),
and TPR (young, 49±3 versus old, 51±3
mm Hg · L-1 ·
min-1 · m-2)
between young and old monkeys.
Responses to Phenylephrine, Ang II,
and ET-1
Increases in TPR to phenylephrine and Ang
II were significantly (P<0.05)
depressed in old monkeys compared with young monkeys
(Figure 1
). For example, 10 µg/kg of
phenylephrine increased TPR by 97±8% in young monkeys
versus 47±6% in old monkeys, and 0.05 µg/kg of Ang II increased TPR
by 87±13% in young monkeys versus 57±3% in old monkeys. The dose
relationship of TPR to ET-1, however, was paradoxically reversed
(P<0.05) in old monkeys
compared with young monkeys
(Figure 1). For example, 25
ng · kg-1 · min-1
of ET-1 increased TPR less
(P<0.05) in young monkeys
(10±2%) versus old monkeys (36±6%).
|
) and old (•) monkeys. *Significance between regression lines. Dose responses in TPR to phenylephrine and Ang II (young, n=10; old, n=8) were significantly (P<0.05) depressed in old monkeys compared with young monkeys. Paradoxically, ET-1 significantly (P<0.05) increased TPR more in old monkeys than young monkeys (young, n=5; old, n=5).
Response to an ETB
Receptor Agonist (S6c) in the Presence of an ETA
Receptor Antagonist (BQ-123) Without NO Synthase
Inhibition
The ETA receptor
antagonist BQ-123 decreased baseline TPR by 10±3.7% in
young monkeys (P=0.05 versus
baseline) but did not change TPR in old monkeys (-0.5±2.1%,
P=0.058 versus young monkeys)
(Figure 2A). In the presence of the BQ-123, the increases in
TPR to the ETB receptor agonist S6c were
significantly (P<0.05)
increased in old monkeys compared with young monkeys
(Table,
Figure 3A).
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Response to an ETB
Receptor Agonist (S6c) in the Presence of ETA
Receptor Antagonist (BQ-123) With NO Synthase
Inhibition
NO synthase inhibition with L-NAME increased baseline
TPR more (P<0.05) in young
monkeys (126±6%) than in old monkeys (99±9%) in the presence of
BQ-123
(Figure 2B
). After L-NAME, there were no differences in the
increases in TPR to S6c in old and young monkeys, because S6c increased
TPR significantly more in young monkeys compared with the response in
the absence of L-NAME
(Figure 3A and 3B). In old monkeys, in contrast,
vasoconstrictor responses to S6c were not enhanced after L-NAME
(Figure 3A and 3B,
Table).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The present investigation examined for the first time the effects of vasoconstrictors in general and endothelin in particular in a monkey model of aging that is phylogenetically closer to humans but devoid of complications secondary to associated cardiovascular diseases. The life span of the monkey is thought to be
25 years. The old monkeys (20 years old) in the
present study are thought to be age-equivalent to humans 60 to 70
years old, ie, old but not senescent, and the young monkeys (7 years
old) are thought to be age-equivalent to humans 20 to 25 years old, ie,
adults, not juveniles. It is generally thought that peripheral vasoconstrictor responses are depressed in older animals,1 2 3 4 5 6 7 8 which might also be predicted for ET-1 if this were simply due to changes in smooth muscle tone. The effects of aging on the vasoconstrictor responses to ET-1, however, are more controversial. Depressed vascular responses to ET-1,9 10 11 12 13 14 19 31 no change,14 15 16 32 or increased responses9 17 18 19 32 have been demonstrated. In part, these differences can be attributed to responses in different vascular beds27 or to differences among species.27 Some of the effects may also be attributed to the denominator, ie, the age of the young animal. Importantly, the controls (young animals) in the present study were 7-year-old adults, ie, not juveniles. In many previous studies, juveniles were actually used as the young animals.9 17 18 19 Clearly, there can be differences between juveniles and adults as well as differences between adults and aged animals. These potential differences only reconcile some of the previous results. Accordingly, the underlying hypothesis of this investigation was that some of these differences could be attributed to the effects of aging on endothelial vascular control.33 Because ET-1 exerts different effects on endothelium versus smooth muscle, it follows that the resultant effects of ET-1 administration in older subjects would be affected differentially to the extent that aging impaired endothelial versus smooth muscle control. This is particularly important for this investigation, because we have recently demonstrated impaired endothelial vasodilation in this model of aging.28
The present results demonstrate depressed
peripheral vasoconstriction to activation of
1-adrenergic receptors and Ang II receptors.
Surprisingly, vasoconstrictor responses to ET-1 were enhanced in the
old monkeys. Importantly, baseline hemodynamics in the
old monkeys were not different from those in young monkeys.
