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Effects of a calcium channel blocker, manidipine, on insulin sensitivity in essential hypertensives
Effects of a Calcium Channel Blocker, Manidipine, on Insulin Sensitivity in Essential Hypertensives Osamu Iimura, Kazuaki Shimamoto, Atsushi Masuda, Katsuhiro Higashiura, Yoshinori Miyazaki, Akifumi Hirata, Masatada Fukuoka, and Hideyuki Murakami
ABSTRACT This study was designed to investigate the effects of the calcium channel blocker manidipine on insulin-dependent glucose uptake (insulin sensitivity) and insulin action to renal sodium handling and pressor systems in essential hypertensive (EHT). Seven EHT were hospitalized and a 2-h euglycemic hyperinsulinemic glucose clamp was performed in a fasting condition before and after 2 weeks administration of manidipine (20 mglday). Insulin sensitivity was evaluated as M-value calculated from the infusion rate of glucose. Manidipine administration decreased mean blood pressure and increased M-value significantly in EHT. Before the manidipine
treatment, hyperinsulinemia during the clamp induced a decrease of urinary sodium excretion and increases of plasma norepinephrine and plasma renin activity in EHT. After manidipine treatment, however, hyperinsulinemia induced natriuresis and did not augment the pressor systems activity. Thus, thg calcium channel blocker improved insulin resistance as assessed by glucose clamp technique in EHT. Suppression of augmented renal sodium reabsorption and pressor system activities of insulin may be connected with the hypotensive mechanisms and the natriuresis caused by calcium channel blockers. (Journal of Diabetes and Its Complications 9;4:215-219, 1995.)
INTRODUCTION
ceptor antagonists improve insulin sensitivity in EHT,4,6,7 suggesting important roles for the vasodilation and blood flow increase brought about by these hypotensive drugs. In a study of the effects of calcium channel blockers in EHT, Berne et al.s reported that diltiazem and verapamil did not affect insulin sensitivity, and nifedipine decreased sensitivity. On the other hand, Sheu et aL9 reported that nifedipine improved insulin sensitivity in EHT. Thus, the effect of the calcium channel blockers on insulin sensitivity remains controversial. This study examined the effect of the calcium channel blocker manidipine on insulin resistance and the insulin actions on renal sodium handling and pressor systems in EHT.
R
ecently, insulin resistance and the accompanying hyperinsulinemia have been reported to play important roles in the occurrence and maintenance of essential hypertension, dyslipidemia and arteriosclerosis.‘-3 Several kinds of hypotensive drugs, such as thiazide diuretics and p-blockers, have been reported to impair insulin sensitivity in essential hypertensive (EHT).4,5 Conversely, it has been recognized that angiotensin-converting enzyme (ACE) inhibitors, al-blockers, and angiotensin-II re-
Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan Reprint requests to be sent to: Dr. Osamu Iimura, Second Department of Internal Medicine, Sapporo Medical University School of Medicine, S-l W-16, Chuo-Ku, Sapporo 060, Japan. Journal of Diabetes and Its Complications 1995; 9:215-229 0 Elsevier Science Inc., 1995 655 Avenue of the Americas, New York, NY 10010
METHODS Seven EHT [World Health Organization (WHO) stage I-II, age 47.1 f 4.6 years, body-mass index 24.4 f 105~8727/95/$9.50 SSDI 1056-8727(95)00011-P
216
IIMLJRA ET AL.
J Diab Camp 1995; 9:215-219
BS mg/dl 100
Insulin plJ/ml 12
M-value mg/m*/min 200
p
10
80
I
150
8 60 6 40 4 20
2 0
0 Control FIGURE 1
Manidipine
I
tControl
I
1 100
50
0
Manidipine
Control
Manidipine
Effect of manidipine on mean fasting plasma glucose CBS), plasma insulin (Insulin), and M value in essential hypertensives.
