(Hypertension. 1995;25:194-200.)
© 1995 American Heart Association, Inc.
Articles |
Different Mechanisms of Endothelial Dysfunction With Aging and Hypertension in Rat Aorta
Presented at the Council for High Blood Pressure Research 48th Annual Fall Conference and Scientific Sessions, Chicago, Ill, September 27-30, 1994.
From the Department of Research, Laboratory of Vascular Research, University Hospital, Basel (C.F.K.), and the Department of Cardiology, Laboratory of Cardiovascular Research, Inselspital, Bern (C.F.K., T.F.L.), Switzerland.
Correspondence to Thomas F. Lüscher, MD, Cardiology, University Hospital, Inselspital, CH-3010 Bern, Switzerland.
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Abstract We analyzed the effects and mechanisms of aging in aortic endothelium and vascular smooth muscle of 12-week-old (adult) and 72-week-old (senescent) normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Aortas were suspended in organ chambers filled with physiological salt solution (95% O2/5% CO2; 37°C), and isometric tension was measured. In WKY, endothelium-dependent relaxations to acetylcholine were diminished with aging (P<.05); in SHR, they were reduced compared with WKY (P<.05) but unchanged with aging. The thromboxane/endoperoxide receptor antagonist SQ 30741 increased relaxations only in adult SHR. Relaxations to sodium nitroprusside were slightly enhanced with age in WKY and SHR (P<.05). Endothelium-dependent contractions to acetylcholine were unmasked by NG-nitro-L-arginine methyl ester (P<.05) and prevented by SQ 30741 or endothelium removal. In WKY, contractions increased with age. In adult SHR, marked endothelium-dependent contractions occurred (P<.05 versus WKY), which diminished with age (P=NS versus senescent WKY). The thromboxane analogue U46619 elicited similar contractions in adult and senescent WKY and adult SHR, whereas responses in senescent SHR were weaker (P<.05). In WKY and SHR, contractions to norepinephrine were similar and unaltered by aging. In WKY, contractions to endothelin-1 remained unaffected by aging. Adult SHR exhibited contractions to endothelin-1 comparable to those in WKY, whereas senescent SHR contracted less (P<.05). Bosentan, a combined endothelin-A/endothelin-B receptor antagonist, inhibited endothelin-1 markedly, especially in SHR (P<.05). Thus, aging causes different alterations in endothelium and smooth muscle in WKY and SHR aorta. In adult SHR, endothelium-dependent relaxations are reduced because of formation of prostaglandin H2, whereas in senescent SHR and senescent WKY, impaired formation or increased inactivation of nitric oxide must be involved. Contractions to endothelin but not to norepinephrine are reduced with aging only in SHR.
Key Words: endothelin • endothelium-derived contracting factor • nitric oxide • aging • endothelium
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Introduction |
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Aging and hypertension are associated with an increased incidence of coronary and cerebrovascular disease and renal failure.1 2 Most of the cardiovascular complications are related to alterations in vascular structure and function.1 3 4 5 The marked enhancement of age-related vascular complications in hypertension suggests an important interaction between the two processes.
The most important cells of the blood vessel wall are the endothelium and vascular smooth muscle cells.3 4 5 Although the endothelium is an important source of vasodilator and vasoconstrictor mediators that can also interfere with platelet and monocyte function,3 6 vascular smooth muscle cells are targets for local and circulating hormones that in turn determine vascular tone, organ blood flow, and peripheral vascular resistance.7 8 Important mediators released by endothelial cells are nitric oxide9 10 11 12 13 and prostacyclin,14 both potent vasodilators3 and inhibitors of platelet function.15 16 Furthermore, the endothelium can produce contracting factors such as thromboxane A2, prostaglandin H2, and endothelin-1 (ET-1).6 17 Whereas the prostaglandins activate both vascular smooth muscle and platelets, ET-1 primarily acts on vascular smooth muscle to cause profound and long-lasting contraction.
