Insulin and Insulin-Like Growth Factor in Normal and Pathological Cardiovascular Physiology
1997; Lippincott Williams & Wilkins; Volume: 29; Issue: 3 Linguagem: Inglês
10.1161/01.hyp.29.3.691
ISSN1524-4563
Autores Tópico(s)Growth Hormone and Insulin-like Growth Factors
ResumoHomeHypertensionVol. 29, No. 3Insulin and Insulin-Like Growth Factor in Normal and Pathological Cardiovascular Physiology Free AccessResearch ArticleDownload EPUBAboutView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticleDownload EPUBInsulin and Insulin-Like Growth Factor in Normal and Pathological Cardiovascular Physiology James R. Sowers James R. SowersJames R. Sowers the Divisions of Endocrinology, Metabolism, and Hypertension, Wayne State University School of Medicine and VA Medical Center, Detroit, Mich. Originally published1 Mar 1997https://doi.org/10.1161/01.HYP.29.3.691Hypertension. 1997;29:691–699Over the past decade considerable data have been garnered suggesting that insulin, normally secreted only by the pancreas, and IGF-1, secreted by cells of the cardiovascular system, regulate normal cardiovascular physiological responses.123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960616263646566676869707172737475767778798081828384858687888990919293949596979899101102 Furthermore, there is emerging evidence that abnormal actions of these factors may contribute to disease states such as hypertension and atherosclerosis.3839 This review presents the current understanding of mechanisms of the hemodynamic, metabolic, and growth effects of insulin and IGF-1 exerted on cardiovascular tissue under both normal and pathological conditions.Hemodynamic Actions of Insulin and IGF-1Insulin and IGF-1 have specific and physiological vascular actions in humans and experimentally derived animals and cause an increase in SMBF and a decrease in vascular resistance.1234567891011121314151617181920212223242526272829303132333435363738394041 Studies by several investigative groups2930313233343540 have shown that insulin increases SMBF in a dose-dependent fashion, with an ED50 for insulin of approximately 35 to 40 μU/mL in lean insulin-sensitive persons.40 In experimental animals, insulin has differential effects in different vascular beds, exerting vasodilatory effects on the femoral, aortic, coronary, and tail vasculature and vasoconstrictor effects in mesenteric arteries.2314151699100101102 There are also differential effects of insulin in the renal vascular bed, exerting a constricting effect on afferent arterioles and efferent arteriole vasodilation.101 Even gender differences in vascular responses to insulin have been reported.102 IGF-1 has effects on the regulation of vascular tone that are similar to those of insulin, with regional differences in vascular responses.31363839103104105 Unlike insulin, however, IGF-1 is produced in cardiovascular tissue,8910111238394041 where it likely exerts autocrine/paracrine effects.Role of NO in the Vascular Effects of Insulin and IGF-1The endothelium-derived relaxing factor NO appears to be an important mediator of insulin-induced and IGF-1–induced vascular relaxation.131429303138394041 Using a specific inhibitor of NOS, L-NMMA, investigators2930106 have demonstrated that insulin-mediated and IGF-1–mediated increases in SMBF are dependent on vascular NO production. Similar studies in experimental animals have demonstrated that both insulin-mediated and IGF-1–mediated vasorelaxation are NO dependent.3138394041 Indeed, studies conducted in my laboratory (Fig 1) and others1314 indicate that these hormones stimulate NO production in cultured vascular endothelial cells. Although it has been suggested that the vasorelaxant effects of insulin-related factors are mediated through endothelium-derived NO production, the relatively slow (30 to 60 minutes) effects of insulin/IGF-1 on vascular tone2930363940106 suggest that other mechanisms may be involved.Our laboratory recently reported that rat tail artery contractile responses to both KCl and norepinephrine in vitro were significantly attenuated by IGF-1 administered systematically in vivo 90 minutes before removing the tail arteries (Fig 2).39105 Similar data were obtained when rat tail artery rings were preincubated in vitro for 90 minutes, and L-NAME, an inhibitor of NO production, administered either in