(Hypertension. 1997;29:1260-1264.)
© 1997 American Heart Association, Inc.
Articles |
Effects of Enalapril, Losartan, and Verapamil on Blood Pressure and Glucose Metabolism in the Cohen-Rosenthal Diabetic Hypertensive Rat
From the Chorley Institute of Hypertension, Chaim Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University (T.R., Y.E.), and Departments of Medicine and Pathology, The Hebrew University–Hadassah Medical School, Jerusalem (E.R., A.C.) (Israel).
Correspondence to Prof Talma Rosenthal, Chorley Institute of Hypertension, Chaim Sheba Medical Center, Tel Hashomer 65261 Israel.
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Abstract |
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Abstract We undertook the present study to examine the effect of the angiotensin-converting enzyme inhibitor enalapril, the angiotensin II antagonist losartan, and calcium antagonist verapamil on systolic pressure and spontaneous blood glucose levels in rats from the Cohen-Rosenthal diabetic hypertensive strain. Genetic hypertension and diabetes developed in this strain after crossbreeding of Cohen diabetic and spontaneously hypertensive rats. The new rat strain was fed their usual copper-poor sucrose diet, which is essential for the development of this model, and for 4 weeks received either enalapril, losartan, or verapamil. Systolic pressure was reduced significantly compared with controls in all treated groups. Chronic treatment with enalapril or verapamil, but not with losartan, succeeded in lowering spontaneous blood glucose, indicating improved diabetic control. Data suggest that angiotensin-converting enzyme inhibition by enalapril, but not angiotensin II antagonism by losartan, can improve glucose metabolism in addition to its hypotensive effect in a genetic diabetic hypertensive rat strain. This confirms that the drop in glucose with converting enzyme inhibition is highly dependent on bradykinin accumulation. Data further suggest that calcium channel blockade by verapamil can also improve glucose metabolism. The question remains whether the reduction in glucose by verapamil was a result of inhibition of glucogenesis.
Key Words: diabetes mellitus, experimental • rats • enalapril • losartan • verapamil
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Introduction |
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Hypertension and NIDDM often occur simultaneously and share the features of insulin resistance and hyperinsulinemia.1 The CRDH rat is a unique animal model in which genetic hypertension and diabetes developed after crossbreeding of CDR and SHR.2 The development of impaired glucose tolerance after copper-poor concentrated sucrose feeding involves both genetic and environmental factors in this combined hypertensive and diabetic rat strain. The combining of hypertension and NIDDM in one experimental model gives us the opportunity to study these concomitant pathologies.
ACE inhibitors, with their beneficial effects on insulin sensitivity,3 are widely used in the treatment of hypertension in diabetic patients and may be the antihypertensive treatment of choice in these patients.4 5 They have the additional property of decreasing insulin resistance, which can mean improved glycemic control. With few exceptions, calcium antagonists have no adverse effect on carbohydrate metabolism6 and are excellent agents for the treatment of hypertension. The Ang II receptor antagonists are a relatively new class of antihypertensive agents, of which losartan is the first orally active one. Losartan potassium has been shown to block the physiological action of Ang II in animals7 8 9 and humans.10 It has been shown to reduce BP in SHR8 and hypertensive dogs.10 The effect of losartan on glycemic control is untested.
The present study examines the ability of the ACE inhibitor enalapril, the Ang II antagonist losartan, and the calcium channel blocker verapamil to improve diabetic control in the CRDH rat.
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Methods |
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We developed a new diabetic hypertensive rat strain in recent years by crossbreeding CDR and SHR. Pairs resulting from the mating of three CDR males with three SHR females as well as three CDR females with three SHR males were maintained apart and fed laboratory chow diet ad libitum. When animals reached a weight of 60 g, they were fed a copper-poor sucrose diet (18% casein, 72% sucrose, 4.5% butter, 0.5% corn oil, 5% salt No. II USP, and water- and fat-soluble vitamins, with a copper content of 1.2 ppm) for 2 months. The interaction of both sucrose and low copper content with genetic susceptibility is needed to induce diabetes and a low insulin response in the CDR. Thus, this unique diet is a prerequisite for the development of diabetes and diabetic vascular complications in both the CDR and CRDH rat strains.
