1 Department of Surgery and 2 Departments of Obstetrics and Gynecology and Physiology, University of Alberta, Edmonton, Alberta, Canada T6G 2S2
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ABSTRACT |
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We tested the hypothesis that aging and insulin resistance interact to increase vascular dysfunction by comparing the function of isolated mesenteric resistance arteries in obese, insulin-resistant JCR:LA-cp rats and lean, insulin-sensitive rats of the same strain at 3, 6, 9, and 12 mo of age. The peak constrictor responses to norepinephrine, phenylephrine, and high potassium were elevated in arteries from obese rats. Responses to these agents increased with age in both obese and lean rats. An eicosanoid constrictor contributed substantially to vasoconstriction in the arteries from both lean and obese animals. Inhibition of nitric oxide synthase increased the vasoconstrictor response to norepinephrine in both obese and lean rats. This effect increased with age in lean rats only. Vascular relaxation in response to acetylcholine and sodium nitroprusside was impaired in the obese rats and did not alter with age. The results suggest that obese JCR:LA-cp rats have enhanced maximal constriction, which originates in the arterial smooth muscle and increases with age. There is evidence that the ability of the arteries to compensate for the enhanced contractility is impaired in obese rats, particularly with advanced age.
obesity; aging; endothelium; vascular smooth muscle
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INTRODUCTION |
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INSULIN RESISTANCE IS A common metabolic abnormality associated with obesity and is present in ~25% of the adult population in prosperous societies. It is associated with a clustering of cardiovascular risk factors (20) such as hyperinsulinemia, an independent predictor of ischemic heart disease (10); elevated triglyceride levels; low levels of high-density lipoprotein cholesterol; and hypertension. Aging is associated with an increase in the incidence of vascular disease. The insulin resistance that is the primary determinant of hyperinsulinemia is associated with the development of vascular disease at an early age, suggesting the existence of an interaction between aging and insulin resistance.
The smooth muscle of arterial walls has an inherent tendency to constrict the lumen under basal conditions. This basal contractile state is further enhanced by endocrine and neural vasoconstrictor agonists, such as norepinephrine (NE), and by vasoconstrictors secreted from the local endothelium, such as endothelin and prostanoids. Endothelial cells also play an important role in modifying the contractility of the vascular smooth muscle by secreting vasodilatory substances, such as prostacyclin and nitric oxide (NO) (17). Aging, in rats, has been reported to be associated with both enhanced (15, 16) and impaired (9, 14, 26) responses to vasoconstrictors. In humans, aging is associated with reduced NO release (24). In insulin-resistant humans, impaired NO release (23, 27) and enhanced vascular constriction (7, 14) have been reported, but the nature of the interaction between aging and insulin resistance has not been well characterized.
We carried out studies on the JCR:LA-cp rat, which, when homozygous for the cp gene (cp/cp) is obese, and, when heterozygous (cp/+) or homozygous (+/+), is lean and metabolically normal (for review, see Ref. 18). The cp/cp animals are hyperphagic, insulin resistant, hyperinsulinemic, and hypertriglyceridemic by 7 wk of age. As young adults they develop large-artery atherosclerotic disease that increases in severity with age. By 9 mo of age they exhibit advanced intimal lesions, as well as myocardial lesions that include cell loss, and old organized scars consistent with an ischemic origin.
Our aim was to compare vascular wall function in mesenteric resistance arteries in obese and lean JCR:LA-cp rats to determine the nature of the interaction between aging and insulin resistance in the pathophysiological process. A secondary objective was to determine whether either or both NO and eicosanoids modulate function in this animal model of vasculopathy.
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METHODS |
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Animals. The study was carried out on obese (cp/cp) and lean (as bred, a 2:1 mixture of +/cp and +/+, referred to as +/?) male rats at 3 (n = 15/group) and at 6, 9, and 12 mo of age (n = 6/group). The +/? rats were used in this study because +/cp and +/+ rats have been found to be indistinguishable in all metabolic and physiological studies to date. The animals were bred in our established JCR:LA-cp colony and were maintained in a controlled environment at 20°C and 40-50% humidity, with 12 h of light per 24-h period. Rat chow (Rodent Diet 5001; PMI Feeds, St. Louis, MO) and distilled water were available ad libitum. Care and treatment of the rats conformed with the guidelines of the Canadian Council on Animal Care and was subject to prior institutional approval as provided for in the guidelines.