vivo or in vitro, reversed the IGF-1 attenuation of vascular contractility (Fig 3).39 We also observed in rat tail vascular strips a significant increase in IGF-1 stimulation of NO production over the same 90-minute period (Fig 4).39 This and preliminary data from our laboratory indicating that insulin and IGF-1 stimulate both rapid (presumably constitutively regulated NO production/cNOS) and more delayed NO production (iNOS) in cultured VSMCs suggest that these hormones stimulate VSMC and endothelial cell production of NO (Fig 5). One investigative team reported that insulin acutely increases intact endothelial cell [Ca2+]i and relaxes VSMCs in an L-NMMA–dependent manner.27 Insulin-mediated and IGF-1–mediated inhibition of VSMC contraction likely occurs via stimulation of the synthesis of NO in both endothelial cells and VSMCs, which in turn increases the VSMC production of cGMP.373839 Alternatively, the increased NO could reduce VSMC [Ca2+]i56738107 by stimulating the Na+,K+-ATPase pump108109 or by directly activating Ca2+-dependent K+ channels110 in VSMCs, which indirectly causes decreased Ca2+ influx via voltage-operated channels (Fig 6).3741110Effects of Insulin and IGF-1 on VSMC Cation MetabolismOne mechanism by which insulin and IGF-1 attenuate vascular contractility is through effects on VSMC divalent cation metabolism (Fig 6).156716242526273738396869107108109110 These hormones reduce Ca2+ influx into VSMCs by attenuating both voltage- and receptor-operated Ca2+ channels in conjunction with reductions in VSMC contractile responses, as measured by VSMC video-imaging techniques.567152627 Another mechanism by which insulin and IGF-1 may modulate VSMC [Ca2+]i, and thus vascular contractility, is through stimulation of the Na+,K+-ATPase pump, which would reduce [Ca2+]i via changes in Na+-Ca2+ exchange.111 Insulin and IGF-1 stimulate Na+,K+-ATPase activity (primarily its catalytic ouabain-sensitive α-subunits) in various tissues, including VSMCs (Fig 7).38108 There is evidence that this stimulation occurs by increases in message expression of new catalytic pump subunits,108 secondary to mass action effects of Na+ (via activation of Na+-H+ exchange),38112 by modification of the enzyme's affinity for ATP, Na+, and K+,113 or by increasing translocation of preformed Na+,K+-ATPase molecules to the plasma membrane.38114115 Recently observed effects of insulin and IGF-1 to increase VSMC glucose transport3841116 may also contribute to regulation of the pump. Since VSMC Na+,K+-ATPase stimulates the transport of Na+ and K+ ions against concentration gradients, energy must be supplied in the form of ATP hydrolysis.117 Thus, the Na+,K+-ATPase pump is a major consumer of ATP in VSMCs.117118 ATP generated by aerobic glycolysis is preferentially used for this process,117118 suggesting that insulin/IGF-1–mediated glucose transport, and thus intracellular availability of glucose, is a potentially important mechanism by which hormones stimulate pump activity in VSMCs (Fig 6).NO produced by endothelial cells and VSMCs also regulates the Na+ pump.109 Incubation of endothelium-denuded aorta with NO or an NO donor, nitroprusside, caused a time-dependent increase in ouabain-sensitive 86Rb uptake, perhaps by stimulating Na+-H+ exchange.109 This NO-mediated stimulator of the pump could, in part, explain the NO-induced hyperpolarization of VSMCs.119 Studies by several groups109120121 suggest that insulin-mediated NO stimulation of the pump is mediated through activation of soluble guanylate cyclase and increases in cGMP. Insulin acutely increases cGMP production by cultured human VSMCs120 and reduces contraction of isolated VSMCs,715 a phenomenon blocked by L-NMMA.121 Furthermore, in rat cardiomyocytes, insulin potentates cytokine-induced NO release by increasing l-arginine uptake.122 Unpublished data from our laboratory indicate that both cNOS and nNOS are present in VSMCs and that there are both rapid and delayed releases of NO induced by insulin/IGF. The slower production of NO occurs over hours and is inhibited by dexamethasone, cycloheximide, and aminoguanidine, suggesting transcription and translation of iNOS (Fig 5). Insulin/IGF-1 may also stimulate the Na+,K+-ATPase pump by increasing VSMC [Mg2+]i, a process that appears defective in states of insulin resistance/deficiency.38Activation