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(Hypertension. 1995;25:1003-1007.)
© 1995 American Heart Association, Inc.

Articles

Role of Bradykinin in Insulin Sensitivity and Blood Pressure Regulation During Hyperinsulinemia

Osvaldo Kohlman, Jr; Francisco de Assis Rocha Neves; Milton Ginoza; Agostinho Tavares; Mario Luiz Cezaretti; Maria Tereza Zanella; Artur Beltrame Ribeiro; Irene Gavras; Haralambos Gavras

From the Division of Nephrology, Escola Paulista de Medicina Sao Paulo (Brazil); and the Section of Hypertension and Atherosclerosis, Boston (Mass) University School of Medicine.

Correspondence to Haralambos Gavras, MD, Hypertension and Atherosclerosis Section, Boston University School of Medicine, 80 E Concord St, Boston, MA 02118.

	Abstract

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Abstract The purpose of these experiments was to determine in normotensive rats the role of endogenous bradykinin, prostaglandins, and nitric oxide in glucose metabolism and blood pressure response to hyperinsulinemia. Normotensive Wistar rats were treated with two different bradykinin antagonists, indomethacin or N-nitro-L-arginine methyl ester, concurrently with a euglycemic clamp with insulin infusion rates of 3 or 6 mU/kg per minute. Glucose uptake, steady-state plasma insulin levels, and insulin sensitivity index were determined over 2 hours. Bradykinin inhibition dramatically reduced glucose uptake and insulin sensitivity index during both the lower and higher insulin infusion rates to 30% and 32%, respectively, of values observed in control rats. Inhibition of prostaglandins or nitric oxide did not alter glucose metabolism in these rats. Blood pressure remained unchanged in the control group throughout the clamp but increased significantly in rats submitted to inhibition of bradykinin, prostaglandins, or nitric oxide, suggesting that these vasodilator systems tend to counteract the hypertensive effect of hyperinsulinemia. The counterregulatory component attributable to bradykinin was about twice as great as that attributable to nitric oxide. These findings suggest that insulin infusion in normotensive Wistar rats fails to raise blood pressure because its effects are offset by mobilization of vasodilator mechanisms, such as bradykinin, prostaglandins, and nitric oxide. Bradykinin seems to play the most important homeostatic role under these conditions, because its inhibition significantly reduces insulin sensitivity and allows blood pressure to rise.

Key Words: bradykinin • prostaglandins • nitric oxide • insulin • euglycemic clamp technique • indomethacin • L-NAME

	Introduction

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Essential hypertension is often associated with various degrees of insulin resistance and hyperinsulinemia.^{1 2} This association has also been observed in some experimental rat models that are considered to be the counterpart of human essential hypertension.^{3 4} Although hyperinsulinemia was thought to raise blood pressure (BP) because it causes sympathetic stimulation⁵ and salt retention,⁶ direct insulin infusion in healthy animals and humans actually lowers BP,^{7 8} possibly by mobilizing counterregulatory forces.

Therefore, the etiologic link, if any, between insulin resistance and hypertension remains obscure. One of the proposed explanations is that vasopressor substances may diminish tissue perfusion and hence impair glucose uptake.⁹ If so, vasodilators would improve glucose tolerance by the same mechanism. Against this theory is evidence that angiotensin II infusion in healthy volunteers does not adversely affect insulin sensitivity,¹⁰ whereas vasodilators such as papaverine are metabolically neutral¹¹ and others, such as the thiazides (including the nondiuretic vasodilator diazoxide), accentuate insulin resistance.^{12 13 14}

Consequently, the documented amelioration in insulin sensitivity after treatment of essential hypertension with angiotensin-converting enzyme inhibitors¹⁵ may not be attributable to improved tissue perfusion. As there is no evidence that angiotensin II suppression might improve glucose utilization, the most likely explanation is that potentiation of bradykinin exerts this action.^{16 17} Indeed, bradykinin has been shown to enhance glucose transport in myocytes in vitro¹⁸ and glucose utilization in vivo.¹⁹ The mechanism of this effect remains unclear, especially because some of the actions of bradykinin are mediated via locally generated vasodilators such as prostaglandins and nitric oxide (NO),²⁰ both of which have been reported to alter insulin sensitivity.^{21 22}

The purpose of the present experiments was to further explore the action of bradykinin on BP and glucose uptake under hyperinsulinemic, euglycemic conditions, while attempting to dissect the role of local mediators (prostaglandins and NO) by use of specific inhibitors.

