(Hypertension. 1996;28:754-757.)
© 1996 American Heart Association, Inc.
Articles |
Contribution of Nitric Oxide to the Beneficial Effects of Enalapril in the Fructose-Induced Hyperinsulinemic Rat
the Chorley Hypertension Institute, Chaim Sheba Medical Center, Tel Hashomer and Tel Aviv (Israel) University Sackler Faculty of Medicine.
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Abstract |
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We examined accumulating evidence of the positive contribution of nitric oxide to the pharmacological effects of converting enzyme inhibitors in 36 rats rendered hypertensive, hyperinsulinemic, and hypertriglyceridemic by a fructose-enriched diet. We studied the response of blood pressure, insulin, and triglyceride levels to inhibition of either converting enzyme–kininase II, nitric oxide synthase, or both. Two weeks of the converting enzyme inhibitor enalapril (20 mg/kg) reduced blood pressure from 137±2 to 105±7 mm Hg, insulin from 7.6±2.0 to 2.2±1.1 pg/mL, and triglycerides from 292±37 to 163±37 mg/dL. Treatment with NG-nitro-L-arginine methyl ester (100 mg/kg) raised blood pressure from 144±7 to 170±8 mm Hg without affecting the other parameters. Two weeks of concomitant treatment with both agents blunted the hypotensive and beneficial metabolic effects of enalapril; thus, final blood pressure (141±7 mm Hg), insulin (6.4±2.4 pg/mL), and triglyceride (231±51 mg/dL) values were no different from those of untreated fructose-fed rats. These data suggest that persistent synthesis of nitric oxide contributes to the vasodilator and metabolic effects of enalapril in the fructose-fed rat model.
Key Words: rats • enalapril • L-NAME • fructose • hyperinsulinism
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Introduction |
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The vasodilator properties of converting enzyme inhibitors (CEIs) not only reflect inhibition of the renin-angiotensin system but also depend on the enhanced production of endothelium-derived mediators. It has been speculated that angiotensin-converting enzyme inhibitors promote vasodilation by increasing the level of endogenous bradykinin generated at subthreshold concentrations in the vascular wall by a local kallikrein-kinin system.1 2 3 The prevention of bradykinin degradation by CEIs induces an augmentation of the production of these substances, thereby potentiating the dilatation evoked by the peptide.
Bradykinin, which is rapidly degraded by CEIs, stimulates the release of endothelium-derived vasodilator mediators, including nitric oxide (NO). The release of this important hemodynamic mediator of the cardiovascular system4 accounts for the biological activity of endothelium-derived relaxing factor. The sustained elevation of endothelial NO production observed after converting enzyme inhibition may have important physiological implications, as impairment of NO production might account for the abnormalities in vascular reactivity that characterize a wide variety of disease states, such as hypertension,5 6 7 8 hypercholesterolemia,9 and diabetes.10 11 Since NO synthesis and release can be altered in diabetes and insulin-mediated vasodilation was shown to be largely NO dependent,12 we sought to define the role of NO in mediating the beneficial effects of converting enzyme inhibition on hyperinsulinemia, hypertension, and hypertriglyceridemia. We used a fructose-induced hyperinsulinemic rat model,13 14 15 16 17 18 originally described by Zavaroni et al13 and Reaven.17 This is an appropriate nonobese model for elucidation of the biochemical mechanisms responsible for impaired insulin sensitivity.14
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Methods |
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Male Sprague-Dawley rats (ANILAB, Kiryat Weizmann, Ness Ziona, Israel) initially weighing 240 to 250 g were used for all experiments. Procedures followed were in accordance with the hospital guidelines for animal studies. Before their diet was altered, the rats were fed standard rat chow (Koffolk) and maintained on a 14-hour light/10-hour dark cycle. Thirty-six rats were fed a fructose-enriched diet (Teklad) for 5 weeks; of these, 10 served as controls (group A). During the last 2 weeks of the diet, one of the following was added to the drinking water: the CEI enalapril (20 mg/kg per day, group B, n=10), NG-nitro-L-arginine methyl ester (L-NAME, Sigma Chemical Co; 100 mg/kg per day, group C, n=6), or a combination of the two substances (group D, n=10). The fructose diet consisted of 21% protein, 5% fat, 60% carbohydrate, 0.49% sodium, and 0.49% potassium.
