Abnormalities in glucose metabolism and disturbances in the plasma lipoprotein profile are frequently found to occur in tandem with hypertension. Such a cluster of cardiovascular risk factors has been termed syndrome X, or the plurimetabolic syndrome, and is commonly associated with visceral (android) obesity and type II diabetes mellitus (1-4). Although the common metabolic pathways leading to the concomitant development of these abnormalities remain uncertain, peripheral resistance of glucose metabolism to the action of insulin appears to constitute a central determinant (2). The latter condition may in turn develop in response to increased availability of lipid substrates delivered from the large visceral adipose depots that characterize android obesity (5).
In addition to genetic determinants that may predispose to the development of obesity (6) and the related abnormalities that define syndrome X, it is clear that one of its main environmental causes is the nature and amount of food ingested. Both the total amount of calories and the amount of fat ingested contribute to energy deposition and deterioration of glucose and lipid metabolism (7-10). In addition, ingestion of large amounts of simple carbohydrates or disaccharides may favor lipogenesis and lead to deterioration of glucose and lipid metabolism (11-14).
Although interventions aimed at dietary habits constitute an obvious first-line approach to overcome the metabolic abnormalities of syndrome X, their effectiveness may in some cases need inclusion of an adjuvant pharmacologic treatment. We and others previously studied the actions of α1-adrenergic antagonists, a class of compounds used for the treatment of hypertension, on lipid metabolism. Contrary to other antihypertensives such as thiazide diuretics and β-blockers without intrinsic sympathomimetic activity, which cause adverse effects on serum lipids and glucose homeostasis (15-17), α1-adrenergic blockers, while they are effective at reducing blood pressure, may at the same time exert beneficial effects on lipid and glucose metabolism and on insulin sensitivity (16,18-20). We showed that short-term administration of the α1-adrenergic antagonist prazosin prevented the postprandial increase of triacylglycerols (TGs) in rats fed a high-sucrose diet (21,22). The α1-blocker exerted its action mainly in the postprandial state, both by decreasing TG secretion and by increasing the rate of intravascular TG catabolism. In addition to their action on TG metabolism, α1-adrenergic blockers have been shown to reduce fasting plasma glucose and insulin in a large group of hypertensive nondiabetic patients (18) and to increase the metabolic clearance rate of glucose (23). These positive changes suggested an improvement of insulin sensitivity.
In view of the potentially beneficial consequences of α1-adrenergic blockade on most of the metabolic alterations typical of syndrome X, and because these have been reported in humans and in various animal models, most often without consideration for nutritional status or diet, our study aimed to assess the potential of α1-blockade to prevent severe metabolic abnormalities brought by extreme dietary conditions. To this end, long-term treatment with prazosin was given to rats fed a nonpurified diet (chow), which maintains low levels of plasma lipids and a high sensitivity of glucose to the action of insulin, and to animals fed a high-sucrose, high-fat, casein diet, which brings about a cluster of metabolic disturbances comparable to that of syndrome X. The characteristics of hyperlipidemia and deterioration of insulin sensitivity brought about by the highly lipogenic diet and the effect of α1-adrenergic blockade thereupon were evaluated in the fasting and postprandial states. Lipoprotein lipase (LPL) bound to the endothelial surface of capillaries partly determines the hydrolysis of plasma TG in most extrahepatic tissues and is central to the intravascular remodeling of lipoproteins (24). The enzyme is modulated by insulin, at least in adipose tissue (24). It was suggested that α1-adrenergic blockade may influence LPL activity (15,25,26). Therefore LPL was assessed in several tissues in the postprandial state to verify its possible involvement in the mechanisms of action of α1-adrenergic blockade on triacylglycerolemia.