Aging and hypertension have been shown to exert functional changes of the endothelium and other parts of the intima. However, studies on the effects of aging and hypertension on endothelial function have yielded inconsistent results,18 19 20 21 22 23 24 possibly because different and sometimes too short aging periods have been studied, and interactions between different endothelial mediators causing relaxation and contraction have not been fully considered. Indeed, endothelial dysfunction may involve alterations in the release of endothelium-derived nitric oxide and/or of endothelium-derived contracting factors.3 6 25 26 27 28 29 Furthermore, the response of vascular smooth muscle to these mediators may be altered by aging and hypertension. Finally, the basal30 31 32 and/or receptor-operated33 34 35 36 stimulation of endothelial mediators may be changed under these conditions.
It was the aim of the present study to delineate the effects of aging and hypertension on endothelium and vascular smooth muscle function in the aorta of normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) at different ages. Particular emphasis was given to the formation and responses of endothelial mediators in the blood vessel wall under the different experimental conditions.
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Animals
Adult (12 to 14 weeks) and senescent (72 to 74 weeks) normotensive WKY and SHR (Charles River WIGA GmbH, Sulzfeld, Germany) were held at the animal facilities of the University Hospital Basel in cages with free access to water and standard rat chow. The animal facilities and all protocols were approved by the committee for animal research (Basel, Switzerland). Blood pressure was measured regularly by the tail-cuff method and repeated several times before the animals were used for experiments. WKY have already been studied up to an age of 3 years, but this appeared impossible with SHR in our studies. After approximately 70 weeks of age, SHR started to die in increasing numbers, and hence this age was chosen for comparison.
Tissue Harvesting
WKY and SHR were anesthetized by inhalation of ether and
injection of pentobarbiturate (50 mg/kg body wt IP) and then killed by
opening the carotid artery. The abdomen and chest were opened through a
medial sternotomy, and the aorta was excised and immediately placed in
cold (4°C) modified Krebs-Ringer bicarbonate solution (control
solution) of the following composition (mmol/L): NaCl 118.6, KCl 4.8,
CaCl2 2.5, MgSO4 1.2,
KH2PO4 1.2, NaHCO3 25.1, edetate
calcium disodium 0.026, and glucose 10.1. The thoracic aorta was then
dissected free under a microscope (Wild AG) and cut into rings (3 mm in
length).
Experimental Setup
The aortic rings were mounted horizontally between two stirrups
in organ chambers filled with 25 mL control solution (37°C, 95%
O2/5% CO2). One stirrup was connected to an
anchor and the other to a force transducer (UTC2, Gould Statham) for
recording of isometric tension. After a 30-minute equilibration period,
rings were progressively stretched until the contractile response to
KCl (100 mmol/L)/Krebs-Ringer solution (composition in mmol/L: NaCl
23.0, KCl 100.0, CaCl2 2.5, MgSO4 1.2,
KH2PO4 1.2, NaHCO3 25.1, edetate
calcium disodium 0.026, glucose 10.1) was maximal. Optimal tension for
the vessels averaged 2.5±0.2 g. The aortic rings were allowed to
equilibrate for 30 minutes before the experiments.
Endothelial Function
The presence or absence of endothelium was verified by
relaxation to acetylcholine (10-6 mol/L) in vessels
precontracted with norepinephrine (3x10-7 mol/L). The
endothelium of the aortas was removed by rubbing the lumen side with a
wooden stick. The absence of endothelium (ie, relaxation to
10-6 mol/L acetylcholine 
10%) and the integrity of
vascular smooth muscle function (by contraction to 100 mmol/L KCl and
3x10-7 mol/L norepinephrine) were assured before use of
preparations without endothelium.
Protocols
For endothelium-dependent relaxations, vessels
were studied in the absence or presence of 10-7 mol/L SQ
30741, a thromboxane/endoperoxide receptor antagonist, for 30 minutes;
rings were contracted with 10-7 mol/L norepinephrine and
then relaxed with 10-9 to 10-4 mol/L
acetylcholine. To study direct relaxation of vascular smooth muscle, we
performed another series of experiments. Vessels were incubated for 30
minutes with 10-4 mol/L
NG-nitro-L-arginine methyl ester
(L-NAME, an inhibitor of nitric oxide formation13 37 ) and
10-5 mol/L indomethacin (to inhibit the formation of
prostaglandins14 ), contracted with 10-7 mol/L
norepinephrine, and then relaxed with 10-10 to
10-5 mol/L sodium nitroprusside.