All animals were studied in the nonfasted state at the end of the dark phase. Rats were anesthetized with 3% halothane at 1 l/min O2. A midline laparotomy was performed and a section of the mesenteric arcade 5-10 cm distal to the pylorus was removed and placed immediately in ice-cold HEPES-buffered physiological saline (in mM: 142 NaCl, 4.7 KCl, 1.17 KH2PO4, 1.2 CaCl2, 10 HEPES, and 5 glucose).
Artery preparation. All fat and connective tissue were removed from mesenteric arteries of ~300 µm in diameter, which were then cut to ~2 mm in length and threaded onto two stainless steel wires of 25 µm diameter. The wires were attached to two polyacrylamide blocks connected to an isometric myograph system (Kent Scientific, Litchfield, CT). One block was attached to a force transducer, and the other was connected to a displacement device. The blocks rested in 5-ml tissue baths with HEPES-buffered physiological saline at pH 7.4 and maintained at 37°C. Four baths were used per experiment. The force produced by the arteries was measured by force-displacement transducers (Kent Scientific) and was recorded on a data acquisition system (Workbench; Strawberry Tree, Sunnyvale, CA).
Resting length tension curve. Arteries
were stretched to ~0.2 mN/mm of vessel length (1 mN 102 mg),
allowed to equilibrate, and then given a conditioning stretch of ~0.6
mN before determining the passive length-tension curve. To generate
this curve, each artery was stretched in four 25-µm incremental steps
and held for 20 s at each step, and the resistive force was measured.
The 25-µm increases in length and the force produced were used to determine the resting length-tension relationship. The arterial circumference was obtained using Laplace's law. With this equation, the circumference the vessel would have at 100 mmHg
(L100) was calculated from the exponential curve fit of tension vs. the
circumference. The concentration-response curves were obtained at
0.8L100, which provides maximum active force generation with minimum passive tension.
Experimental design. Cumulative
concentrations of NE were added to three baths over the range of
108 to
10
5 mM, and the force
produced was measured. The concentration-response curve to
phenylephrine (PE; 10
8 to
10
5 mm) was determined in
the fourth bath. The arteries were washed three times, between
concentration-response curve determinations, by changes in buffer at
10-min intervals. The concentration-response curves to NE and PE were
determined in a crossover design in two baths. In two other baths,
arteries were preconstricted to 50% of their maximal constriction with
NE. Cumulative concentrations of either sodium nitroprusside (SNP;
10
9 to
10
4 mM) or acetylcholine
(ACh; 10
9 to
10
6 mM) were added, and the
percent relaxation was calculated. To examine the role of vasoactive
eicosanoids in the constrictor and dilator responses being studied,
meclofenamate was added
(10
6 mM) to block the
cyclooxygenase component of prostaglandin H (PGH) synthase and to
prevent the production of eicosanoids. The role of NO was studied by
administering NG-nitro-L-arginine
methyl ester (L-NAME;
10
4 mM) to prevent the
production of NO from
L-arginine. Only one inhibitor
was used in any particular bath. Concentration-response curves to NE,
PE, ACh, and SNP were determined in the presence of either
meclofenamate or L-NAME. On
completion of the protocol, the maximal constriction of each artery to
buffer containing 125 mM potassium was measured.
Additional experiments were carried out on arteries only, from 3-mo-old
cp/cp and
+/? rats. The constriction in response
to cumulative concentrations of serotonin (5-hydroxytryptamine;
108 to
10
5 mM;
n = 8/group) and arginine vasopressin
(AVP; 10
10 to
10
7,
n = 8/group) was measured. In separate
groups of rats, two arteries were perfused with 0.3%
3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) for 3 min to remove the endothelium before mounting on the
myograph system, so that two arteries with and two arteries without
endothelium from the same rat were studied at the same time
(n = 6 for
+/? and
n = 8 for
cp/cp rats). The achievement of
complete endothelial removal was assessed by the absence of relaxation
of preconstricted arteries in response to ACh
(10
6 mM).
Concentration-response curves to NE were then determined.
Plasma glucose, insulin, and triglyceride concentrations. Blood was collected in rats in their normal fed state via left ventricular puncture and was placed into tubes containing EDTA. Plasma glucose was assayed using a glucose oxidase procedure (Beckman Instruments, Brea, CA). Insulin was measured by radioimmunoassay with rat insulin standards (Kabi Pharmacia Diagnostics, Uppsala, Sweden). Triglyceride concentrations were measured by an enzymatic colorimetric assay (Peridochrom Triglycerides GPO-PAP; Boehringer Mannheim).
