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(Hypertension. 1997;29:280.)
© 1997 American Heart Association, Inc.
Arthur C. Corcoran Memorial Lecture |
Relationship Between Insulin Resistance and Endothelium-Dependent Vascular Relaxation in Patients With Essential Hypertension
From the First Department of Internal Medicine (Y.H., N.S., N.I., M.Y., K.I., H.M., G.K.) and the Department of Clinical Laboratory Medicine (T.O., Y.N., R.O.), Hiroshima University School of Medicine, Japan.
Correspondence to Yukihito Higashi, MD, First Department of Internal Medicine, Hiroshima University School of Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima 734, Japan
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Abstract |
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The infusion of L-arginine induces the production of nitric oxide and stimulates the immediate secretion of insulin. To examine the relationship between insulin resistance and endothelium-dependent vascular relaxation in patients with essential hypertension, we evaluated the renal and insulin responses to L-arginine, 500 mg/kg infused intravenously over 30 minutes, in 23 patients with mild essential hypertension who were neither obese nor diabetic and in 20 normotensive control subjects. We found no difference between the two groups in blood glucose or insulin in the fasting condition. The renovascular relaxation induced by L-arginine was significantly less in patients with essential hypertension than in normotensive control subjects. The increase in plasma cyclic GMP in response to L-arginine was lower in hypertensive patients than in normotensive subjects. Although the serum concentrations of glucose in response to L-arginine were similar in the two groups, the serum insulin response of the essential hypertensives was significantly higher than that of the normotensive subjects. In all subjects, the peak cyclic GMP response to L-arginine was significantly correlated with the peak
glucose/ insulin ratio response to L-arginine (r=.69, P<.001). Findings suggested that an impairment of endothelium-dependent renal vascular relaxation and a reduced sensitivity to insulin are present in patients with essential hypertension. A link may be present between the abnormality of the L-arginine/nitric oxide/cyclic GMP pathway and insulin resistance in patients with essential hypertension.
Key Words: L-arginine • nitric oxide • cyclic GMP • hypertension, essential • insulin resistance • renal circulation
Abbreviations: FF = filtration fraction • GFR = glomerular filtration rate • LDL = low-density lipoprotein • NO = nitric oxide • PAH = para-amino hippurate • PRA = plasma renin activity • RPF = renal plasma flow • RVR = renal vascular resistance
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Introduction |
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Essential hypertension is associated with insulin resistance and hyperinsulinemia.1–4 While the mechanism by which insulin contributes to blood pressure regulation has not been clarified, factors appear to include a stimulation of the sympathetic nervous system,5 promotion of growth of vascular smooth muscle cells,6 increase in renal sodium absorption,7 and decrease in agonist-induced vasoconstriction.8 A direct action of insulin on vascular tone has been proposed.9
NO is known to play a vital role in the regulation of systemic and renal hemodynamics.10–16 This substance is produced from L-arginine in the presence of NO synthase in the endothelium, stimulates cytosolic guanylate cyclase, and increases the concentration of guanosine 3',5'-cyclic monophosphate (cGMP) in vascular smooth muscle cells, resulting in relaxation of vascular tone.17,18 Several investigators have reported a disturbance of endothelium-dependent vascular relaxation in patients with essential hypertension and in animals with experimentally induced hypertension.19–24 We previously reported that even patients with mild essential hypertension exhibit an impairment in endothelium-dependent renal vascular relaxation.15,25 Such findings suggest that abnormalities in endothelium-dependent vasodilation in the renal circulation may participate in the development of hypertension.
The vasodilatory effect of insulin is reportedly mediated by the stimulation of the release of NO.26,27 If so, there should be a direct physiological correlation between insulin resistance and vascular endothelial dysfunction in patients with essential hypertension. The infusion of L-arginine induces the production of NO-cGMP and stimulates the immediate secretion of insulin. An elevated plasma level of arginine is a particularly potent stimulus for insulin secretion, although the mechanism is not completely known.28,29 We examined the responses to renal circulation and glucose/insulin to infused L-arginine to evaluate the relationship between insulin sensitivity and endothelial function in patients with essential hypertension.