	Methods

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Eighty male normotensive Wistar rats weighing 250 to 320 g were used in these experiments. All rats were kept on a 12-hour dark/light cycle and had free access to regular Purina rat chow and tap water to drink.

Drugs
Bradykinin inhibition was accomplished by a continuous intra-arterial infusion of the B₂ receptor antagonist Aaa[D-Arg⁰,Hyp³,Thi^5,8,D-Phe⁷]bradykinin²³ at 200 µg/kg per minute for 130 minutes via an infusion pump (Harvard Apparatus). This infusion started 10 minutes before and continued throughout the euglycemic insulin clamp period. Prostaglandin synthesis was inhibited by indomethacin at 2 mg/kg per day SC for 7 days before the euglycemic clamp studies. NO synthesis was inhibited by a continuous infusion of N-nitro-L-arginine methyl ester (L-NAME) at 200 µg/kg per minute for 120 consecutive minutes concurrently with the euglycemic insulin clamp. For the insulin clamp studies, insulin (mixed porcine/bovine insulin solution) was continuously infused intravenously at two different rates: 3 and 6 mU/kg per minute for 120 consecutive minutes. After this study had been completed, an additional confirmatory experiment was conducted on seven rats studied according to the same protocol with a different bradykinin antagonist. Bradykinin inhibition was accomplished in this group with the use of Hoe 140²⁴ at an initial dose of 33 mg/kg SC followed by continuous infusion at 330 ng/kg per minute for 120 minutes. Only the insulin dose rate of 6 mU/kg per minute was used in this group.

Groups
Four groups of normotensive Wistar rats were prepared. Each group was subdivided into A and B subgroups according to the insulin infusion rate used in the clamp (3 mU/kg per minute for the A subgroups, and 6 mU/kg per minute for the B subgroups): Group 1, control: 15 untreated normotensive Wistar rats (subgroup 1A, n=8; 1B, n=7); group 2, bradykinin antagonist group: 22 normotensive rats treated with the bradykinin antagonist (subgroup 2A, n=14; 2B, n=8); group 3, indomethacin group: 22 normotensive Wistar rats treated with indomethacin (group 3A, n=11; 3B, n=11); group 4, L-NAME group: 14 normotensive rats infused with the NO inhibitor L-NAME (group 4A, n=8; 4B, n=6); and group 5, Hoe 140 group: 7 normotensive rats treated with Hoe 140; insulin infusion rate, 6 mU/kg per minute. An additional group of 7 rats received only L-NAME infusion along with the vehicle of the euglycemic clamp solution (but no insulin or glucose).

Euglycemic Insulin Clamp
All rats underwent the euglycemic insulin clamp studies as described by Kraegen et al.²⁵ After an overnight fast, rats had PE-10 catheters inserted into two veins and one artery of the tail under light ether anesthesia. After a 2-hour recovery period, rats were started on a 2-hour continuous insulin infusion (at 3 or 6 mU/kg per minute) and delivery of 10% glucose solution through the vein catheters at a rate sufficient to maintain euglycemia. The arterial catheter was used for blood sampling for plasma glucose and insulin measurements and for determination of BP in those groups submitted to the higher insulin infusion rate.

The following parameters were recorded for all rats: (1) fasting plasma glucose and insulin levels, (2) plasma glucose levels at each 5-minute interval throughout the 120-minute clamp period, (3) steady-state plasma glucose level as reflected by the mean of plasma glucose levels in the last 30 minutes of the clamp, (4) steady-state plasma insulin level as reflected by the mean of plasma insulin levels determined at 90 and 120 minutes of the clamp, (5) glucose uptake as reflected by the mean glucose amount delivered in the last 30 minutes of the clamp, and (6) insulin sensitivity index calculated as the ratio of glucose uptake to steady-state plasma insulin level x10². Plasma glucose was determined with a glucose analyzer (Beckman Instruments, Inc) and plasma insulin levels by radioimmunoassay.

In all rats submitted to the higher insulin infusion rate, mean arterial pressure levels were directly monitored before and every 10 minutes throughout the clamp period via the arterial catheter connected to a recorder (Gould Electronics). These values are presented as variation from the baseline.

Data are presented as mean±SEM; statistical comparisons were performed by ANOVA.

	Results

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The Table shows blood glucose and insulin parameters. It is evident that steady-state plasma glucose levels were not significantly different from those observed in each group at the fasting state. Fasting plasma insulin levels were similar among the B subgroups (receiving higher insulin infusion rates), whereas among the A subgroups, those in group 4A (L-NAME) had lower fasting plasma insulin. Both insulin infusion rates significantly increased the circulating insulin levels (steady-state levels) in all groups (P<.05). Throughout the 120-minute period, a stable level of euglycemia was maintained in all groups at both insulin doses.