Systolic pressure was measured weekly in conscious rats by the indirect tail-cuff method with an electrosphygmomanometer and pneumatic pulse transducer (Narco Biosystems Inc). The mean of five consecutive readings was used for blood pressure evaluation.
Blood samples, taken from a retro-orbital sinus puncture with rats under light anesthesia, were collected from all rats at the beginning of the experiment and after 3 and 5 weeks for fructose-fed rats following 5 hours of fasting. The samples were centrifuged, aliquoted, frozen, and assayed for insulin (rat insulin 125I RIA kit, Incstar) and triglyceride (triglycerides GPO-PAP kit, Boehringer Mannheim GmbH) concentrations.
Data are expressed as mean±SD. The paired t test and nonparametric signed rank test were applied to test paired differences between baseline and all postbaseline assessments for quantitative parameters. Repeated measures ANOVA was used to test changes between baseline and all postbaseline assessments. All tests applied were two tailed, and a probability value of 5% or less was considered statistically significant. Data were analyzed with the SAS software.
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Results |
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Fructose feeding for 3 weeks resulted in hyperinsulinemia, hypertension, and hypertriglyceridemia in all groups (Table
). Although insulin levels rose after 1 week of the diet, hypertension developed only at the end of the second week. Converting enzyme inhibition with enalapril (group B) diminished hyperinsulinemia and hypertension. In fructose-fed rats, insulin concentration decreased from 7.6±2.0 to 2.2±1.1 pg/mL (P<.01), and blood pressure fell from 137±2 to 105±7 mm Hg (P<.01). Triglyceride levels were also lowered, from 292±37 to 163±37 mg/dL (P<.01).
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L-NAME, an inhibitor of NO synthase, by itself (group C) increased blood pressure (from 144±7 to 170±8 mm Hg, P<.01) (Table
) as well as triglycerides but had no significant effect on insulin. Coadministration of L-NAME and enalapril (group D) blunted these beneficial effects such that eventually blood pressure (141±7 mm Hg), insulin (6.4±2.4 pg/mL), and triglyceride (231±51 mg/dL) levels were not statistically different from those of untreated fructose-fed rats.
After finding that the effect of treatment was statistically significant in all four study groups for the three examined parameters, we applied multiple comparison analysis to determine which groups differed statistically. All groups were found to differ significantly in blood pressure and triglyceride levels except for groups A and D. All groups differed significantly in insulin except for groups A and C and groups A and D.
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Discussion |
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The model we used13 14 15 16 17 18 has shown similar results in other animals as well, such as normal mongrel dogs, in which high-fructose feeding elicited insulin resistance, hyperinsulinemia, and hypertension.19 Thus, fructose-induced hypertension in our animals appears to be a suitable model for the study of the interaction between hypertension and impaired glucose tolerance. It is noteworthy that when hypertension was not provoked in fructose-fed animals, sympathetic stimulation was absent.20 21 22
Since Moncada et al23 first described the inhibition of the NO system, numerous investigators have used very potent inhibitors of this system, including NG-monomethyl-L-arginine (L-NMMA),24 25 26 27 28 29 30 31 32 33 34 35 NG-nitro-L-arginine,36 37 38 39 40 and L-NAME,41 42 43 44 45 46 47 48 49 50 51 52 which we chose to use. The marked elevation of systemic blood pressure after acute or chronic inhibition of NO synthesis40 50 has been demonstrated in anesthetized rabbits,38 53 rats,* and dogs.31 37 42 43 48 Long-term inhibition of NO synthesis has been shown to cause a sustained increase in arterial pressure in different species24 41 42 46 48 and led Ribeiro et al41 to propose that NO blockade may constitute a new model of severe arterial hypertension with renal deterioration.