0.7 kg/m21 were employed for this study. They were hospitalized and kept under standard diet containing 120 mEq of sodium and 75 mEq of potassium per day. After the 2-week control period, the 2-h euglycemic hyperinsulinemic glucose clamp according to DeFronzo et al.‘O was carried out to estimate in vivo sensitivity for insulin. At 8:00 a.m. in the morning of the study, the patients drank 150 mL/m2 of water. After a l-h equilibration period, they were asked to empty their bladder, and urine collection was begun for 1 h before the clamp. Urine samples were also collected for 2 h during the clamp. Blood samples were obtained at 30 min before and just before termination of the clamp study. In the glucose clamp study, blood was continuously withdrawn at 2.0 mL/h through a double-lumen catheter for glucose analysis of arterialized blood. In addition, a contralateral antecubital vein was cannulated with a no. 18 plastic cannula for infusion of insulin and glucose. Continuous insulin infusion rate, monitoring of glucose concentration, and infusion of variable amounts of glucose for clamping glucose levels at the basal state were performed with a model STG-22 artificial endocrine pancreas (Nikkiso Corp., Tokyo, Japan). The infusion rate of insulin (Actrapid Human, Novo Industries, Copenhagen, Denmark) was 40 mu/m2 of body surface arealmin. During insulin infusion, euglycemia was maintained by a variable infusion of a 20% glucose solution. The mean rate of glucose infusion for the last 30 min of the clamp was used as an indicator of insulin sensitivity (M-value):
milligrams of glucose per square meter of body surface area per minute. The patients were then given manidipine at 20 mgl day for 2 weeks, and the above measurement was repeated. Before and after the clamp, mean blood pressure, urinary sodium excretion (UNaV), fractional excretion of sodium (FENa), plasma norepinephrine levels (PNE), and plasma renin activity (PRA) were measured in each subject. The study protocol was approved by the ethics committee of Sapporo Medical University. All patients gave written or verbal informed consent for all procedures. Statistical Analysis. All the data are given as mean f SEM. Student’s t test was used to determine significance in comparison of paired and unpaired data. All calculated probability values less than 0.05 were considered to indicate significance. RESULTS A 2-week treatment with manidipine elicited a significant decrease in mean blood pressure (from 111.9 f 2.9 to 90.0 + 5.3 mm Hg, p < 0.01). There was no change in fasting blood sugar and plasma insulin level in the manidipine treatment (from 87.9 f 2.2 to 88.7 f 2.0 mg/dL, and from 9.2 f 0.8 to 7.9 + 0.8 @/mL, respectively) (Figure 1).Insulin sensitivity assessed by the M value was significantly increased after treatment with manidipine (from 126.9 f 13.5 to 154.1 f 12.7 mglm’lmin, p < 0.02) (Figure 1).
EFFECTS OF MANIDIF’INE ON INSULIN SENSITIVITY
1 DiczbCotnp 1995; 9:215-219
AFENa
AUNaV ~mollmin 100
,
pco.05
217
,
% . -0.6
D
0.4
50
0.2
0
0 -50 -0.2
i
-100 -150
-0.6 Control
Manidipine
FIGURE 2 Changes of urinary sodium excretion (A UNaVJ and fractional excretion of sodium ( AFENa) induced by hyperinsulinemia before and after treatment with manidipine in essential hypertensives.