View this table: [in this window] [in a new window]   Table 1. Parameters of Glucose Metabolism in Normotensive Wistar Rats

As expected, glucose uptake during the euglycemic insulin clamp tended to be greater with the higher insulin infusion rate, although the differences were not statistically significant (Fig 1). With both insulin infusion rates, inhibition of bradykinin, but not of prostaglandins or NO, caused a significant reduction in glucose uptake. Indeed, glucose infusion rates needed to maintain euglycemia in rats treated with the bradykinin inhibitor were 6.6±1.4 and 6.1±1.6 mg/kg per minute with the lower (3 mU/kg per minute) and higher (6 mU/kg per minute) insulin doses, respectively. These values are only 46% and 30% of those required by the control rats infused with the lower and higher insulin doses (14.4±2.2 and 20.3±0.7 mg/kg), respectively. In other words, inhibition of endogenous bradykinin in normotensive rats reduced the need for glucose infusion by 54% and 70% during low- and high-dose insulin administration, respectively. Glucose uptake values for the indomethacin- and L-NAME–treated groups at lower and higher insulin infusion rates were 14.6±0.7 and 20.1±1.0 mg/kg per minute (indomethacin) and 19.3±3.2 and 20.1±1.8 (L-NAME), respectively, and were no different from those observed in the control groups.

View larger version (16K): [in this window] [in a new window]   Figure 1. Bar graphs show glucose uptake of the four experimental groups during euglycemic hyperinsulinemic clamp with two different insulin infusion rates: 3 (open bars) and 6 (closed bars) mU/kg per minute. *P<.05 vs remainder receiving the same insulin dose. L-NAME indicates rats treated with N-nitro-L-arginine methyl ester; BKI, rats treated with bradykinin inhibitor; and INDO, rats treated with indomethacin.

The insulin sensitivity index (Table) was significantly decreased by bradykinin inhibition at 7.7±2.3 and 7.2±2.0 mg · kg^-1 · min^-1 · mU^-1 · mL^-1, respectively, for the low and high insulin infusion rates. By comparison, the control groups had values of 21.4±3.5 and 22.7±1.8 mg · kg^-1 · min^-1 · mU^-1 · mL^-1, respectively. Neither NO inhibition nor prostaglandin synthesis inhibition decreased the insulin sensitivity index significantly. The results obtained with Hoe 140 were essentially similar to those of the other bradykinin antagonist.

Fig 2 shows changes in mean arterial pressure from baseline during the insulin clamp. In control rats, BP did not change significantly throughout the clamp. However, in the three groups submitted to blockade of the various vasodilators, insulin infusion was accompanied by significant and sustained increases in BP. The increase was modest in indomethacin-treated rats, intermediate in rats infused with the bradykinin inhibitor, and highest in rats submitted to inhibition of NO synthesis. A transient fall in mean arterial pressure was observed in the group treated with L-NAME at the 90th minute of the infusion period, when blood was collected for plasma insulin determination. Fig 3 shows mean changes in BP. In the control group, mean increase in BP was only 1.4±2.7 mm Hg. In contrast, in the rats treated with indomethacin, bradykinin inhibitor, or L-NAME, mean increases in arterial pressure were 11.8±1.7, 19.7±4.0, and 42.2±4.6 mm Hg, respectively. In the Hoe 140–treated rats, the mean BP rise was 20.4±5.0 mm Hg, which was virtually identical to that obtained by the other bradykinin inhibitor. In rats submitted to inhibition of NO synthesis alone, the increase in mean BP was 32.0±5.7 mm Hg, ie, only 10.2 mm Hg lower than that observed in rats submitted to concurrent insulin and L-NAME infusion (not significantly different).

View larger version (20K): [in this window] [in a new window]   Figure 2. Line graph shows time course of changes in mean arterial pressure (MAP) from baseline in the control (), bradykinin antagonist (), indomethacin (), and N-nitro-L-arginine methyl ester () groups during euglycemic hyperinsulinemic clamp (insulin infusion rate: 6 mU/kg per minute). *P<.05 vs baseline. Changes in MAP in the control group were not statistically significant.