MATERIALS AND METHODS
Animals and treatments
Forty male Sprague-Dawley rats initially weighing 150-175 g were housed individually in stainless steel cages in a vivarium maintained at 24 ± 1°C with a 12:12 h light/dark cycle (lights on at 20h30). The animals were divided into two dietary groups of 20 rats each. One group was fed a powdered nonpurified diet (Charles River Rat Chow RMH4020; Charles River, St. Constant, Canada) that provided 62% of energy as carbohydrate, 14% as fat, and 24% as protein, with an energy density of 14.4 kJ/g. The other group was fed a purified high-sucrose, high-fat, casein diet that provided 41% of energy as carbohydrate, 39% as fat, and 20% as protein, with an energy density of 19.4 kJ/g. The composition of this diet, which will subsequently be referred to as the hyperlipidemic (HL) diet, is given in Table 1. Ten rats from each dietary cohort were treated over the long term with prazosin by including the drug in their diet, at a dose of 3 mg/kg of body weight, during the whole experimental period. The dose of the blocker was adjusted weekly for body weight.
Animals were allowed to acclimate to their environmental conditions and diet for 3 weeks before the experiment began. During this period, body weight and food intake were recorded every other day. At the beginning of the fourth week, access to food was restricted to the dark period. The animals were adapted during 5 days to eat a meal consisting of their habitual diet within a period of 30 min, 1 h after the beginning of the dark period, according to a protocol previously reported (27). Free access to food was restored 90 min after meal intake.
Plasma/serum and tissue sampling
Two days before the end of the experiment, the animals were kept fasted for 10 h, and a blood sample was taken from the tail vein with a syringe containing disodium ethylenediamine tetraacetate (EDTA; 1.5 mg/ml blood) under light isoflurane anesthesia. After 2 days of recovery, animals were given their meal for 30 min, and 2 h after the onset of meal intake, they were killed by decapitation. Pilot studies showed that at this time point, serum TGs were maximally increased, regardless of the type of diet, and that tissue LPL was altered by food intake. Blood was collected and immediately centrifuged at 1,500 g, 4°C, for 15 min. Plasma (fasting) and serum (postprandial) were stored at −70°C until further biochemical analysis. Retroperitoneal white adipose tissue (WAT), heart, and vastus lateralis muscle (VLM) were excised. Tissues were weighed, and ∼50 mg was taken and homogenized as previously described (28). Tissue homogenates were frozen at −70°C until later measurement of LPL activity. The care of animals was approved by the Laval University Animal Care Committee.
Plasma/serum insulin was measured by radioimmunoassay, by using reagent kits from Incstar (Stillwater, MN, U.S.A.) with rat insulin as standard (29). Plasma/serum glucose was determined by using the Beckman glucose analyzer (Beckman Instruments, Palo Alto, CA, U.S.A.). Plasma/serum TGs were determined by an enzymatic colorimetric method by using reagents from Boehringer Mannheim (Montréal, Québec, Canada), which allowed correction for free glycerol. Total cholesterol also was determined in plasma and serum by an enzymatic colorimetric method by using reagents from Boehringer (Montréal, Québec, Canada). LPL activity was quantitated by measuring hydrolysis by tissue homogenates of a substrate containing emulsified [carboxyl-[14C]triolein, as previously detailed (28). LPL activity was calculated by subtracting lipolytic activity determined in a final NaCl concentration of 1 M (non-LPL activity) from total lipolytic activity measured in a final concentration of 0.1 M. Under the present conditions, 1 M NaCl inhibited 82-91% of total lipolytic activity in all tissue homogenates. LPL activity was expressed as microunits (1 μU = 1 μmol nonesterified fatty acids released per hour of incubation at 28°C). Protein content of the tissue extracts was determined by the method of Lowry et al. (30).
Data are reported as mean ± standard error of the mean. Statistical analysis was performed separately on fasting and postprandial data by using a 2 × 2 factorial analysis of variance (ANOVA) to determine and compare main treatment effects as well as treatment interactions. The two factors were Diet with two levels (chow or HL diet), and Blocker with two levels (absence or presence). When a significant interaction was detected by ANOVA, individual between-group comparisons were performed by using post hoc Fisher's protected least squares difference (PLSD) test. Statistical significance was accepted when the p value was <0.05.