Before manidipine administration, UNaV and FENa were decreased significantly by the hyperinsulinemia duirng the glucose clamp (UNaV: 117.4 f 47.4 to 45.3 f 8.0 umollmin, p < 0.05; FENa: 0.95 f 0.38 to 0.69 f 0.30%, p < 0.02). However, after manidipine treatment, UNaV and FENa showed a tendency to be increased by hyperinsulinemia (UNaV: 44.2 f 8.3 to 96.8 f 32.2 umollmin, p < 0.1; FENa: 0.36 f: 0.08 to 0.65 + 0.21%, p < 0.1). The changes of UNaV and FENa by hyperinsulinemia were significantly higher after manidipine treatment than before (Figure 2). Before manidipine administration, PNE and PRA showed significant increases by hyperinsulinemia (PNE; 140.2 f 0.04 to 184.7 + 19.7 pg/mL, p < 0.02, PRA; 0.99 f 0.42 to 1.46 f 0.43 nglmllh, p < 0.01). After manidipine, PNE was not changed by hyperinsulinemia and the increase of PRA was insignificant (PNE; 248.6 f 43.8 to 230.0 f 41.8 pg/mL, IRA; 1.46 f 0.40 to 1.64 f 0.46 nglmllh). The reduction of PNE change after manidipine was significant, and PRA also tended to change less (Figure 3). DISCUSSION
Several clinical studies have demonstrated that ACE inhibitors,4*8a1-blockers,6,8and angiotensin-II receptor antagonists’ improve insulin sensitivity in EHT. One
of the proposed mechanisms for the improvement of insulin resistance by these drugs is increased skeletal muscle blood flow through their vasodilating action. One would then expect calcium channel blockers to improve insulin resistance because of their strong vasodilation action; however, the nondihydropyridinederivative calcium antagonists diltiazem5~8and verapanriP have been shown neither to improve nor to aggravate insulin resistance in EHT. The dihydropyridine-derivative calcium channel blocker, nifedipine, has yielded conflicting results.8,9 In this study, we demonstrated that manidipine improves insulin sensitivity in EHT, suggesting that long-acting dihydropyridine-derivative calcium antagonists improve insulin resistance, in accordance with Sheu’s results with long-acting nifedipine.9 It was reported that nifedipine impaired insulin sensitivity in EHT.* However, as nifedipine capsules were used in their study,8 reactive stimulation of sympathetic activity may have exacerbated the effect of shortacting nifedipine on insulin sensitivity. We already reported that hyperinsulinemia increased PNE, PRA, and renal sodium reabsorption during 2-h glucose clamp in EHT.” ln this study, the effects of the calcium channel blocker, manidipine, on insulin action in renal sodium handling and pressor systems were investigated in EHT. After manidipine
218
1 Diab Comp 2995; 9:215-219
IIMURA ET AL.
APNE
APRA ng/mI/hr
PWI 100
0.6
p
p
1
0
I
0.4
50
I
-I
0.2
-
-
0
-50 Control
-
Control
Manidipine
I
Manidipine
FIGURE 3 Changes of plasma norepinephrine (APNE) and plasma renin activity (APRA) induced by hyperinsulinemia after treatment with manidipine in essential hypertensives.
treatment, hyperinsulinemia did not induce sodium retention but elicited natriuresis. Moreover, manidip-
ine suppressed the stimulating action of insulin in PNE and IRA. The suppression of insulin-induced sympathetic augmentation may be due to the decreased intracellular ionized calcium by manidipine.12 The suppressed IRA reaction by insulin seems to be explained by the attenuation of sympathetic activity, because renin release is augmented by sympathetic nerve stimulation. As the mechanisms of insulin-induced natriuresis under the manidipine treatment, suppression of insulin-induced pressor system activities, restoration of insulin-induced vasodilation in renal artery, and suppression of renal tubular sodium reabsorptiorG3 should be considered; although the detail of the mechanisms remains unknown. It has been suggested that insulin resistance that leads to hyperinsulinemia may be associated with hypertensive arteriosclerotic complications including coronary heart disease, I-3 and that metabolic side effects should be considered when selecting the antihypertensive agents. ** In this study, it was clarified that manidipine improved insulin resistance as assessed by glucose clamp method in EHT. These results strongly suggest that long-acting dihydropyridine-derivative calcium channel blockers will be useful antihyperten-
sive drugs in essential hypertensive sulin resistance.
before and
patients with in-
REFERENCES 1. Reaven GM: Role of insulin resistance in human disease. Diabetes 37:1595-X07, 1988. 2.
Kaplan NM: The deadly quartet: Upper-body obesity, glucose intolerance in hypertriglyceridemia and hypertension. Arch Intern Med 149:1514-1520, 1989.
3.
DeFronzo RA, Ferrannini E: Insulin resistance: A multifactorial syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 14:173-194, 1991.
4.
Pollare T, Lithe11H, Berne C, et al.: A comparison of the effects of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension. N Engl J Med 321:868-873,
1989.
5.