Drugs. NE, PE, ACh, L-NAME, meclofenamate, serotonin, AVP, SNP, and CHAPS were obtained from Sigma (St. Louis, MO). Stock solutions of the drugs were prepared in distilled water and added directly to the organ baths. All concentrations are expressed as the final concentration in the tissue bath fluid.
Statistical analysis. The force produced was calculated as the tension acquired at a given concentration of drug (i.e., measured tension minus baseline tension). Data from concentration-response curves were fitted to sigmoidal curves using the Prism computer program (Graphpad, San Diego, CA), and the EC50 was calculated. A two-way ANOVA was used to determine the association between the measured variables, age and genotype. With the measured variable as the dependent variable, and age and genotype as the independent variables, an interaction coefficient for age and genotype was included. A value of P < 0.05 for age was taken to indicate the existence of a difference between the means of the dependent variable of the genotypes combined for age groups, and for genotype this value indicated that the mean for all ages combined was different for cp/cp and +/? rats. A value of P < 0.05 for the interaction coefficient was taken to indicate that the mean difference in the dependent variable for cp/cp and +/? rats varied with age. An analysis of covariance was included in the model with insulin levels or triglycerides to determine the impact of these variables on the relationship of the dependent variable with the independent variables.
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RESULTS |
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Body weights of cp/cp animals were
greater than those of +/? rats and
increased in both groups with age (Table
1). Both insulin and nonfasting plasma
triglycerides and insulin were significantly elevated in
cp/cp rats
(P < 0.001); however, insulin levels
decreased with age (P < 0.05),
whereas those of triglycerides did not. Nonfasting plasma
glucose levels were not different between groups
(P = 0.102) but did decrease with age
(P = 0.022).
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Figures 1 and
2 show the concentration-response curves
to NE and PE, respectively, as a function of age. The arteries of
cp/cp rats showed significantly
elevated maximal constriction compared with those of
+/? animals with both NE and PE
(P < 0.001). Both genotypes had
increased constriction with age in response to NE and PE
(P < 0.001). However, there was no
significant interaction between age and genotype in response to either
NE (P = 0.246) or PE
(P = 0.821). The maximal constriction
to 125 mM potassium (Fig. 3) was positively
associated with both age (P < 0.02)
and the cp/cp genotype
(P < 0.001). Neither insulin nor
triglyceride levels were significant covariates in any of these
analyses.
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To determine whether or not the enhanced maximal constriction observed
in the arteries of cp/cp animals was
agonist specific, several other constrictors were used (Fig.
4). At 3 mo of age, maximum constriction
was elevated in cp/cp rats in response
to NE (P < 0.0001), PE
(P < 0.05), serotonin
(P < 0.05), and high potassium
(P < 0.02), but a similar trend for
AVP was not significant (P > 0.08).
To determine whether the endothelium played a role in the enhanced
maximal constriction in cp/cp animals,
deendothelialized arteries were studied. In these arteries, a
difference in maximal constriction in response to NE remained between
3-mo-old cp/cp and
+/? rats (1.56 ± 0.09 and 1.18 ± 0.14, respectively, P < 0.05).
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The maximal response to NE or PE in the presence of
L-NAME (an inhibitor of NO
release) was elevated in all groups. The difference between maximal
constriction in response to NE with and without L-NAME (Fig.
5) was greater with advanced age
(P < 0.01) and in the
+/? genotype
(P < 0.005). There was a significant
interaction between age and genotype
(P < 0.05). The difference between
maximal constriction to PE with and without
L-NAME (Fig.
6) was not associated with genotype
(P = 0.097) but did increase with age
(P < 0.02). Neither insulin nor
triglyceride levels were significant covariates in any of these
analyses.
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The maximum response to NE or PE was decreased in all groups in the
presence of meclofenamate. The difference between maximum response to
NE (Fig. 7) or PE (data not shown) with and
without meclofenamate decreased with age, to 9 mo of age
(P < 0.05) but was not genotype
dependent.
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Relaxation in response to ACh was significantly impaired in the
arteries from cp/cp rats compared with
those of +/? animals (P < 0.05) but did not change
significantly with age, and neither insulin nor triglycerides were
significant covariates. There was no interaction between age and
genotype (Fig. 8). Relaxation in response
to ACh was completely inhibited by the presence of
L-NAME at the concentration of
ACh inducing 50% relaxation in arteries from both
cp/cp and
+/? rats at all ages. The presence of
meclofenamate in the organ bath had no significant effect on relaxation
in response to ACh in cp/cp rats but
did enhance sensitivity to ACh in +/? rats (P = 0.002). The effect of
meclofenamate on ACh-mediated relaxation showed no dependence on age.
