(Hypertension. 1995;26:290-293.)
© 1995 American Heart Association, Inc.
Articles |
Insulin Modulation of Vascular Reactivity Is Already Impaired in Prehypertensive Spontaneously Hypertensive Rats
From IRCCS Sanatrix, Pozzilli (G.L., C.V.), and the Department of Internal Medicine, School of Medicine, Federico II University, Naples (G.I., V.R., B.T.), Italy.
Correspondence to Bruno Trimarco, MD, Medicina Interna, Federico II University, via S. Pansini 5, 80131 Napoli, Italy.
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Abstract |
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Abstract Hyperinsulinemia reduces the vasoconstrictive response to norepinephrine in Wistar-Kyoto rats (WKY) but not in spontaneously hypertensive rats (SHR). It has been hypothesized that this difference in the vascular effect of insulin could be a hallmark of the hypertensive state. To test this hypothesis we studied SHR before (5 weeks old, n=10) and after (15 weeks old, n=10) the establishment of hypertension as well as two groups of age- and sex-matched WKY (5 weeks old, n=14; 15 weeks old, n=13). Blood pressure was significantly higher in SHR compared with WKY (181±5 versus 118±6 mm Hg, respectively, P<.001) in the 15-week-old rats but not in the 5-week-old rats (121±5 versus 117±3 mm Hg, P<NS). We tested vascular reactivity using increasing amounts of norepinephrine (from 10-10 to 10-5 mmol/L) on isolated aortic rings in control conditions and after 30 minutes of exposure to 715 pmol/L insulin. In WKY insulin reduced the vascular response to norepinephrine in both the 5-week-old (repeated-measures ANOVA with grouping factor: F=2.443, P<.05) and 15-week-old (F=9.667, P<.01) groups. In SHR at both ages insulin failed to modify the vascular response to norepinephrine (5 weeks: F=0.107, P<NS; 15 weeks: F=0.075, P<NS). Sodium nitroprusside was able to attenuate the vascular response to norepinephrine in WKY and SHR at 5 and 15 weeks. Our data demonstrate that in SHR the vascular resistance to insulin action is specific and not acquired with the hypertensive condition; thus, it seems to be a genetically inherited trait.
Key Words: insulin resistance • hyperinsulinemia • aortic rings • norepinephrine • hypertension, genetic
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Introduction |
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Many epidemiological data clearly indicate a meaningful association between insulin and hypertension. Patients with non–insulin-dependent diabetes mellitus and obesity show an elevated risk of developing arterial hypertension,1 2 whereas many nonobese, nondiabetic patients with essential hypertension display resistance to insulin-induced glucose disposal3 4 accompanied by hyperinsulinemia.5 The nature and significance of this association are still unclear and under active investigation. Paradoxically, insulin modulates various factors with opposing effects on blood pressure homeostasis. In humans, hyperinsulinemia evokes a net reflex increase in sympathetic nervous activity,6 7 8 whereas it is able to attenuate the vasoconstrictive effects of the reflex sympathetic activation.9 Resistance to vascular insulin effect has been reported in several diseases, such as non–insulin-dependent diabetes mellitus,10 obesity,11 and essential hypertension12 ; this vascular defect could play a key role in the setting of increased blood pressure in these pathological conditions. Based on these findings, a hypothetical sequence may be formulated in which, on the one hand, resistance to insulin-induced glucose disposal leads to compensatory hyperinsulinemia and then to sympathetic overactivity7 and, on the other hand, the resistance to the vasorelaxant action of insulin might result in an unbalance of the sympathetic control on peripheral vascular tone. A critical point is to clarify whether altered vascular responses to insulin preexist in the hypertensive state.
Experimental hypertensive rats are a widely used model in the investigation of the pathogenesis of human essential hypertension. There is evidence that resistance to insulin-induced glucose disposal and hyperinsulinemia exists in various rat genetic models of hypertension, such as Zucker obese,13 Dahl salt-sensitive,14 and spontaneously hypertensive rats (SHR).15
The purpose of this study was to characterize in SHR, the best available animal model of essential hypertension,16 whether in addition to the defect in insulin-mediated glucose uptake there also exists a resistance to the vascular insulin action and to eventually clarify whether this vascular abnormality is a hallmark of the hypertensive state or possibly is already present before the onset of hypertension. In particular, we evaluated the effects of insulin on contractile responses of aortic rings to graded doses of norepinephrine, the major sympathetic neurotransmitter, in both SHR and Wistar-Kyoto rats (WKY), the normotensive reference strain. We adopted this experimental model because it has been clearly demonstrated that insulin induces a vasorelaxant response in aortic rings17 similar to that observed in resistance vessels.18 19
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Forty-seven rats (20 SHR and 27 WKY, Charles River Laboratory) were included in the study. The experimental protocol was in accordance with institutional guidelines of the University of Naples, School of Medicine. Rats lived two to a cage with temperature controlled between 23° and 25°C and a 12-hour light/dark cycle. Food and water were provided ad libitum. Ten SHR and 14 WKY were killed at 5 weeks of age before the development of arterial hypertension in SHR. The remaining were killed at 15 weeks.