The daily amount of food ingested (an average of 21 g/day) was comparable in the two dietary cohorts, which resulted in a daily energy intake that was 30% larger in the HL-fed than in the chow-fed rats (Table 2). Energy intake was not significantly modified by long-term prazosin during the 4-week experimental period. Rats fed the HL diet gained 8-10% more weight than those given the nonpurified chow diet. The α1-blocker slightly but significantly decreased final body weight (−4%) and daily weight gain (−12%) in both dietary groups. Therefore treatment with prazosin reduced gross energetic efficiency (mg weight gained/kJ ingested, −15%) in both dietary cohorts. The HF animals ingested 34% (p < 0.005) more grams of their diet during the last meal than those given chow, which resulted in an energy intake that was twofold larger. Long-term treatment with the α1-blocker did not affect the size of the last meal. No treatment interaction was noted on any of these variables.
As shown in Fig. 1, fasting plasma concentration of TGs was ∼40% higher in rats fed the HL diet than in those given chow and was not affected by long-term prazosin. Plasma TG levels 2 h after meal intake were increased twofold over fasting values in the chow-fed group and 10-fold in the HL-fed group. Administration of prazosin did not modify postprandial TGs in the chow-fed group, whereas the blocker reduced by half the increase in TGs that followed intake of the HL meal, as confirmed by the significant Diet × Blocker interaction.
Animals fed the HL diet displayed fasting hypercholesterolemia (Fig. 1). Long-term prazosin exerted a significant overall reducing effect on fasting cholesterol levels. Although treatments did not interact, this effect tended to be larger in the HL (−15%) than in the chow (−8%) cohort. The 50% increase in plasma cholesterol that followed ingestion of the HL meal was blunted by prazosin, whereas in chow-fed animals, cholesterol did not change in a significant manner postprandially and was not affected by prazosin (significant Diet × Blocker interaction).
Fasting plasma glucose was higher in rats fed the HL diet than in those given chow, in the presence or absence of the blocker (Fig. 2). Serum glucose was higher 2 h after ingestion of the high-carbohydrate chow meal than after the HL meal. The postprandial increase in serum glucose was not affected by prazosin.
Long-term treatment with prazosin nearly abolished fasting hyperinsulinemia in the HL cohort but remained without effect in the chow group (significant Diet × Blocker interaction) (Fig. 2). The postprandial increase in insulin levels was significantly higher in the HL group when compared with the chow group and was not affected by prazosin in either of the dietary cohorts.
The effects of the HL diet and long-term treatment with prazosin on tissue weights and LPL activity are presented in Table 3. In animals fed the HL diet compared with those receiving standard chow, WAT, heart, and muscle were significantly heavier (all p values <0.01), regardless of the presence or absence of the blocker. In both dietary cohorts, the effects of long-term administration of prazosin on body weight and weight gain (Table 2) were not reflected in the tissues examined, as the blocker did not significantly affect organ weights. The HL diet resulted in a large reduction of LPL specific activity in WAT. However, adipose weight being twice as large and containing more protein (data not shown) in the HL group compared with the chow group, total activity per retroperitoneal depot was significantly larger in the HL cohort (collapsed mean for chow cohort, 26 ± 3 μU/tissue; HL cohort, 36 ± 4 μU/tissue; p < 0.03). The diet did not alter enzyme activity in the heart or vastus lateralis. LPL activity was not affected by long-term treatment with prazosin.