These studies and our present experiment, in which L-NAME caused an additional rise in blood pressure and blunted the hypotensive effect of enalapril in fructose-fed rats, constitute independent evidence that NO, now recognized as the most potent vasodilating substance,54 plays a crucial role in the long-term regulation of systemic blood pressure. According to De Nicola et al,30 NO represents a physiological antagonist of angiotensin II.
CEIs prevent both the generation of the potent vasoconstrictor angiotensin II and degradation of the powerful vasodilator bradykinin, which promotes endothelial cell release of NO. All CEIs tested potentiate endothelium-dependent relaxations to bradykinin, whether given exogenously or formed locally in the blood vessel wall.55 When infused in perfused isolated arteries with endothelium, they caused a marked relaxation that can be attributed to the release of endothelial factors.37 In humans, they also augment the hemodynamic vasodilator action of bradykinin.56 Relaxation induced by CEIs or bradykinin injection can be reversed by selective B2-kinin antagonists,57 58 59 indicating the role of bradykinin in the relaxation. Indeed, in kinin-deficient Brown Norway rats, ramipril was markedly less effective than in other rat strains.60
Numerous investigators have demonstrated inhibition of the NO system in the presence of different CEIs.28 33 36 37 38 44 46 47 49 NO blockade increased blood pressure and attenuated or delayed the hypotensive effect of all CEIs.28 The same occurred in our fructose-induced hypertensive rat model with L-NAME. Although an additional rise in blood pressure induced by L-NAME was prevented, the antihypertensive effect of enalapril was attenuated. In addition, the sensitivity to insulin was not improved, and the fall in triglyceride levels was prevented. These results suggest that the depressor effect of the drugs is in part attributable to the action of NO, which accounts for hemodynamic changes and might also account for metabolic activity.
Endothelium-dependent relaxations mediated by NO were impaired in arteries from diabetic rats39 61 62 63 64 and diabetic rabbits.65 There is also evidence for impaired forearm arteriolar dilator responses to endothelium-dependent and smooth muscle vasodilators in patients with type 2 diabetes mellitus11 ; the impaired dilatation is considerably less impressive in type 1 diabetic patients.66
Changes occur also in hyperinsulinemia, since insulin appears to be a novel modulator of the NO system.34 In insulin-treated rats, the median effective dose of the L-NAME dose-response curve was much lower than in the control group, suggesting an enhanced pressor response to NO inhibition.67 Attenuated insulin-mediated skeletal muscle blood flow appears to be a major cause of insulin resistance in subjects with elevated mean arterial pressure.34 68
CEI-induced bradykinin accumulation results in increased vascular permeability, which might increase glucose and insulin delivery to the tissue. Rett et al26 demonstrated the beneficial effect of kinins on glucose metabolism, and indeed, kinin antagonist attenuated the increased glucose requirement in enalapril-treated spontaneously hypertensive rats.59 These findings were supported in the present study, in which enalapril treatment resulted in decreased insulin levels, indicating higher insulin sensitivity; coadministration of L-NAME countered that improvement. The decrease in triglyceride levels after enalapril treatment was also blunted by the concomitant blockade of NO synthase.
Our findings confirm the beneficial effects of CEIs on insulin sensitivity and highlight the importance of an unimpaired NO system in these effects. Although our study was performed on a small number of animals, the interesting data point to the need for further studies to elucidate the mechanisms involved in the impaired responses to exogenous vasodilators. It would be of interest to perform similar studies in other hypertensive models with hyperinsulinemia or diabetes.
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Acknowledgments |
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This work is part of the PhD thesis of Yael Erlich.
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Footnotes |
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Reprint requests to Talma Rosenthal, MD, Chorley Hypertension Unit, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel.
*References 24, 28-30, 32, 33, 39-41, 44, 46, 47, 49, 50, 52.
Received April 8, 1996;
first decision May 13, 1996; first decision June 19, 1996;
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