Endothelium-dependent contractions were also tested. Aortic segments were incubated for 30 minutes with 10-4 mol/L L-NAME, alone or in combination with 10-7 mol/L SQ 30741,38 and then 10-9 to 10-4 mol/L acetylcholine was added. Control vessels without preincubation with the drugs were tested in parallel. In some of the experiments, the effects of L-NAME preincubation were also tested in rings without endothelium.
Aortic contractions were analyzed with three different contractile agonists with a direct effect on vascular smooth muscle, ie, norepinephrine (10-10 to 10-5 mol/L), ET-1 (10-10 to 10-7 mol/L), or U46619 (a thromboxane analogue, 10-10 to 10-6 mol/L). ET-1 was studied with or without preincubation with different concentrations (10-7, 10-6, or 10-5 mol/L) of bosentan, a combined ETA/ETB receptor antagonist.39
Drugs
The following drugs were used: acetylcholine hydrochloride,
angiotensin I, angiotensin II, indomethacin, L-NAME,
L-norepinephrine, sodium nitroprusside, U46619 (all from
Sigma Chemical Co), ET-1 (Novabiochem), bosentan (F. Hoffmann–La Roche
Ltd), SQ 30741 (Squibb Institute for Medical Research, Princeton, NJ),
and pentobarbital (Abbott Laboratories). All drug concentrations used
are expressed as final organ chamber concentration.
Data Analysis
For statistical calculations, the concentration of the substance
(expressed as negative log mol/L) evoking 50% contraction or
relaxation (pD2 value), the maximal contraction or
relaxation (expressed as percentage of a previous contraction to an
agonist), and the area under the concentration-response curve (AUC,
expressed in arbitrary units) were calculated. Contractions were
expressed as percentage of the response to KCl (100 mmol/L). For the
calculation of pD2 values, ED50 was taken
whenever possible. Data are given as mean±SEM. In all series of
experiments, n is the number of rats from which blood vessels were
obtained. Unpaired or paired Student's t test or ANOVA
followed by Dunnett's multiple range test for repetitive observations
was used for statistical analysis. A two-tailed value of
P<.05 was considered to indicate a statistically
significant difference.
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Results |
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Body Weight and Systolic Blood Pressure
In adult rats, body weight was similar in WKY and SHR (Table 1). However, WKY had a markedly higher body weight than SHR at 72 weeks of age (P<.05).
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Differences in systolic blood pressure were as expected: SHR exhibited significantly higher blood pressures than WKY (P<.05 for both ages). Interestingly, although blood pressure in adult and senescent SHR was comparable (P=NS), adult WKY exhibited a slightly higher blood pressure than the older rats (P<.05), but both ages of WKY were clearly normotensive (no values higher than 140 mm Hg in both WKY groups).
Endothelial Function
Endothelium-Dependent Relaxation
Adult WKY exhibited a significantly better relaxation to
acetylcholine (10-9 to 10-4 mol/L) than
senescent WKY (P<.05 for maximal response and AUC, Fig 1). Preincubation of vessels with SQ 30741
(10-7 mol/L) did not affect the response to acetylcholine.
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On the other hand, both adult and senescent SHR showed impaired relaxations compared with their age-matched WKY groups (P<.05 for maximal response and AUC, Fig 2). There was little difference between adult and senescent SHR under control conditions (P=NS); however, the relaxation to acetylcholine in adult SHR was significantly enhanced if vessels were preincubated with SQ 30741 (P<.05 versus control for maximal response and AUC), whereas the responses of the older SHR remained unchanged (Table 2).