The next question addressed was the mechanism for the paradoxical responses of ET-1–mediated vasoconstriction in the old monkeys, which has not yet been elucidated. The responses to ET-1 are mediated by at least 2 receptor subtypes, the ETA and ETB receptors. Stimulation of ETA receptors located on smooth muscle cells mediates vasoconstriction via activation of phospholipase C.20 24 In addition, vasoconstriction is also mediated by the ETB receptor, which is located in smooth muscle.25 Conversely, ETB receptors located on endothelium mediate vasodilation through the release of endothelium-derived relaxing factors, such as NO and prostacyclin.20 21 22 23 ET-1 is generally regarded as a potent vasoconstrictor, but the vascular response to ET-1 must be based on a balance of vasoconstrictor and vasodilator influences. Thus, enhanced vasoconstrictor responses to ET-1 in old monkeys could be due to enhanced vasoconstriction mediated by either ETA receptors or ETB receptors, which are located on smooth muscle cells, or to depressed vasodilation mediated by endothelial ETB receptors. Because peripheral endothelial dysfunction was observed in old monkeys,28 we hypothesized that the paradoxically enhanced vasoconstrictor response to ET-1 in old monkeys was related to dysfunction of ETB receptors located on endothelium. To test this hypothesis, we examined the effects of an ETB receptor agonist in the presence of ETA receptor blockade. ETA blockade was used to allow full expression of ETB effects.
The ETB agonist S6c increased TPR more in old monkeys than in young monkeys. In the presence of NO inhibition with L-NAME, however, vasoconstriction induced by S6c was enhanced in young monkeys but did not change in old monkeys, resulting in abolition of the differential response of endothelin-induced vasoconstriction in old and young monkeys. These findings suggest that ETB receptor–derived NO production was impaired in old monkeys. This is consistent with the concept of impaired NO-mediated endothelin-dependent vasodilator activity, which has been observed in old monkeys.28 Responses to an NO donor, sodium nitroprusside, were intact, however, indicating that responses to NO are not impaired.
Because vasoconstrictor responses mediated by the ETB receptor were not enhanced with aging, as evidenced by the data demonstrating similarities between young and old monkeys when the NO synthase pathway was inhibited with L-NAME, depressed endothelial ETB receptor function rather than enhanced smooth muscle ETB receptor function explains the findings in this investigation.
In addition, the ETA receptor
antagonist BQ-123 decreased TPR in young monkeys
(P=0.05) but did not change TPR
in old monkeys. Therefore, it is likely that ETA
receptor function is depressed in old monkeys rather than enhanced
(Figure 2A). This also suggests a greater role for endothelin
in regulating peripheral resistance in young monkeys. We
did not measure blood endothelin levels in these animals. It has been
demonstrated, however, that plasma ET-1 level increases with
age,14 which may induce
desensitization and could result in a more important role for
endothelin in regulating peripheral resistance in young
monkeys.
Seo and Lüscher19 investigated the effects of aging on ET receptor subtypes in normotensive rats and hypertensive rats. In isolated renal arteries from normotensive rats, they demonstrated that the sensitivity to ET-1 was lower in old rats than in adult rats (but the maximal response to ET-1 was enhanced in old rats), and ETB receptor stimulation induced little vasoconstriction in both adult and old rats. Furthermore, they showed that the release of NO by endothelial ETB receptor stimulation increases with age. This difference from our results may be due to differences in species and vessels studied,27 to the methods (in vivo versus in vitro), or, as noted above, to differences in the age of the controls ("young" animals), where previous studies compared juveniles with aged animals.9 17 18 19
Recently, an important role of ETB receptors in the pathogenesis of cardiovascular disease has been suggested.34 35 36 37 Although it is still controversial whether selective ETA receptor antagonists or nonselective ETA/ETB receptor antagonists are more effective as vasodilators, beneficial vasodilator effects of nonselective ETA/ETB receptor antagonists have been demonstrated in patients with essential hypertension compared with the effect of selective ETA receptor antagonist.38 Conversely, in healthy subjects, the vasodilator effects of selective ETA receptor antagonists seem to be greater than those of nonselective antagonists.26 This discrepancy may be, in part, due to impaired ETB receptor–mediated vasodilation in relation to endothelial dysfunction in essential hypertension but not in healthy subjects, which is consistent with the concept put forth in the present investigation. Furthermore, important roles of the ETB receptor subtype in patients with LV systolic dysfunction,34 in the progression of atherosclerosis,35 and in the pathogenesis of neointima formation36 37 have been demonstrated. Aging, in relation to enhanced responses to ETB receptor–mediated vasoconstriction, may complicate the role of endothelin in these pathological conditions.
In summary, paradoxically enhanced vascular responses to ET-1 have been demonstrated in old monkeys without associated cardiovascular diseases compared with young monkeys. The enhanced responses could be explained by impaired endothelial vasodilator function mediated by ETB receptors, which may be a more important mechanism to explain the enhanced vasoconstriction to ET-1 in old monkeys than depressed smooth muscle vasoconstrictor activity with aging. These findings should be considered when ET receptor agonists and antagonists are administered to older patients with cardiovascular disease.
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Acknowledgments |
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This study was supported in part by US Public Health Service grants HL-59139, HL-33107, HL-37404, and AG-14121-03.
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Footnotes |
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Guest Editor for this article was Donald D. Heistad, MD, University of Iowa Hospitals and Clinics, Iowa City.
Received November 7, 2000; revision received December 31, 2000; accepted January 9, 2001.
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