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Methods |
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Subjects
We studied 23 Japanese inpatients with mild to moderate essential hypertension (16 males and 7 females; mean age 47±3 years) and 20 normotensive control subjects (14 males and 6 females; mean age 45±2 years). Hypertension was defined as a systolic or diastolic blood pressure of more than 160 mm Hg or/and 95 mm Hg, determined in sitting position on at least three different occasions. Measurements were obtained in the outpatient clinic of Hiroshima University School of Medicine. Patients with secondary forms of hypertension were excluded by the appropriate clinical and biochemical examinations. None of the patients had a history of cardiovascular or cerebrovascular disease, diabetes mellitus, hypercholesterolemia, liver disease, or renal disease. Normotension was defined as a systolic blood pressure of less than 140 mm Hg and a diastolic blood pressure of 80 mm Hg. The normotensive control subjects had no history of serious disease. The body mass index of each subject was less than 27 kg/m2. The study protocol was approved by the ethical committee of the First Department of Internal Medicine, Hiroshima University School of Medicine. Informed consent for participation was obtained from each subject.
Study Protocol
None of the participants took any antihypertensive agents for at least 4 weeks before the study. One week before the study, they were started on a regular diet that contained 170 mmol sodium chloride per day to allow the stabilization of the sodium balance and blood pressure. They ingested a constant amount of potassium (100 mmol/d) and calcium (40 mmol/d) during the study. Their caloric intake was 40 calories per kilogram per day. All inpatients received meals prepared in the Hiroshima University Hospital kitchen. Rigid compliance to the diet was confirmed by measuring the 24-hour urinary excretion of sodium, chloride, and potassium throughout the study.
The L-arginine infusion study began at 8:30 AM of the seventh morning of the period of regular sodium chloride ingestion. Subjects had fasted overnight for at least 12 hours. They were kept in the supine position in a quiet, dark, air-conditioned room (constant temperature 22°C to 25°C) throughout this study. A 19-gauge polyethylene catheter (Terumo Co) was inserted into the right antecubital vein for the infusion of PAH, inulin, and L-arginine. A second catheter was inserted into the left antecubital vein to obtain blood samples. After a 30-minute rest period, an initial dose of PAH (8.0 mg/kg) and inulin (16 mg/kg) was infused as a bolus. PAH and inulin were subsequently infused at a constant rate of 12 and 20 mg/min by means of a syringe pump (Terfusion; Terumo Co) throughout the study.30,31 Sixty minutes after beginning those infusions, we initiated the infusion of L-arginine (500 mg/kg) given over 30 minutes using an infusion pump (PEI-1000; Pal Medical Co). The end of the L-arginine infusion was followed by a 30-minute recovery period. Blood pressure and heart rate were determined every minute by attaching a TM2420 monitor (AND Co) to the upper part of the left arm. Mean blood pressure was calculated as the diastolic pressure plus one third of the pulse pressure. Blood samples were obtained to determine serum PAH, inulin, glucose, insulin, and plasma cGMP at 0 minutes and at 15, 30, and 60 minutes after the start of L-arginine administration. Baseline fasting serum concentrations of total cholesterol, creatinine, and electrolytes and PRA were obtained at 0 minutes.
Drugs
The L-arginine used for intravenous administration was L-arginine hydrochloride (Morishita Pharmaceutical Co). The administered inulin was Inutest (Laevosan-Gesellschaft Co), and the PAH was para-amino hippurate (Daiichi Pharmaceutical Co).
Analytical Methods
Routine chemical methods were used to determine the serum concentrations of total cholesterol, creatinine, glucose, and electrolytes and of urinary electrolytes. PRA was measured by radioimmunoassay (gamma coat PRA kit, Special Reference Laboratory). Plasma cGMP levels were measured by radioimmunoassay (cGMP kit, Yamasa Shoyu Co). RPF was measured by PAH clearance. Serum PAH concentrations were analyzed spectrophotometrically. GFR was measured by inulin clearance.32 Serum inulin concentration was analyzed by the anthrone method.33 Renal blood flow was calculated from PAH clearance and the hematocrit. RVR was calculated as the mean blood pressure divided by renal blood flow, and FF was calculated as GFR divided by RPF. RPF, GFR, and RVR were correlated to body surface area divided by 1.48 m2 (1.48 m2 being the average body surface area of the Japanese population).
Statistical Analysis
Results are presented as mean±SEM. Baseline parameters were compared by Student's paired t test. Differences between the hypertensive patients and normotensive control subjects were compared by Student's unpaired t test. Their responses to L-arginine were compared by ANOVA for repeated measures followed by Scheffé's F test. A level of P<.05 was considered statistically significant.
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Results |
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Clinical Characteristics
The baseline clinical characteristics in the 23 patients with mild essential hypertension and the 20 normotensive control subjects before the infusion of L-arginine appear in the Table. The mean blood pressure and RVR were significantly higher in the hypertensive patients than in the normotensive subjects. Age, sex, body mass index, serum concentrations of glucose and insulin in the fasting condition, and the other parameters of renal hemodynamics did not differ significantly in the two groups.