Pollare T, Lithe11H, Marlin C, et al. : Metabolic effects of diltiazem and atenolol: Results from a randomized, double-blind study with parallel groups. J Hypertens 7: 551-559, 1989.
6.
Pollare T, Lithe11 H, Selinus I, et al.: Application of prazosin is associated with an increase of insulin sensitivity in obese patients with hypertension. Diabetologia 31:415-420,
7.
1988.
Iimura 0, Shimamoto K, Matsuda K, et al.: Effects of angiotensin receptor antagonist and angiotensin converting enzyme inhibitor on insulin sensitivity in fruc-
] Diab Camp 1995; 9:X5-219
EFFECTS
tose-fed hypertensive rats and essential hypertensives.
9.
10.
11.
Sheu WH-H, Swislocki ALM, Hoffman B, et al.: Comparison of the effects of atenolol and nifedipine on glucose, insulin and lipid metabolism in patients with hypertension. Am f Hypertens 4:199-205, 1991. DeFronzo RA, Tobian JD, Anders R: Glucose clamp technique: A method for quantifying insulin secretion and resistance. Am J Pkysiol237:E214-E22.3, 1979. Shimamoto K, Hirata A, Fukuoka M, et al.: Insulin
ON INSULIN
SENSITIVITY
219
sensitivity and the effects of insulin on renal sodium handling and pressor systems in essential hypertensive patients. Hypertension23 (suppl I) I-29-1-33, 1994.
Am J Hypertens 1995 (in press).
8. Berne C, Pollare T, Lithe11H: Effects of antihypertensive treatment on insulin sensitivity with special reference to ACE inhibitor. Diabetes Care 14 (suppl4):39-47, 1991.
OF MANIDIPINE
12.
Iimura 0, Kikuchi K, Shimamoto K: Studies on the mechanism of the antihypertensive effect of long-term administered nifedipine in patients with benign essential hypertension, in Kelly DT (ed), Adalat in the Asian Pacific Region. Berlin, Springer-Verlag, 1989, 85-96.
13.
Gupta AK, Clark RV, Kirchner KA: Effects of insulin on renal sodium excretion. Hypertension 19:(suppl l)I-7% I-82, 1992.
14.
Houston MC: The effects of antihypertensive drugs on glucose intolerance in hypertensive nondiabetics. Am Heart J 115640-656, 1988.
ABSTRACT This study was designed to investigate the effects of the calcium channel blocker manidipine on insulin-dependent glucose uptake (insulin sensitivity) and insulin action to renal sodium handling and pressor systems in essential hypertensive (EHT). Seven EHT were hospitalized and a 2-h euglycemic hyperinsulinemic glucose clamp was performed in a fasting condition before and after 2 weeks administration of manidipine (20 mglday). Insulin sensitivity was evaluated as M-value calculated from the infusion rate of glucose. Manidipine administration decreased mean blood pressure and increased M-value significantly in EHT. Before the manidipine
treatment, hyperinsulinemia during the clamp induced a decrease of urinary sodium excretion and increases of plasma norepinephrine and plasma renin activity in EHT. After manidipine treatment, however, hyperinsulinemia induced natriuresis and did not augment the pressor systems activity. Thus, thg calcium channel blocker improved insulin resistance as assessed by glucose clamp technique in EHT. Suppression of augmented renal sodium reabsorption and pressor system activities of insulin may be connected with the hypotensive mechanisms and the natriuresis caused by calcium channel blockers. (Journal of Diabetes and Its Complications 9;4:215-219, 1995.)
INTRODUCTION
ceptor antagonists improve insulin sensitivity in EHT,4,6,7 suggesting important roles for the vasodilation and blood flow increase brought about by these hypotensive drugs. In a study of the effects of calcium channel blockers in EHT, Berne et al.s reported that diltiazem and verapamil did not affect insulin sensitivity, and nifedipine decreased sensitivity. On the other hand, Sheu et aL9 reported that nifedipine improved insulin sensitivity in EHT. Thus, the effect of the calcium channel blockers on insulin sensitivity remains controversial. This study examined the effect of the calcium channel blocker manidipine on insulin resistance and the insulin actions on renal sodium handling and pressor systems in EHT.