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Endothelium-Independent Relaxation
Senescent WKY relaxed better (121±3%) to sodium nitroprusside
than adult WKY (114±2%, P<.05 for maximal response and
AUC). Similarly, senescent SHR (135±6%) showed greater relaxations
compared with younger SHR (116±4%, P<.05 for maximal
response). There was no significant difference between WKY and SHR.
Endothelium-Dependent Contractions
Addition of L-NAME (10-4 mol/L) alone in quiescent
aortas with endothelium caused only negligible changes in tension
(<5% of 100 mmol/L KCl, data not shown). However, in quiescent aortas
of WKY of both ages, acetylcholine exhibited small but distinct
contractions in untreated control rings (P<.05 for maximal
response and AUC in both ages), which were more pronounced if the
preparations were preincubated with L-NAME (Fig 3).
Senescent WKY exhibited more pronounced responses than adult WKY
(P<.05). Preincubation with both L-NAME and SQ 30741
prevented these contractions (P<.05 versus L-NAME alone).
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Whereas L-NAME–preincubated adult SHR vessels strongly contracted to acetylcholine (79±9% versus 8±1% without preincubation [control], P<.05; Fig 4), senescent SHR vessels showed contractions to acetylcholine similar to those in senescent WKY aortas preincubated with L-NAME (23±5% versus 2±1% control; P=NS versus old WKY). The difference between adult and senescent SHR was significant (P<.05). Again, also in SHR, pretreatment with L-NAME plus SQ 30741 prevented contractions to acetylcholine (Fig 4). Vessels without endothelium preincubated with L-NAME exhibited no contractions to acetylcholine (n=4, data not shown).
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Contractions to the thromboxane analogue U46619 were similar in adult (162±12%; pD2, 7.9±0.1) and senescent (165±7%; pD2, 7.7±0.1; P=NS) WKY and also in adult SHR (167±9%; pD2, 8.0±0.1; P=NS versus adult WKY; Fig 5). In contrast, aortas of senescent SHR (125±8%; pD2, 7.5±0.1) contracted less to U46619 than segments from adult SHR (P<.05 for maximal response, AUC, and pD2).
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Contractile Responses
Contractions to KCl
Contractions to 100 mmol/L KCl were markedly reduced by aging in
both groups (P<.05 for maximal response in WKY and SHR).
Contractions to KCl were significantly stronger in WKY (4.4±0.2 mN/mm
in adult and 3.3±0.2 mN/mm in senescent) compared with those in SHR
(2.9±0.2 mN/mm in adult and 2.3±0.2 mN/mm in senescent;
P<.05 for maximal response for WKY versus SHR at both
ages).
Norepinephrine
Norepinephrine evoked concentration-dependent contractions in all
groups (Fig 6). Responses in WKY and SHR did not differ
at both ages.
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Endothelin-1
In WKY, contractions to ET-1 were similar in adult and senescent
rats (P=NS, Fig 7). In both adult and
senescent WKY, preincubation with bosentan inhibited contractions to
ET-1 in a competitive manner. In adult WKY, a significant shift to the
right was observed already at 10-7 mol/L bosentan
(pD2, 8.2±0.1) compared with control (8.4±0.1; log shift,
1.3-fold; P<.05; Fig 7, left). At 10-6 mol/L
bosentan, the concentration- response curve was shifted fourfold to
the right (7.7±0.1, P<.001). At the highest concentration
of bosentan (10-5 mol/L), a marked shift to the right was
observed, which did not allow a full concentration-response curve to
ET-1 to be constructed. In senescent WKY, a significant shift to the
right was observed again already at 10-7 mol/L bosentan
(twofold, 8.1±0.1, P<.05), and at 10-6 mol/L
bosentan, the concentration-response curve was also shifted twofold to
the right (8.0±0.1; P<.05; Fig 7, right). At
10-5 mol/L, bosentan evoked a marked and comparable shift
to the right as in adult WKY.