View larger version (13K): [in this window] [in a new window]   Figure 3. Bar graph shows changes in mean arterial pressure (MAP) in the four experimental groups during euglycemic hyperinsulinemic clamp (insulin infusion rate: 6 mU/kg per minute). *P<.05 vs control group. Group definitions are as in Fig 1 legend.

	Discussion

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Our data demonstrate that bradykinin inhibition by two different B₂ receptor antagonists induced insulin resistance in unanesthetized normotensive Wistar rats. They also show that inhibition of prostaglandin synthesis or NO did not alter glucose metabolism in these rats. These results differ from previous data that have shown prostaglandins of the E series to act in vitro as modulators of insulin-stimulated glucose metabolism²¹ or NO inhibition to reduce glucose uptake in Sprague-Dawley rats.²² Possible explanations for these discrepancies include the fact that different species were studied (Sprague-Dawley versus Wistar rats), the insulin infusion rates were different (12 mU/kg per minute versus 3 and 6 mU/kg per minute), and the inhibitor of NO synthesis was different (N-monomethyl-L-arginine versus L-NAME).

In our present experiments, glucose uptake during hyperinsulinemia induced by two different insulin infusion rates was dramatically reduced by bradykinin inhibition only and was similar with both bradykinin inhibitors tested. Likewise, the insulin sensitivity index was diminished to only 36% and 32% of that observed in control rats at the lower and higher insulin infusion rates, respectively. These data indicate that the naturally occurring vasodilator bradykinin in its physiological range is involved in the normal glucose metabolism of normotensive Wistar rats. This is in agreement with previous reports that exogenous bradykinin administration producing circulating levels above the physiological range improves insulin sensitivity in both humans^{19 26} and normotensive animals.²⁷ These results are also in keeping with data showing that bradykinin influences insulin-mediated glucose transport in vitro.¹⁸ Inhibition of endogenous bradykinin by a B₂ receptor antagonist causes alterations in certain regional blood flows, with a decrease in coronary and renal flows and increase in pulmonary flow, whereas muscle blood flow remains virtually unchanged.²⁸ Accordingly, the change in glucose uptake observed during bradykinin inhibition could not be attributed to a change in muscle perfusion. A further corroboration of these findings comes from a recent publication²⁹ which demonstrated that the improvement in insulin sensitivity produced by angiotensin-converting enzyme inhibition could be abolished by the bradykinin antagonist Hoe 140; this indicated that the bradykinin-mediated pharmacological action of angiotensin-converting enzyme inhibition was responsible for this effect.

In essential hypertension, hyperinsulinemia associated with insulin resistance can increase BP.³⁰ However, in normotensive volunteers, BP remains in the normal range or decreases during insulin infusion^{7 8} despite enhancement in sympathetic activity, suggesting that vasodilator mechanisms come into play to counterbalance the hypertensive effect of high insulin levels. Our finding that insulin infusion did not raise BP in the control group is in accordance with these data. Moreover, the significant increases in BP during pharmacological blockade of each one of the three vasodilator systems studied confirm the hypothesis that they act as counterregulatory mechanisms against the hypertensive effects of elevated plasma insulin levels. In this respect, it should be noted that under normal conditions, inhibition of either bradykinin or prostaglandins alone does not raise BP in intact rats,³¹ whereas inhibition of NO synthesis does.^{28 32} Therefore, the contribution of augmented NO activity³³ as a counterregulatory mechanism to the hypertensive effect of hyperinsulinemia could not be quantified solely by the rise in BP in response to L-NAME under these conditions. This contribution is represented by the difference in BP rise of insulin-infused versus non–insulin-infused rats treated with L-NAME (42 versus 32 mm Hg, respectively), ie, about 10 mm Hg. By comparison, the contribution of prostaglandins to the BP equilibrium during hyperinsulinemia would be about 12 mm Hg and the contribution of bradykinin approximately 20 mm Hg.

In summary, our data suggest that under resting conditions, bradykinin plays an important role in maintaining normal glucose metabolism, and under conditions of hyperinsulinemia, its vasodilator action serves as a major counterregulatory mechanism to prevent a rise in BP. On the basis of these findings, it is tempting to speculate that a chronically impaired endogenous bradykinin system may participate in the pathogenesis of both insulin resistance and BP elevation in some forms of essential hypertension.

	Acknowledgments

 
This work was supported in part by grant HL-18318 from the National Institutes of Health and was carried out during the period that Dr Tavares held a fellowship and Drs Ribeiro and Zanella spent a sabbatical at the Boston University School of Medicine.

Received March 18, 1994; first decision May 4, 1994; accepted November 17, 1994.

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