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Effects of L-Arginine Infusion on Systemic Hemodynamics
Fig 1 shows the percent change in mean blood pressure and heart rate over the baseline level during the infusion of L-arginine in the subjects studied. The mean blood pressure decreased promptly and reached a plateau at 20 minutes in both groups after the start of the L-arginine infusion. A prompt return to baseline levels occurred after the end of L-arginine infusion in both groups. Groups did not differ with respect to the time course of percent change in mean blood pressure. The administration of L-arginine increased the heart rate in both groups. The heart rate gradually returned to baseline during the resting period. There was no significant difference between the two groups in the time course of changes in heart rate.
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Effects of L-Arginine Infusion on Renal Hemodynamics
The intravenous infusion of L-arginine produces renal vasodilation, resulting in an increase in RPF and a decrease in the RVR and the FF. L-Arginine infusion did not affect the GFR in either group. The increase in RPF induced by L-arginine was significantly less in hypertensive patients than in normotensive subjects (9.8±1.9% versus 16.2±2.2%, P<.001). The decrease in RVR in response to the L-arginine infusion was also significantly smaller in the group with essential hypertension than in the normotensive group (-10.9±2.9% versus -19.6±2.8%, P<.001) (Fig 2). The decrease in FF induced by L-arginine was significantly lower in the group with essential hypertension than in that with normotension (-1.72±1.2% versus -7.3±1.4%, P<.01).
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Effects of L-Arginine Infusion on Plasma cGMP Concentration
We measured the plasma cGMP concentration as an indicator of NO production. Baseline plasma cGMP levels were similar in both groups (Table). The L-arginine-induced increase in cGMP was significantly smaller in the hypertensive group than in the normotensive group (1.9±0.3 versus 3.0±0.2 pmol/mL, P<.05) (Fig 3).
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Effects of L-Arginine Infusion on the Secretion of Insulin and Glucose
The intravenous infusion of L-arginine significantly increased the serum levels of glucose and insulin. Peaks in serum glucose and insulin occurred at 30 minutes and returned to baseline in 60 minutes. Although the increase in glucose levels induced by L-arginine was similar in the two groups, the insulin response to the L-arginine infusion was significantly higher in the hypertensive subjects (667±30% versus 542±28%, P<.01) (Fig 4). The peak cGMP response was significantly correlated with the peak glucose/insulin ratio in response to L-arginine in all subjects (r=.69, P<.001) (Fig 5).
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Discussion |
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Findings suggest that insulin resistance and an impaired endothelium-dependent renal vascular relaxation are present in patients with essential hypertension. An abnormality in the L-arginine/NO/cGMP pathway may be linked to insulin resistance.
Insulin Resistance in Essential Hypertension
Abnormalities in the metabolism of glucose and insulin are common in patients with essential hypertension and may be involved in the pathogenesis of this disease as well as in its complications. The insulin sensitivity of glucose utilization has variously been evaluated by the euglycemic clamp technique, the insulin suppression method, glucose challenge, and their various combinations. The present study determined the response of serum glucose and insulin to the infusion of L-arginine. While the L-arginine-induced change in serum glucose level was similar in both groups, the insulin response was significantly greater in the group with essential hypertension versus the group with normotension. A strong correlation has been reported between the insulin response to the oral glucose challenge and the level of resistance, such as the insulin response and insulin action during the glucose clamp34 or during insulin suppression.35 Results indicate that the ability of insulin to stimulate glucose uptake was significantly reduced in nonobese, nondiabetic patients with essential hypertension. Circulating insulin levels did not differ in the fasting condition in the two groups. Thus, the patients with essential hypertension studied exhibited insulin resistance but not hyperinsulinemia.
Although the mechanism responsible for the association between hypertension and the resistance to insulin has not been clarified, several mechanisms for the pressure effect of insulin have been postulated. These include the stimulation of sympathetic nervous system activity,5 the promotion of the growth of vascular smooth muscle cells,6 and an increase in the reabsorption of renal sodium.7 A direct vasodilator action of insulin has been established, although the underlying mechanism is not known.8,9 The presence of insulin resistance may disturb the balance between the pressor (sympathetic, growth, and renal) and the depressor (vasodilation) actions of insulin.
Endothelium-Dependent Renal Vascular Relaxation in Essential Hypertension
In patients with essential hypertension, the endothelium-dependent vasodilation induced by acetylcholine or bradykinin is impaired in the coronary and brachial arteries.19–21,36 We recently reported that the endothelium-dependent renovascular relaxation is impaired even in patients with mild essential hypertension who had normal RPF and GFR and lacked objective signs of end-organ damage compared with healthy subjects.15,25 Thus, our findings suggest that changes in renal endothelial function may be a cause, not an effect, of hypertension.