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In the presence of L-NAME, low concentrations of ACh appear to induce a small increase in constriction (<15%). The maximum percentage increase in tension in NE-preconstricted arteries in response to ACh, with L-NAME present in the organ bath, decreased with age (P < 0.01) but was not associated with genotype (P = 0.27).
Relaxation in response to SNP was also significantly impaired in the
arteries from cp/cp rats
(P < 0.01) but did not change significantly with age (P = 0.076).
There was no interaction between age and genotype (Fig.
9), and neither insulin nor triglycerides were significant covariates. The presence of meclofenamate in the organ
bath tended to reduce sensitivity to SNP in
cp/cp animals (P = 0.057) but had no effect on
+/? rats. The effect of meclofenamate on SNP-mediated relaxation showed no dependence on age.
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A limited number of observations showed no difference in results between cp/+ and +/+ rat vessels (data not shown), confirming the use of +/? rats for the overall study.
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DISCUSSION |
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Constrictor function. We have identified enhanced maximal vascular constriction with NE, PE, and 125 mM potassium in cp/cp rats. Maximum response to all three constrictors was greater with age, and the rate of increase in response to constrictors with age was similar for both cp/cp and +/? animals. Enhanced vasoconstriction with increasing age is consistent with some reports (6, 16) but inconsistent with others (9, 14, 26). Some studies have shown no increase in KCl-induced peak constriction in either young or old rats but have shown an enhanced maximal constriction to NE expressed as a percentage of maximal constriction to KCl (14), indicating a specific, increased sensitivity to NE with age. The variability in these results may be largely explained by the different strains of rats used, the differences in methodology and types of arteries studied, and the different ages of animals studied. It is noteworthy that NE release from adrenergic nerves is enhanced with age (25) and, therefore, the decreased contractile response seen with age in some strains of rats may be an adaptive response.
We also report that the maximum contractile response to serotonin and
AVP is elevated in 3-mo-old cp/cp rats
in comparison with +/? animals. The
vasoconstrictors that we used act via different mechanisms. PE
stimulates 1 receptors,
responsible for vasoconstriction, whereas NE stimulates
1,
2, and
receptors, which
facilitate both vasoconstriction
(
1) and vasodilation
(
2 and
) via the NO pathway
(5). Serotonin acts through two subtypes of serotonin receptors and
also activates phospholipase A2.
AVP acts primarily on V1 receptors
but also facilitates endothelium-dependent vasodilation via a PGH
synthase pathway. Potassium facilitates depolarization of smooth
muscle, independently of any receptor. Because each of these
vasoconstrictors caused enhanced maximal constriction in
cp/cp compared with
+/? animals, a specific receptor is
not the primary cause of the greater contractility seen. Our results suggest an increase in the efficacy of the contractile machinery of
smooth muscle cells in the presence of insulin resistance. Furthermore,
an increase in constriction was observed over 3-12 mo of age in
both cp/cp and
+/? rats, suggesting that these
changes are also a component of aging.
L-NAME, an NO synthase
inhibitor, increased maximal contractility in response to NE and PE in
all groups, suggesting that basal NO release modulates the contractile
response of arteries. For NE, the effect of
L-NAME on the contractile
response increased with age in the +/?
animals but was unchanged with age in the cp/cp animals. This suggests that
basal NO release increases with age in the normal insulin-sensitive
state but that this adaptive response fails when insulin resistance is
present. As also seen for NE, the maximum constriction in response to
PE was increased by L-NAME. The
difference in response to PE in the presence or absence of
L-NAME was enhanced with age
but, unlike that seen with NE, was not different between
cp/cp and
+/? rats. These different responses
may be related to the different receptors stimulated by NE and PE. The
2 and
receptors stimulate
the vasodilatory component of the activity of NE (unlike PE) via an
NO-dependent mechanism (5). Thus it may be that the lack of increase in constriction observed in the response to NE in the presence of L-NAME in older
cp/cp rats was related to reduced NO release.
Vascular wall function may also be modified by eicosanoids such as PGH2, prostacyclin, and thromboxane. When meclofenamate, a PGH synthase inhibitor, was present in the bath, the maximal responses to both NE and PE were substantially reduced in both cp/cp and +/? rats and in all age groups. This has also been reported in other strains of rats (8, 28) and suggests that a PGH-synthase-dependent constrictor plays an important role in arterial constriction. The vasoconstrictor involved is most likely either PGH2 or thromboxane. However, despite being muted in all groups in the presence of meclofenamate, maximal constriction in response to NE or PE was still greater in cp/cp than in +/? and in older rats, indicating that the enhanced contractility seen was not primarily due to an effect of eicosanoids.