This study outlines the effects of diet-induced changes in fasting and postprandial TGs, cholesterol, glucose, and insulin concentrations, and their alteration by long-term α1-adrenergic blockade. The diets used were chosen on the basis of their extremely divergent effects on variables of lipid and glucose metabolism. Indeed, laboratory chow constitutes the diet that maintains the lowest plasma lipid levels and the highest sensitivity to insulin in rats. In contrast, the combination of sucrose (31), a large amount of fat (32), and casein as the protein source (33) brings about the most severe forms of diet-induced dyslipidemia and insulin resistance. The hypothesis to be tested was that hypertriacylglycerolemia, hypercholesterolemia, and disturbances in insulin action brought by the HL diet could be prevented by long-term treatment with prazosin.
Rats fed the HL diet displayed fasting hypertriacylglycerolemia, which was likely the result of a stimulation of hepatic lipogenesis caused by long-term ingestion of dietary sucrose. Indeed, dietary fat usually leads to hypercholesterolemia rather than hypertriacylglycerolemia (34), but the fructose moiety of sucrose is highly lipogenic in rats (35). Ingestion of a chow meal doubled serum TGs, whereas the HL meal increased triacylglycerolemia 10-fold. Both chylomicrons and very low density lipoproteins (VLDLs) contributed to this postprandial increase in the HL group, as previously shown by Reaven et al. (36). Long-term treatment with the α1-blocker affected neither fasting TGs in both dietary cohorts nor the postprandial increase in the chow-fed animals, but resulted in a substantial dampening of the postprandial hypertriacylglycerolemia in the HL animals. These results confirm and extend previous findings on the short-term effects of the blocker on triacylglycerolemia (21,22). Indeed, it was previously shown that short-term prazosin had minimal effects on fasting TGs of rats fed a high-sucrose diet, and the blocker exerted a strong effect on postprandial triacylglycerolemia of sucrose-fed, but not starch-fed animals (27,37). Therefore the effect of prazosin on TG metabolism appears to be related to alterations of metabolic events induced by food intake and is expressed when the latter substantially increases serum TG levels.
The increase of plasma TG concentration in the postprandial state was markedly prevented (∼50%) by longterm prazosin. This blunting effect of the blocker may have been caused by the decrease of hepatic VLDL-TG output, as previously shown by us with short-term prazosin given to rats fed a high-sucrose diet (27). We also demonstrated that prazosin accelerates postprandial TG catabolism (22). Although α1-blockers have been reported to increase adipose LPL activity in some animal models, such as the norepinephrine-treated hamster (25), and postheparin plasma LPL was shown to increase in hypertensive patients treated with prazosin (15), postprandial tissue LPL was found to remain unaltered by the blocker in our study. However, even in the presence of unchanged LPL availability, vasodilation induced by α1-blockade may have accelerated postprandial TG catabolism by enhancing the rate of delivery of TG-rich lipoproteins to LPL (38).
Previous studies on the metabolism of TGs, mainly of endogenous origin, strongly suggested that the short-term reducing effect of α1-blockade on postprandial TGs was related at least partly to a potentiation of postprandial insulin secretion (21). This appeared not to be the case in our study, wherein the long-term effects of the blocker were studied in animals fed a diet that leads to overt insulin resistance. This apparent discrepancy may be accounted for by an improvement in overall insulin sensitivity brought about by long-term exposure of HL-fed rats to the blocker, as suggested by their lower fasting insulinemia. If that was the case, the same postprandial increase in insulin could have had dramatically different actions on the handling of TGs in the postprandial state. There is indeed strong evidence that insulin decreases hepatic VLDL secretion when the sensitivity of glucose metabolism to the hormone is normal, but that this action is lost in the presence of hepatic insulin resistance (39-41).