R
ecently, insulin resistance and the accompanying hyperinsulinemia have been reported to play important roles in the occurrence and maintenance of essential hypertension, dyslipidemia and arteriosclerosis.‘-3 Several kinds of hypotensive drugs, such as thiazide diuretics and p-blockers, have been reported to impair insulin sensitivity in essential hypertensive (EHT).4,5 Conversely, it has been recognized that angiotensin-converting enzyme (ACE) inhibitors, al-blockers, and angiotensin-II re-
Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan Reprint requests to be sent to: Dr. Osamu Iimura, Second Department of Internal Medicine, Sapporo Medical University School of Medicine, S-l W-16, Chuo-Ku, Sapporo 060, Japan. Journal of Diabetes and Its Complications 1995; 9:215-229 0 Elsevier Science Inc., 1995 655 Avenue of the Americas, New York, NY 10010
METHODS Seven EHT [World Health Organization (WHO) stage I-II, age 47.1 f 4.6 years, body-mass index 24.4 f 105~8727/95/$9.50 SSDI 1056-8727(95)00011-P
216
IIMLJRA ET AL.
J Diab Camp 1995; 9:215-219
BS mg/dl 100
Insulin plJ/ml 12
M-value mg/m*/min 200
p
10
80
I
150
8 60 6 40 4 20
2 0
0 Control FIGURE 1
Manidipine
I
tControl
I
1 100
50
0
Manidipine
Control
Manidipine
Effect of manidipine on mean fasting plasma glucose CBS), plasma insulin (Insulin), and M value in essential hypertensives.
0.7 kg/m21 were employed for this study. They were hospitalized and kept under standard diet containing 120 mEq of sodium and 75 mEq of potassium per day. After the 2-week control period, the 2-h euglycemic hyperinsulinemic glucose clamp according to DeFronzo et al.‘O was carried out to estimate in vivo sensitivity for insulin. At 8:00 a.m. in the morning of the study, the patients drank 150 mL/m2 of water. After a l-h equilibration period, they were asked to empty their bladder, and urine collection was begun for 1 h before the clamp. Urine samples were also collected for 2 h during the clamp. Blood samples were obtained at 30 min before and just before termination of the clamp study. In the glucose clamp study, blood was continuously withdrawn at 2.0 mL/h through a double-lumen catheter for glucose analysis of arterialized blood. In addition, a contralateral antecubital vein was cannulated with a no. 18 plastic cannula for infusion of insulin and glucose. Continuous insulin infusion rate, monitoring of glucose concentration, and infusion of variable amounts of glucose for clamping glucose levels at the basal state were performed with a model STG-22 artificial endocrine pancreas (Nikkiso Corp., Tokyo, Japan). The infusion rate of insulin (Actrapid Human, Novo Industries, Copenhagen, Denmark) was 40 mu/m2 of body surface arealmin. During insulin infusion, euglycemia was maintained by a variable infusion of a 20% glucose solution. The mean rate of glucose infusion for the last 30 min of the clamp was used as an indicator of insulin sensitivity (M-value):
milligrams of glucose per square meter of body surface area per minute. The patients were then given manidipine at 20 mgl day for 2 weeks, and the above measurement was repeated. Before and after the clamp, mean blood pressure, urinary sodium excretion (UNaV), fractional excretion of sodium (FENa), plasma norepinephrine levels (PNE), and plasma renin activity (PRA) were measured in each subject. The study protocol was approved by the ethics committee of Sapporo Medical University. All patients gave written or verbal informed consent for all procedures. Statistical Analysis. All the data are given as mean f SEM. Student’s t test was used to determine significance in comparison of paired and unpaired data. All calculated probability values less than 0.05 were considered to indicate significance. RESULTS A 2-week treatment with manidipine elicited a significant decrease in mean blood pressure (from 111.9 f 2.9 to 90.0 + 5.3 mm Hg, p < 0.01). There was no change in fasting blood sugar and plasma insulin level in the manidipine treatment (from 87.9 f 2.2 to 88.7 f 2.0 mg/dL, and from 9.2 f 0.8 to 7.9 + 0.8 @/mL, respectively) (Figure 1).Insulin sensitivity assessed by the M value was significantly increased after treatment with manidipine (from 126.9 f 13.5 to 154.1 f 12.7 mglm’lmin, p < 0.02) (Figure 1).