Systolic blood pressure (SBP) and heart rate in conscious restrained rats were measured noninvasively by tail-cuff plethysmography (PE-300, Narco Biosystems Inc) and recorded on a multichannel polygraph (Universal oscillograph, Harvard Instruments). In our laboratory a close relationship was found when tail-cuff and direct intrafemoral arterial pressures were simultaneously recorded in both WKY and SHR (n=15, age from 5 to 20 weeks; tail-cuff SBP, 149±13 mm Hg versus intrafemoral SBP, 148±12 mm Hg; r=.919, P<.001).
On the day of contractile testing on isolated aortic rings, rats were weighed and then decapitated. The thoracic aorta was excised from each rat and placed in cold Krebs-Henseleit bicarbonate buffer solution with the following composition (mmol/L): NaCl 118.3, KCl 4.7, CaCl2 2.5, MgSO4 · 7H2O 1.2, KH2PO4 1.2, NaHCO3 25, and glucose 5.6. The aorta was cleaned of adhering fat and connective tissue and cut into rings 3 mm long. Aortic rings were suspended in isolated tissue baths filled with 20 mL Krebs' solution continuously bubbled with a mixture of 5% CO2/95% O2 (pH 7.37 to 7.42) at 37°C. One end of the aortic ring was connected to a tissue holder and the other to an isometric force transducer (GM3, Gould Instruments). The rings were equilibrated for 90 minutes in the unstretched condition, and the buffer was replaced every 20 minutes. Pilot studies were performed to set the optimal passive wall tension of the arterial rings. This was determined by repeated exposure to 10-3 mol/L norepinephrine (Sigma Chemical Co) at increasing levels of passive wall tension. The rings were then held at the optimal point of passive wall tension at which maximal active wall tension was produced after stimulation with norepinephrine. Passive wall tension was calculated as F/2x, where F is the force (grams) measured by the transducer and x is the longitudinal length (millimeters) of the vascular preparation. For all subsequent experiments optimal passive wall tension was maintained at 0.5 g/mm in 5-week-old rats and 0.67 g/mm in 15-week-old rats. No differences in optimal passive wall tension were observed between the normotensive and hypertensive strains. To study contractions evoked by norepinephrine, at the end of the equilibration period we added increasing concentrations of the neurotransmitter (10-10 to 10-5 mol/L) directly to the muscle bath before and after 30 minutes of preincubation with human regular insulin (715 pmol/L). After each dose was added, a plateau was obtained before the subsequent dose was added. All concentrations are expressed as final molar concentration in the organ chambers. At the end of each dose-response curve, an adequate interval of time of at least 30 minutes elapsed, during which the buffer was repeatedly replaced, to allow the rings to return from generated active tension. In another set of experiments to assay the specificity of the insulin action, we evaluated the contractile responses to norepinephrine before and after incubation with sodium nitroprusside (6x10-7 mmol/L). In all experiments no effort was made to remove the endothelium; the functional integrity of this structure was reflected by the response to 10-7 mol/L acetylcholine (WKY5week, 26±9%; WKY15week, 26±7%; SHR5week, 21±8%; SHR15week, 26±6%).
Contractile responses were evaluated as a percentage of maximal contraction. Moreover, the concentration of norepinephrine causing half-maximal absolute contraction (EC50) was calculated both in control conditions and during insulin treatment. EC50 was expressed as negative log molar (pD2 value) and was used as a measure of the sensitivity of the tissue to norepinephrine. A shift factor was calculated according to the following formula to estimate the magnitude of change in norepinephrine sensitivity after insulin addition: shift factor=(pD2 value in control conditions)-[(pD2 value during insulin)/(pD2 value in control conditions)] · 100.
Results are presented as mean±SEM. Statistical evaluation was done by paired and unpaired Student's t test or by repeated-measures ANOVA with grouping factors for evaluation of the interaction between agonist and insulin. Mean values were considered significantly different at a value of P<.05.
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Results |
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As shown in Table 1, SBP and body weight were similar in both 5-week-old rat strains, whereas at 15 weeks SBP was significantly higher in SHR. Body weight increased comparably in both strains. Cumulative addition of norepinephrine (10-10 to 10-5 mol/L) to the muscle bath caused contractions in all aortic segments. Arteries from WKY were sensitive to insulin treatment, as shown by the rightward shift in the concentration-response curve relative to control values both at 5 weeks (change at 10-5 mol/L norepinephrine: -24±4%) and 15 weeks (change at 10-5 mol/L norepinephrine: -24±4%) (Figure). In SHR insulin was not able to attenuate the norepinephrine-induced aortic contractions both during the hypertensive state (change at 10-5 mol/L norepinephrine: 4±9%) and at 5 weeks when SBP was still in the normal range (change at 10-5 mol/L norepinephrine: 9±10%) (Figure). Moreover, as shown in Table 2, this observation is corroborated by the analysis of pD2 values calculated on the absolute responses. The pD2 values were significantly reduced in SHR compared with WKY in control conditions at 15 weeks. The addition of insulin was able to significantly reduce pD2 values only in WKY at both 5 and 15 weeks; values remained substantially unmodified in age-matched SHR, as demonstrated by the relative shift factor.