Further mating was carried out between male and female siblings with the highest spontaneous blood glucose and BP levels.2 This procedure was applied to subsequent generations (S1, S2, and S3) up to the 14th generation.
Experiments were conducted on four groups of male rats (weight, approximately 250 g) maintained on a 14-hour light/10-hour dark cycle. Thirty-three rats with the highest spontaneous blood glucose and systolic BP levels were selected from the 10th to 14th generations of the strain. Rats were habituated in metabolic cages, and urine was collected for 24 hours for determination of protein excretion. Animals fed their usual copper-poor sucrose diet received either enalapril (20 mg/kg, n=9), losartan (15 mg/kg, n=8) or verapamil (20 mg/kg, n=9) in drinking water for 4 weeks. A fourth untreated group (n=7) served as control.
BP and Biochemical Measurements
Systolic BP was measured once a week at 11
AM by the indirect tail-cuff method using an
electrosphygmomanometer and pneumatic pulse transducer (Narco
Biosystems Inc). Two hours before each measurement, rats were taken
from the animal room to the laboratory, where they were kept in a quiet
area and allowed free access to food and water.
For measurement of spontaneous blood glucose, food was given at 8 AM and withdrawn at 10 AM for 4 consecutive days, and on day 4 at 10 AM, blood was sampled for plasma glucose estimation. Blood samples were taken before, during (2 weeks), and at the end of the experiment (4 weeks) from a retro-orbital sinus with rats under light ether anesthesia. The samples were centrifuged, aliquoted, frozen, and assayed for spontaneous blood glucose and creatinine (SMAC II system, Technion Instrument Corp). Spectrophotometric determination of urine protein concentration was performed with sulfosalicylic acid.
Data were analyzed with SAS software. The paired t test and nonparametric signed rank test were applied for determination of paired differences between baseline and postbaseline assessments for quantitative parameters in each of the four study groups. Repeated ANOVA measurements were performed for determination of changes between baseline and postbaseline assessments in the four groups. Multiple comparison analysis (the Duncan method) was applied for determination of which of the groups differed statistically from the others. All tests were two-tailed, and results were considered statistically significant at a value of P<.05. Results are expressed as mean±SEM.
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Results |
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Spontaneous blood glucose and BP levels in the new rat strain rose steadily throughout the breeding process. The rats in the present experiment were taken from the 10th to the 14th generations, when diabetes and hypertension were well-established.
Body weight did not change significantly throughout the experiment in any of the four groups, although in the losartan group, it rose nonsignificantly from 248±18 to 262±32 g.
Systolic BP was reduced significantly (P<.001) in
all treated groups compared with control (Fig 1
): The
levels from baseline to after 4 weeks of treatment in the control
animals were 184±5 and 182±6 mm Hg, whereas during the same
period, the level in the enalapril group fell from 183±9 to
120±5 mm Hg (P<.001), in the losartan group
from 178±6 to 131±5 mm Hg (P<.001), and in the
verapamil group from 175±9 to 149±19 mm Hg
(P<.001).
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Chronic treatment with enalapril or verapamil but not with
losartan lowered spontaneous blood glucose, indicating improved
diabetic control (Fig 2). Blood glucose levels from
baseline to after 4 weeks of treatment fell in the enalapril group from
425±106 to 233±72 mg/dL (P<.001) and in the
verapamil group from 427±90 to 255±107 mg/dL
(P<.001); levels rose in the losartan group from
405±52 to 427±125 mg/dL and in the control group from 377±5 to
403±130 mg/dL.
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Proteinuria did not change in animals treated with losartan and verapamil during the study and decreased highly significantly in the enalapril group from 28.3±12.9 to 10.8±3.8 mg/24 h.