Vasodilatory function. ACh-stimulated relaxation has been reported to be impaired with increasing age in both animal (9, 15) and human studies (24). In humans, limb blood flow response to ACh has been reported to be impaired in obese, insulin-resistant subjects (23) and in those with non-insulin-dependent diabetes (27). ACh-mediated vasodilation was impaired in cp/cp rats but remained unchanged with age in either cp/cp or +/? rats. At the concentration of ACh at which 50% relaxation occurred, relaxation was inhibited by L-NAME for both cp/cp and +/? rats, confirming that it is primarily NO mediated. The presence of meclofenamate in the organ bath had no effect on relaxation in response to ACh, indicating that eicosanoids were not involved.
The absence of change in ACh-stimulated relaxation with age, seen in +/? rats only, contrasts with the increase in constriction in response to NE when L-NAME was present, probably due to basal NO release. The difference in maximal constriction with L-NAME did not increase with age in the cp/cp rats but did increase in the +/? animals, and it may be that basal release of NO is the physiologically important element. Our observation of a small increase in NE-stimulated constriction induced by L-NAME in aging cp/cp rats may also indicate impairment of this important aspect of NO-mediated vasodilation.
Relaxation of the arteries in response to the NO donor SNP was impaired in cp/cp rats in comparison with those from +/? rats. This suggests that, in addition to the smooth muscle hypercontractility previously discussed, the smooth muscle of the cp/cp rat is also less responsive to NO, one of the main modulators of vascular contractility. Thus the impaired relaxation in response to ACh in arteries from cp/cp rats is due, at least partially, to impaired smooth muscle response to NO. Such an effect is consistent with our observations of abnormal behavior of aortic smooth muscle cells from cp/cp rats in vitro (1, 2).
Relationship between age and hyperinsulinemia. Insulin is a vasodilator that acts at least partially via the NO pathway (4), and obese, insulin-resistant human males have been reported to have impaired vasodilation in response to insulin (12). In the present study insulin levels were elevated in cp/cp rats and decreased somewhat in old rats, as previously found (3). The hypertriglyceridemia associated with insulin resistance may contribute to disease, and we have identified lipid deposits within both skeletal muscle and aortic media in cp/cp rats (21, 22). Insulin resistance is also associated with increased oxidative stress (19), and we have previously shown that an increase in lipid peroxidation over time is associated with changes in endothelial function (8). Aortic relaxation in response to ACh has been reported to be more severely impaired in older rats after exposure to oxidative stress (11). Hence the combination of age and insulin resistance may act synergistically via oxidative stress to alter vascular function. Because insulin functions as a growth factor, hyperinsulinemia may also cause changes in vascular wall function, consistent with our observations of enhanced contractility and abnormal smooth muscle cell behavior in cp/cp rats.
Conclusions. We have identified enhanced maximal constriction in the arteries of cp/cp rats and those of older rats, both cp/cp and +/?. The positive interaction between age and the cp/cp genotype is probably due to changes in the contractile machinery of smooth muscle. An eicosanoid constrictor is an important component of adrenergic vasoconstriction but contributes less to constriction with advancing age, up to 9 mo. In the cp/cp rat, the greater vasoconstriction appears to be due, in part, to inadequate NO release as the animals age. NO-mediated relaxation of arteries from cp/cp rats was also deficient at the smooth muscle cell level. These results support the hypothesis that age and the obese, insulin-resistant state both contribute to impaired vascular function of both endothelial and smooth muscle cell origins.
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ACKNOWLEDGEMENTS |
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We thank Damon Mayes, biostatistician of the University of Alberta Perinatal Research Centre, for statistical advice and Sandra Graham for essential technical support.
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FOOTNOTES |
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This study was supported by grants from the Medical Research Council of Canada to Sandra T. Davidge and J. C. Russell.
S. T. Davidge is a Scholar of the Heart and Stroke Foundation of Canada and the Alberta Heritage Foundation for Medical Research. S. F. O'Brien was a Fellow of the Alberta Heritage Foundation for Medical Research.
Present address of S. F. O'Brien: Canadian Blood Service, Toronto Blood Central, Toronto, Ontario, Canada.
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: J. C. Russell, Department of Surgery, 275 Heritage Medical Research Centre, Univ. of Alberta, Edmonton, Alberta, Canada T6G 2S2 (E-mail: Jim.Russell{at}ualberta.ca).
Received 24 February 1999; accepted in final form 17 June 1999.
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