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indicates control; 
, insulin.
WKY5week, control vs insulin: F=2.443,
*P<.05, n=9. WKY15week, control vs
insulin: F=9.667, *P<.01, n=8. SHR5week,
control vs insulin: F=0.107, P<NS, n=5.
SHR15week, control vs insulin: F=0.075,
P<NS, n=5.
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Sodium nitroprusside attenuated the response to norepinephrine in both WKY and SHR at the age of 5 weeks (change at 10-5 mol/L norepinephrine during nitroprusside: WKY, -41±5%; SHR, -33±8%) and 15 weeks (change at 10-5 mol/L norepinephrine during nitroprusside: WKY, -54±11%; SHR, -49±9%). In addition, pD2 values were significantly affected by sodium nitroprusside exposure (Table 3).
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Discussion |
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The current data in WKY are in accordance with those reported in several previous studies, performed in both humans and experimental animals, that have definitely established that insulin has the ability to modulate the vascular contractile response evoked by various vasoactive substances.17 18 19 20 21 22 The analysis of the concentration-contraction curves to norepinephrine in WKY revealed a significant insulin-mediated vasorelaxation even in the lower range of the curve (10-10 mol/L). It has been clearly demonstrated that during norepinephrine administration, an enormous reverse gradient is needed to simulate a state of physiological noradrenergic activation.23 In addition, we tested only the functional responses to norepinephrine because in vivo a cross talk between insulin and the sympathetic nervous system has clearly been demonstrated6 7 8 ; such a close physiological association has not been described for other vasoconstrictive pathways.
More important, our results clearly show that insulin is not able to modulate norepinephrine-induced vasoconstriction in aortic rings of SHR and that the resistance to the vascular action of insulin is already present at the age of 5 weeks, before the onset of arterial hypertension. In addition, the lack of insulin-induced vasorelaxation in SHR is also specific for the insulin-signaling pathway because another vasodilator, sodium nitroprusside, exerts the same action in both rat strains. Meanwhile, we confirm the previous observation showing that during the hypertensive state aortic rings of SHR are less sensitive to the contractile effects of norepinephrine than those of WKY.24
The coexistence of insulin resistance and hypertension has long been recognized3 5 ; this association has been localized primarily in skeletal muscle tissue.25 Additionally, several studies have clarified that insulin, besides having metabolic effects on the target tissues, also has a vasorelaxant action. This latter action could be due to both a direct effect on the vascular smooth muscle cell26 and an indirect endothelium-mediated effect.27 Recently, we12 and others10 11 have shown that the vascular action of insulin is significantly reduced in insulin-resistant hypertensive conditions. However, it is not clear whether the abnormal vascular action of insulin is a primary event in essential hypertension or a feature acquired in conjunction with high blood pressure. In fact, the enhanced vasoconstriction caused by vascular smooth muscle hypertrophy28 or vascular endothelium dysfunction29 and the reduced tissue sensitivity to norepinephrine,24 which are all observed in hypertension, may account for the lack of the vascular modulatory action of insulin.
The results of the present study indicate that when at early stages SBP does not appear to be different in SHR compared with WKY, the defect in vascular response to insulin is already present in the hypertensive rat strain. This observation suggests that the vascular insulin resistance could precede the appearance of a stable hypertensive condition, such as demonstrated for insulin resistance and hyperinsulinemia in human offspring of hypertensive parents.30 Furthermore, the recent experimental evidence showing that insulin resistance, evaluated as in vivo glucose uptake, is present in SHR but not in two different models of secondary hypertension, such as deoxycorticosterone acetate–salt and two-kidney, one clip rats,31 supports the conclusion that blood pressure itself does not play a major role in the determination of insulin resistance. Thus, the resistance to insulin modulation of vascular reactivity seems to be inherited and not acquired with the hypertensive condition, although some reports have demonstrated early structural changes in the vasculature of SHR,32 which could contribute to the differences in the vascular response to insulin.
The pathophysiological relevance of an impaired insulin action in SHR aortic rings before the hypertensive state cannot be firmly established. However, since the vasorelaxant action of insulin on aortic rings is similar to that observed in other vessels18 19 that are more important in overall blood pressure control, we used aortic rings as a model of the overall vascular responses. Thus, we can speculate that the compensatory hyperinsulinemia that inevitably occurs together with insulin resistance is a strong stimulus for norepinephrine release,6 7 8 and the lack of the modulatory action of insulin might result in an impaired balance of the sympathetic control of peripheral vascular resistance. It remains to be determined whether the vascular insulin resistance already present in the prehypertensive state plays a causative or permissive role in the development of spontaneous hypertension.
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Acknowledgments |
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We are grateful to Drs Carmine Morisco and Michele Romano for their technical assistance and Dr Carmine Battaglia for his helpful technical advice.
Received February 14, 1995; first decision March 8, 1995; accepted April 25, 1995.
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