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In SHR, the sensitivity and maximal contractions to ET-1 were markedly decreased with aging (P<.05, Fig 8). In adult SHR, contractions to ET-1 were comparable to those in adult WKY (P=NS). In contrast, in senescent SHR, responses were markedly reduced compared with those in senescent WKY (P<.05). In adult SHR, bosentan exerted more pronounced effects than in adult WKY (P<.05). At 10-7 mol/L, bosentan shifted the concentration-response curve fivefold to the right (pD2, 7.9±0.1; P<.05; Fig 8, left), and at 10-6 mol/L, the shift was 14-fold (7.4±0.1, P<.05). In senescent SHR, the responses were weak and inhibited by bosentan (Fig 8, right). In SHR of both ages, high concentrations of bosentan prevented contractions to ET-1 (P<.05).
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Discussion |
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In the present study, adult and senescent normotensive WKY were compared with age-matched SHR. During the wide age range of the study, blood pressure remained the same in both groups (although as expected, it was markedly higher in the hypertensive rats). The major results of the study are that in the aorta of the rat, endothelium-dependent relaxations to acetylcholine are decreased by different mechanisms with aging and hypertension, involving an impaired formation of nitric oxide and an enhanced production of prostaglandin H2, respectively. Although the response of vascular smooth muscle to nitric oxide did not differ importantly with aging or hypertension, the contractions to potassium chloride were reduced under both conditions. The sensitivity to norepinephrine was comparable in all rats, whereas aging specifically reduced the response to ET-1 in the SHR only.
The endothelium plays an important protective role in the circulation as a vasodilator3 9 and inhibitor of platelet aggregation15 16 and of monocyte invasion.40 Hence, also in large conduit arteries, which do not contribute to peripheral vascular resistance, alterations in endothelial function may be important for the occurrence of vascular disease and its complications, such as myocardial infarction and stroke. In the aorta of the adult SHR, impaired endothelium-dependent relaxations to acetylcholine have previously been described.33 34 35 36 In the present study, we confirm these earlier observations and demonstrate that in the adult SHR not only inhibition of cyclooxygenase33 but also inhibition of the thromboxane receptor (in this case by the endoperoxide/thromboxane receptor antagonist SQ 3074138 ) is able to normalize the impaired response in the SHR. Similar findings have been reported with indomethacin in the human forearm circulation.29 As in previous studies, we were able to elicit endothelium-dependent contractions in quiescent vessels, particularly after inhibition of nitric oxide production by L-NAME. These contractions cannot be explained by the withdrawal of nitric oxide, but rather inhibition of nitric oxide unmasked the effects of an increased release of endothelium-derived vasoconstrictor prostaglandins. Indeed, L-NAME by itself did not cause significant changes in tension. However, after stimulation with acetylcholine, endothelium-dependent contractions were unmasked after inhibition of nitric oxide synthase. In line with this interpretation, the thromboxane receptor antagonist SQ 30741 prevented endothelium-dependent contractions to acetylcholine.
Aging reduced endothelium-dependent relaxations to acetylcholine also in WKY; indeed, at the older age, relaxations were similarly impaired in both WKY and SHR. Interestingly, the responses to the nitric oxide donor sodium nitroprusside, which as endothelium-derived nitric oxide exerts its effects also via activation of soluble guanylyl cyclase and formation of cGMP,41 were comparable in both adult and senescent rats of either strain. Most interestingly, the responsiveness of vascular smooth muscle to nitric oxide was not impaired but rather slightly enhanced. These results therefore clearly demonstrate that the impaired response to acetylcholine must be due to functional alterations of the endothelium rather than vascular smooth muscle. As the relaxations to acetylcholine were unaffected by inhibitors of endoperoxide/thromboxane in both senescent SHR and WKY, the contribution of a cyclooxygenase-derived contracting factor must be minimal at that age. In line with this interpretation, adult SHR exhibited marked endothelium-dependent contractions to acetylcholine, whereas the response was comparable in senescent WKY and SHR. Although, even in senescent rats of either strain, some endothelium-dependent contractions to acetylcholine occurred, they were not potent enough to affect endothelium-dependent relaxations to the muscarinic agonist. Indeed, SQ 30741 did not affect the relaxations in senescent rats. The responsiveness of vascular smooth muscle to agonists acting at the endoperoxide/thromboxane receptor such as the thromboxane analogue U46619 was fully maintained in the WKY at both ages and was comparable to that in adult SHR. Hence, in adult SHR, the impaired response to acetylcholine must be due to an enhanced production of endothelium-derived endoperoxide/thromboxane, whereas alterations in the response of vascular smooth muscle to the endothelium-derived contracting factors do not occur. In contrast, in senescent SHR the response to U46619 was slightly but significantly reduced. However, the reduction in endothelium-dependent contractions to acetylcholine occurring with aging was so dramatic in senescent SHR that a reduced production of the cyclooxygenase-derived endothelium-derived contracting factor appears to be the predominant age-related change in the SHR, whereas alterations in vascular smooth muscle responsiveness to the contracting factor contribute only slightly.