The mechanism of the impaired endothelium-dependent vascular relaxation in essential hypertension is less clear. One explanation is that abnormalities in the L-arginine/ NO/cGMP pathway contribute to the blunted endothelium-dependent vasodilation in these individuals. Our findings and those of others are consistent with this explanation.15,19–23,25,37–39 Other possibilities have been postulated, such as increase in endothelium-derived contracting factors, decrease in endothelium-derived hyperpolarizing factors, and decrease in the number and/or affinity of receptors for vasoactive agents on the endothelial membrane.
Relationship Between Insulin Resistance and Endothelium-Dependent Vascular Relaxation in Essential Hypertension
The mechanism by which insulin induces vasodilation is not fully clarified. It has been suggested that insulin's vasodilatory action may be closely associated with an endothelium-dependent vasorelaxant mechanism. Petrie et al26 recently suggested that endothelial NO synthesis in the forearm circulation and insulin sensitivity are positively related in healthy humans. Scherrer et al27 suggested that the vasodilatory effects of insulin are mediated by stimulation of NO production and that insulin-induced NO release is decreased by physiologic hyperinsulinemia in the forearm of humans. In an experimental study, Han et al40 recently showed that insulin acts on the vascular endothelium by increasing endothelial [Ca2+]i and releasing NO, which decreases vascular smooth muscle [Ca2+]i and the Ca2+ sensitivity of the contractile elements in the isolated aorta of Wistar rats. Baron et al41 recently reported that the administration of NG-monomethyl-L-arginine, which is an inhibitor of NO synthesis, caused both hypertension and a reduction in rates of insulin-stimulated glucose uptake in rats. Their data suggest the possibility that NG-monomethyl-L-arginine-induced NO deficiency may itself have caused insulin resistance.
Modest elevations in LDL are common in populations with hypertension or insulin resistance. Oxidized LDL, LDL that has undergone oxidative modification, has been shown to interfere with formation of NO42 and to directly inactivate NO.43 The suppression of NO formation by oxidized LDL may contribute to a link between insulin resistance and endothelial dysfunction.
This is the first report on the relationship between insulin resistance and endothelium-dependent renal vascular relaxation in patients with essential hypertension. The most important finding was that there exists a negative correlation between the increase in cGMP in response to L-arginine as an indicator of NO production and insulin sensitivity (glucose/insulin). The relationship between insulin resistance and a disturbance in endothelial function can be explained by three possibilities. First, an increase in insulin resistance promotes a decrease in NO-cGMP production. Second, conversely, a deficiency in NO-cGMP production promotes an increase in insulin resistance. Finally, an increase in insulin resistance and a decrease in NO-cGMP production are inherited as separate traits that develop in a parallel but independent fashion. Additional studies are required to investigate these possibilities.
In the present study, we administered L-arginine intravenously to humans and evaluated their renal hemodynamics by the clearance method using inulin and PAH. This method does not require arterial cannulation or exposure to radiation. It provided a safe, reproducible, and accurate in vivo assessment of the endothelial L-arginine/NO/ cGMP pathway in the renal circulation. Several studies have used L-arginine infusion in other vascular beds, such as the pulmonary38 and femoral arteries.39 The use of specific NO synthase inhibitors such as NG-monomethyl-L-arginine and NG-nitro-L-arginine methyl ester and agonists to stimulate NO release such as acetylcholine or bradykinin would allow us to draw more specific conclusions concerning the role of the basal and stimulated release of NO in the renal circulation. As the intravenous infusion of NO synthase inhibitors can increase the blood pressure and vascular resistance, these agents may carry a degree of risk in hypertensive patients. We therefore did not investigate these agents from certain aspects due to ethical considerations.
In conclusion, this appears to be the first report to demonstrate that insulin resistance and an impairment of endothelium-dependent renal vascular relaxation coexist and are related to each other in patients with essential hypertension. These factors may be involved in the pathogenesis of essential hypertension. Studies are required to evaluate the effects of antihypertensive drug treatment on insulin resistance and endothelium-dependent renovascular relaxation in patients with essential hypertension.
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Acknowledgments |
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This study was supported in part by a grant-in-aid for scientific research (07407065) from the Ministry of Education, Science, and Culture of Japan. The authors thank Sumiko Nakamura for preparing the diets and Yuko Omura for her secretarial assistance.
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