EFFECTS OF MANIDIF’INE ON INSULIN SENSITIVITY
1 DiczbCotnp 1995; 9:215-219
AFENa
AUNaV ~mollmin 100
,
pco.05
217
,
% . -0.6
D
0.4
50
0.2
0
0 -50 -0.2
i
-100 -150
-0.6 Control
Manidipine
FIGURE 2 Changes of urinary sodium excretion (A UNaVJ and fractional excretion of sodium ( AFENa) induced by hyperinsulinemia before and after treatment with manidipine in essential hypertensives.
Before manidipine administration, UNaV and FENa were decreased significantly by the hyperinsulinemia duirng the glucose clamp (UNaV: 117.4 f 47.4 to 45.3 f 8.0 umollmin, p < 0.05; FENa: 0.95 f 0.38 to 0.69 f 0.30%, p < 0.02). However, after manidipine treatment, UNaV and FENa showed a tendency to be increased by hyperinsulinemia (UNaV: 44.2 f 8.3 to 96.8 f 32.2 umollmin, p < 0.1; FENa: 0.36 f: 0.08 to 0.65 + 0.21%, p < 0.1). The changes of UNaV and FENa by hyperinsulinemia were significantly higher after manidipine treatment than before (Figure 2). Before manidipine administration, PNE and PRA showed significant increases by hyperinsulinemia (PNE; 140.2 f 0.04 to 184.7 + 19.7 pg/mL, p < 0.02, PRA; 0.99 f 0.42 to 1.46 f 0.43 nglmllh, p < 0.01). After manidipine, PNE was not changed by hyperinsulinemia and the increase of PRA was insignificant (PNE; 248.6 f 43.8 to 230.0 f 41.8 pg/mL, IRA; 1.46 f 0.40 to 1.64 f 0.46 nglmllh). The reduction of PNE change after manidipine was significant, and PRA also tended to change less (Figure 3). DISCUSSION
Several clinical studies have demonstrated that ACE inhibitors,4*8a1-blockers,6,8and angiotensin-II receptor antagonists’ improve insulin sensitivity in EHT. One
of the proposed mechanisms for the improvement of insulin resistance by these drugs is increased skeletal muscle blood flow through their vasodilating action. One would then expect calcium channel blockers to improve insulin resistance because of their strong vasodilation action; however, the nondihydropyridinederivative calcium antagonists diltiazem5~8and verapanriP have been shown neither to improve nor to aggravate insulin resistance in EHT. The dihydropyridine-derivative calcium channel blocker, nifedipine, has yielded conflicting results.8,9 In this study, we demonstrated that manidipine improves insulin sensitivity in EHT, suggesting that long-acting dihydropyridine-derivative calcium antagonists improve insulin resistance, in accordance with Sheu’s results with long-acting nifedipine.9 It was reported that nifedipine impaired insulin sensitivity in EHT.* However, as nifedipine capsules were used in their study,8 reactive stimulation of sympathetic activity may have exacerbated the effect of shortacting nifedipine on insulin sensitivity. We already reported that hyperinsulinemia increased PNE, PRA, and renal sodium reabsorption during 2-h glucose clamp in EHT.” ln this study, the effects of the calcium channel blocker, manidipine, on insulin action in renal sodium handling and pressor systems were investigated in EHT. After manidipine
218
1 Diab Comp 2995; 9:215-219
IIMURA ET AL.