With the exception of two rats treated with enalapril, plasma creatinine did not rise in any of the groups. Creatinine levels before and after 4 weeks of treatment in the four groups were as follows: control group, 1.00±0.19 and 0.87±0.25 mg/dL; verapamil group, 0.80±0.16 and 0.79±0.06 mg/dL; enalapril group, 1.06±0.44 and 1.44±1.00 mg/dL; and losartan group, 0.76±0.18 and 0.69±0.46 mg/dL. When the creatinine level in the enalapril group was calculated without the two rats in which the level rose, the values were 0.9±0.11 mg/dL at baseline and 1.04±0.19 mg/dL after 4 weeks of treatment. None of the alterations before and after treatment were significant.
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Discussion |
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Experimental animal models have contributed extensive information about diabetes mellitus. The most common hypertensive diabetic rat model is the SHR with chemically (streptozotocin)–induced insulin-dependent diabetes mellitus.11 12 13 14 15 The Zucker fatty rat, which is an obese hyperphagic and hyperinsulinemic animal in which insulin resistance develops, may be considered a suitable model for NIDDM.16 However, since not all NIDDM patients are obese, our model, the CRDH rat, is the closest to the human patient having NIDDM.
According to Yamori et al,17 SHR, although not known as diabetic, showed a mild deviation of glucose metabolism detected by glucose tolerance. This was confirmed by Mondon and Reaven,18 who observed impaired insulin-stimulated glucose uptake and hyperinsulinemia in SHR like that found in hypertensive humans. Sucrose diet is known to be important for the development of diabetes.19 According to Hallfrisch and coworkers,20 high sucrose diet even in the Wistar rat adversely affected glucose tolerance. Chronic sucrose ingestion can induce mild hypertension in Sprague-Dawley rats,21 and BP in SHR rises even higher when carbohydrate intake is increased and sodium intake unaltered.22 23 Our CRDH strain, created by breeding diabetic rats with hypertensive rats that also have impaired glucose tolerance, provides a potentially useful tool for studying the combination of diabetes and hypertension.
ACE inhibitors are a beneficial group of drugs used to treat hypertension in patients with diabetes.24 Since they have the further benefit of decreasing insulin resistance with potential improvement in glycemic control,3 24 they are considered the antihypertensive therapy of choice in diabetic patients.25
The favorable effects of ACE inhibitors on glucose metabolism have been demonstrated in numerous studies, but few well-designed studies have been performed.26 Interpretation of their results is often complicated by poor trial design, lack of full placebo data, use of various indirect measurements of insulin sensitivity, and heterogeneous patient populations with different biochemical mechanisms of insulin resistance (and drug responses).26
Passa et al27 found that enalapril did not modify metabolic condition or renal function, whereas other authors27 28 29 30 31 showed it effective in controlling glycemia in hypertensive diabetic patients.28 29 30 31 32 Uniform findings in these studies indicate a slight increase in metabolic control in type II diabetic patients with enalapril. Although anecdotal reports of ACE inhibitors inducing hypoglycemia have appeared,33 34 they have not been confirmed by other researchers,35 36 who claim that long-term enalapril treatment has no effect on glucose tolerance in nonobese, non–insulin-resistant patients with mild to moderate hypertension.
Our results in a previous study37 indicate a positive effect of enalapril on insulin sensitivity and glucose metabolism. The benefit of enalapril was also demonstrated in another work in fructose-induced hyperinsulinemic rats38 and in the CRDH rat.39 The present study further confirms the efficacy of enalapril in improving hypertension and the metabolic parameter of glucose.