This study did not attempt to delineate the vascular production of endothelin in the SHR, but previous studies suggest normal release of the peptide as judged from plasma levels42 and from isolated mesenteric resistance arteries.43 Similarly, the response of vascular smooth muscle of the aorta to ET-1 was fully maintained in adult SHR compared with WKY. However, in the aging SHR, the response to ET-1 was dramatically reduced, indicating downregulation of endothelin receptors, as has been previously demonstrated.44 45 Endothelin acts on specific receptors on the endothelium and vascular smooth muscle to exert its vascular effects, in particular, vasoconstriction.46 47 Recently, potent endothelin receptor antagonists have been developed that are able to interfere with the response to the peptide.48 49 50 51 52 Bosentan is a newly developed nonpeptidic orally available ETA/ETB receptor antagonist that may have a great clinical potential in cardiovascular medicine.47 The present study demonstrates that bosentan inhibits endothelin-induced contractions in a concentration-dependent and competitive manner. In WKY, inhibitory effects of bosentan were apparent at 10-7 mol/L and most pronounced at 10-5 mol/L of the antagonist. Most interestingly, although the control response to endothelin was similar in adult SHR, the effects of bosentan were more pronounced than in adult WKY. This could indicate that although the control responses to the peptide are maintained at that age in the SHR, the receptor reserve was already reduced, an effect that obviously became markedly more pronounced with aging in both the absence and presence of the ETA/ETB antagonist.
Aging significantly reduced the contractions to KCl in both WKY and
SHR. As KCl is a receptor-independent agonist, this indicates that the
contractile machinery becomes less effective with aging, and this
process is more pronounced in SHR than in WKY, suggesting that
hypertension is associated with premature aging of the contractile
machinery of vascular smooth muscle cells. In contrast, the sensitivity
to norepinephrine was comparable in all four rat groups, suggesting
that the expression and signal transduction of adrenergic receptors
remain maintained in aging and hypertension. This contrasts markedly
with ET-1 and indicates that hypertension is associated with a specific
reduction of the response to ET-1 but not to norepinephrine. Hence,
endothelin receptors are downregulated in the aging SHR, and
-adrenergic receptors are not.
In summary, this study shows that in the rat aorta, endothelium-dependent relaxations to acetylcholine are decreased by different mechanisms with hypertension and aging, involving an enhanced production of prostaglandin H2 and an impaired formation of nitric oxide, respectively. The response of vascular smooth muscle to nitric oxide did not differ importantly with aging or hypertension, whereas the contractions to potassium chloride were reduced under both conditions. The sensitivity to norepinephrine was comparable in all rats, whereas aging specifically reduced the response to ET-1 in SHR.
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Acknowledgments |
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This study was supported by the Swiss National Research Foundation (No. 32-32541.91); the Sandoz Foundation for Gerontological Research; a grant-in-aid of Hoffmann–La Roche AG, Basel, Switzerland; and the Karl Mayer Foundation, Liechtenstein. C.F.K. was supported by a stipend of the Senglet Foundation.
Received July 22, 1994; first decision September 8, 1994; accepted October 13, 1994.
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