The HL cohort displayed fasting hypercholesterolemia, which was totally prevented by long-term treatment with prazosin. This may be related to an effect of prazosin on the activity of lecithin:cholesterol acyl-transferase (LCAT), the enzyme responsible for the intravascular esterification of cholesterol (42). It was indeed reported that some α1-blockers increase the activity of LCAT (17,43) with a concomitant decrease in total cholesterol. Enhanced cholesterol esterification would favor global cholesterol transport toward the liver. In addition, hepatic de novo cholesterol synthesis could have been dampened by α1-blockade, as reported for doxazosin, another α1-adrenergic antagonist, in hypercholesterolemic hamsters (25). On the other hand, serum cholesterol levels were increased by the intake of the HL meal, which contained a sizable amount of cholesterol. Because there is no evidence that prazosin affects intestinal lipid absorption, the fact that prazosin greatly diminished the postprandial increase in cholesterol suggests that chylomicron remnant catabolism was accelerated by α1-blockade. It remains to be determined whether this could be caused by an increase in remnant receptor activity in the liver or by an improved delivery of remnants by virtue of hepatic vasodilation.
Long-term ingestion of the HL diet resulted in fasting hyperglycemia. Although long-term treatment with prazosin tended to improve this condition slightly, the effect did not reach statistical significance. However, treatment with the α1-blocker greatly diminished the extent of fasting glucose intolerance that developed with ingestion of the HL diet, as demonstrated by the much lower fasting insulin levels and insulin-to-glucose ratio. In fact, fasting insulin levels in HL-fed, prazosin-treated animals were only slightly above those of chow-fed rats, whereas the insulin-to-glucose ratio was completely normalized. This resulted from an improvement in peripheral insulin sensitivity, rather than a loss of competence for insulin secretion, because the postprandial increase in insulin after meal intake was comparable in both untreated and prazosin-treated HL groups. The postprandial increase in glucose was larger in the groups given the high-carbohydrate chow than in those fed the HL diet. As was the case in the fasted state, serum glucose measured 2 h after ingestion of the chow meal was not altered by prazosin in either of the two dietary cohorts. Likewise, postprandial insulin levels attained much higher levels in the HL than in the chow groups, despite lower glucose concentrations, most likely because of insulin resistance. Prazosin treatment did not alter the insulin response to meal intake, so although prazosin appeared to improve fasting glucose tolerance, this was not reflected in the insulin response to meal intake. However, the postprandial time point chosen corresponded to the peak for TGs, but not for glucose and insulin, which peaked earlier after meal intake (N. Fajardo and Y. Deshaies, unpublished observations). Therefore definitive conclusions about the effects of α1-blockade on the postprandial handling of glucose and on the response of insulin to intake of a highly lipogenic diet must await more detailed studies.
It is worth noting that long-term treatment with prazosin resulted in a modest but significant reduction in gross energetic efficiency, independent of the type of diet, a finding that was since confirmed in another study (N. Fajardo and Y. Deshaies, unpublished observations). Assuming unaltered intestinal nutrient absorption, the lack of change in food intake suggests an increase in energy expenditure. The possibility of a stimulation of energy expenditure by α1-blockade is, however, difficult to reconcile with the ability of the α1-adrenergic pathway modestly to stimulate brown adipose tissue thermogenesis in the rat (44). However, this apparent effect of α1-blockade on energetic efficiency may be related to vasodilation or to as yet undetermined indirect metabolic events.
In conclusion, our data demonstrate that long-term treatment with the α1-adrenergic blocker prazosin significantly attenuated most of the abnormalities typical of syndrome X, such as postprandial hypertriacylglycerolemia and hypercholesterolemia and fasting hyperinsulinemia, which were produced by long-term ingestion of the HL diet. However, some of the abnormalities, such as fasting hypertriacylglycerolemia and hyperglycemia, were not corrected by prazosin. The improvements brought by long-term treatment with the α1-adrenergic blocker were especially notable, given the extreme lipogenicity of the HL diet and its high potential for bringing about hyperlipidemia and insulin resistance.
Acknowledgment: We acknowledge the professional assistance of Mr. Alain Demers. This work was made possible by a grant from the Heart and Stroke Foundation of Canada. During the course of these studies, Ms. Fajardo was the recipient of a studentship from the Consejo Nacional de Ciencia e Tecnologia de Mexico.
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