It is conceivable that an increase in capillary insulin transport secondary to vasodilatation with increased capillary area is reflected in greater insulin sensitivity and in increased risk of hypoglycemia.29 40 41 Insulin resistance of both muscle and liver has been shown to be reduced by kinins and ACE inhibitors, resulting in lowering of both BP level and blood glucose concentration.42 Recently, Bao et al,42 using the highly potent, specific, long-acting bradykinin B2 receptor antagonist Hoe 140, showed that the potentiation of endogenous kinins can contribute to the antihypertensive action of ACE inhibitors, thereby improving glucose metabolism. When we gave bradykinin antagonists with ramipril to fructose-induced hyperinsulinemic rats, we could also demonstrate that the decrease in insulin and lipid levels induced by the ACE inhibitor was highly dependent on the accumulation of bradykinin.43
Information on the effect of Ang II antagonism on glucose metabolism is meager. According to Moan et al,44 losartan improved insulin sensitivity in a few patients, but the authors caution against drawing conclusion from their results because three of their five patients were also getting enalapril and lisinopril, and the washout period was only 3 days. When losartan was given to streptozotocin-induced diabetic rats,45 it completely prevented an increase in systolic BP; preservation of glomerular structure and function was noted as well. Improved glomerulosclerosis was also observed in reduced renal mass hypertensive rats46 treated with another Ang II antagonist, MK 954, whereas albuminuria was reduced in different rat models45 46 47 48 treated with different Ang II antagonists, losartan and MK 954. These findings suggest that the favorable effects previously observed with ACE inhibition depend directly on the reduction of Ang II activity. Glucose metabolism was not altered in two different rat models treated with Ang II antagonists.45 46
In our rat model, the decrease in BP after losartan treatment was not accompanied by a fall in glucose level, which indicates that the beneficial effect on glucose metabolism produced by ACE inhibition depends on bradykinin accumulation and is not related to Ang II antagonism.49
Calcium channel blockers given to hypertensive patients with and without diabetes mellitus do not produce clinically relevant changes in glucose homeostasis,50 51 although there may be minor changes at high doses. Hermansen and Iversen52 noted that concentrations of verapamil that inhibited glucagon release from the isolated perfused canine pancreas far exceeded the concentration effective as an antiarrhythmic. The reduction in insulin release and subsequent increase in plasma glucose is a pharmacological effect of verapamil that occurs at a drug concentration unlikely to be achieved during clinical use. Dominic et al,53 however, noted an impairment in glucose tolerance after verapamil in the conscious dog. Kaymaz et al54 and Chellingsworth et al55 pointed out that verapamil seems to have some beneficial effects on the metabolic parameters of the mechanism of BP control in NIDDM rats.
Several authors56 57 found no difference in levels of plasma glucose, C peptide, insulin, and glucagon between verapamil and placebo. Whitcroft58 and Cruickshank et al59 did not find significant changes in glucose and Hb A1c, and Ferrier et al29 could show stable carbohydrate indexes during 30 weeks of active treatment with verapamil. Evidence suggests, however, that verapamil interferes with glibenclamide metabolism, since concomitant administration of verapamil resulted in higher levels of glibenclamide at each time point.57 Observations of unchanged Hb A1c levels, together with constant body weight and antidiabetic therapy, indicate that slight variations in glucose handling, if they do occur during calcium antagonist therapy, may not attain clinical relevance in the overall management of patients with diabetes mellitus.60
Andersson and Rojdmark61 showed that verapamil improves glucose tolerance in NIDDM patients without affecting insulin secretion. This dissociation may occur because verapamil also decreases glucagon release in diabetic patients, thereby improving their tolerance for oral glucose. It is also possible that verapamil acts directly on liver cell membranes and induces an improved glucose tolerance in diabetic patients.
In a study carried out in 10 normotensive patients with NIDDM,62 brief verapamil treatment decreased fasting plasma glucose and glucose turnover in these NIDDM patients, possibly by inhibition of gluconeogenesis. A tendency to improved glucose tolerance during verapamil treatment was also seen by Lyngsoe et al,63 who found that verapamil decreased fasting blood glucose and glucose turnover in NIDDM patients on dietary treatment. These findings are in agreement with our results in the CRDH rat, in which glucose decreased significantly during verapamil treatment.
In summary, on the basis of our findings and the material discussed above, our hypertensive diabetic strain of rats appears to offer an informative model for determination of appropriate therapy in a homogenic animal model that carries the genetic basis for both hypertension and NIDDM. Using this model, we were able to determine that ACE inhibition by enalapril and calcium channel blockade by verapamil, but not Ang II antagonism by losartan, can improve glucose metabolism, in addition to their hypotensive effects.
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Selected Abbreviations and Acronyms |
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Received August 14, 1996; first decision September 24, 1996; accepted October 23, 1996.
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