APNE
APRA ng/mI/hr
PWI 100
0.6
p
p
1
0
I
0.4
50
I
-I
0.2
-
-
0
-50 Control
-
Control
Manidipine
I
Manidipine
FIGURE 3 Changes of plasma norepinephrine (APNE) and plasma renin activity (APRA) induced by hyperinsulinemia after treatment with manidipine in essential hypertensives.
treatment, hyperinsulinemia did not induce sodium retention but elicited natriuresis. Moreover, manidip-
ine suppressed the stimulating action of insulin in PNE and IRA. The suppression of insulin-induced sympathetic augmentation may be due to the decreased intracellular ionized calcium by manidipine.12 The suppressed IRA reaction by insulin seems to be explained by the attenuation of sympathetic activity, because renin release is augmented by sympathetic nerve stimulation. As the mechanisms of insulin-induced natriuresis under the manidipine treatment, suppression of insulin-induced pressor system activities, restoration of insulin-induced vasodilation in renal artery, and suppression of renal tubular sodium reabsorptiorG3 should be considered; although the detail of the mechanisms remains unknown. It has been suggested that insulin resistance that leads to hyperinsulinemia may be associated with hypertensive arteriosclerotic complications including coronary heart disease, I-3 and that metabolic side effects should be considered when selecting the antihypertensive agents. ** In this study, it was clarified that manidipine improved insulin resistance as assessed by glucose clamp method in EHT. These results strongly suggest that long-acting dihydropyridine-derivative calcium channel blockers will be useful antihyperten-
sive drugs in essential hypertensive sulin resistance.
before and
patients with in-
REFERENCES 1. Reaven GM: Role of insulin resistance in human disease. Diabetes 37:1595-X07, 1988. 2.
Kaplan NM: The deadly quartet: Upper-body obesity, glucose intolerance in hypertriglyceridemia and hypertension. Arch Intern Med 149:1514-1520, 1989.
3.
DeFronzo RA, Ferrannini E: Insulin resistance: A multifactorial syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 14:173-194, 1991.
4.
Pollare T, Lithe11H, Berne C, et al.: A comparison of the effects of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension. N Engl J Med 321:868-873,
1989.
5.
Pollare T, Lithe11H, Marlin C, et al. : Metabolic effects of diltiazem and atenolol: Results from a randomized, double-blind study with parallel groups. J Hypertens 7: 551-559, 1989.
6.
Pollare T, Lithe11 H, Selinus I, et al.: Application of prazosin is associated with an increase of insulin sensitivity in obese patients with hypertension. Diabetologia 31:415-420,
7.
1988.
Iimura 0, Shimamoto K, Matsuda K, et al.: Effects of angiotensin receptor antagonist and angiotensin converting enzyme inhibitor on insulin sensitivity in fruc-
] Diab Camp 1995; 9:X5-219
EFFECTS
tose-fed hypertensive rats and essential hypertensives.
9.
10.
11.
Sheu WH-H, Swislocki ALM, Hoffman B, et al.: Comparison of the effects of atenolol and nifedipine on glucose, insulin and lipid metabolism in patients with hypertension. Am f Hypertens 4:199-205, 1991. DeFronzo RA, Tobian JD, Anders R: Glucose clamp technique: A method for quantifying insulin secretion and resistance. Am J Pkysiol237:E214-E22.3, 1979. Shimamoto K, Hirata A, Fukuoka M, et al.: Insulin
ON INSULIN
SENSITIVITY
219
sensitivity and the effects of insulin on renal sodium handling and pressor systems in essential hypertensive patients. Hypertension23 (suppl I) I-29-1-33, 1994.
Am J Hypertens 1995 (in press).
8. Berne C, Pollare T, Lithe11H: Effects of antihypertensive treatment on insulin sensitivity with special reference to ACE inhibitor. Diabetes Care 14 (suppl4):39-47, 1991.
OF MANIDIPINE
12.
Iimura 0, Kikuchi K, Shimamoto K: Studies on the mechanism of the antihypertensive effect of long-term administered nifedipine in patients with benign essential hypertension, in Kelly DT (ed), Adalat in the Asian Pacific Region. Berlin, Springer-Verlag, 1989, 85-96.
13.
Gupta AK, Clark RV, Kirchner KA: Effects of insulin on renal sodium excretion. Hypertension 19:(suppl l)I-7% I-82, 1992.
14.
Houston MC: The effects of antihypertensive drugs on glucose intolerance in hypertensive nondiabetics. Am Heart J 115640-656, 1988.