of the Sympathetic Nervous System by Insulin/IGF-1In addition to its vasodilatory effects, acute hyperinsulinemia induces systemic sympathetic activation measured by direct muscle sympathetic nerve activity measurements.4123124 This sympathetic nervous system activation is due to hyperinsulinemia per se and not to associated glucose infusion in clamp procedures.124 However, there are data suggesting that acute hyperinsulinemia-induced sympathetic activation is due to a baroreflex-mediated response to a slight insulin-induced vasodilation. This notion, which couples sympathetic activation and vasodilation, is supported by the observation that in autonomous failure, insulin causes hypotension.125 Nevertheless, there is evidence that insulin may chronically stimulate the SNS through central nervous system actions, as extensively reviewed.42Actions of Insulin/IGF-1 Regulation of Carbohydrate Metabolism in Cardiovascular TissueInsulin/IGF-1 regulates glucose transport in cardiovascular tissue138126127128 and in classical insulin-sensitive tissue, such as skeletal muscle and fat.126 Facilitative glucose transport depends on the functionality of a family of transmembrane proteins, which include GLUT-1 and GLUT-4, which are expressed in mammalian heart82126 VSMCs.3841126127128129 GLUT-1 is present on the cell membrane and is therefore responsible for basal glucose uptake, and GLUT-4 is associated with intracellular membranes, is mobilized by insulin/IGF-1 to the cell surface, and is responsible for the increases in glucose uptake under insulin/IGF-1 stimulation.126 Insulin stimulates GLUT-4 translocation to rat myocardial sarcolemma129130 and glucose transport.131 Hearts from diabetic animals have a decreased rate of glucose uptake132 and decreases in GLUT-1 and GLUT-4 expression and levels.133134 Furthermore, insulin treatment in insulinopenic diabetic rats normalizes glucose uptake as well as a return to tissue GLUT-4 expression and protein levels.134 These observations underscore the importance of insulin in regulating myocardial carbohydrate metabolism.IGF-1 and insulin increase glucose uptake in cultured VSMCs.38116 This increase in glucose transport occurs via a protein synthesis–independent pathway. As GLUT-4 is expressed in VSMCs,38 this stimulation appears to be accomplished by translocation of this insulin/IGF-1–sensitive glucose transporter.38 The maximal velocity for glucose transport is altered in VSMCs from insulin-resistant Zucker obese rats.116 This observation is relevant to actions of insulin/IGF in regulating vascular tone, because glucose transport in VSMCs appears to be critical for regulation of vascular contractility118 and cation transport.117 Thus, decreased IGF-1/insulin–mediated glucose in VSMCs could contribute to the decreased ability of IGF-1/insulin to stimulate vascular NO production14 and the Na+,K+-ATPase pump38108109 and to attenuate VSMC [Ca2+]i and contractile responses to vasoconstrictors.1638116Role of Insulin Resistance and/or Hyperinsulinemia in Pathogenesis of HypertensionInvestigations have shown an association between insulin resistance, hyperinsulinemia, and hypertension.4243444546474849505152555657585960616263646566676869 One notion that has developed is that the diminished response to insulin's action on glucose uptake in skeletal muscle and fat (classical sites of insulin action) leads to compensatory hyperinsulinemia, which, in turn, elicits responses of the kidneys, SNS, and the cardiovascular system.8586878889909192939495 This notion presupposes that insulin resistance is selective to specific tissues (ie, skeletal muscle and fat), whereas other tissues, such as the kidneys and SNS, retain their sensitivity to insulin.4294 However, there is evidence that insulin, per se, does not contribute to the pathogenesis of hypertension.94 Acutely, insulin is a vasodilator in most vascular beds,12341617181928293031323334353637383940 and long-term insulin infusion in dogs reduces pressor responses and lowers blood pressure.9495 Furthermore, blood pressure is generally not elevated in persons with insulinomas, and some epidemiological studies have failed to confirm a relationship between plasma insulin concentrations and hypertension,94135136 particularly in Pima Indians and Mexican-Americans.135136 Thus, accumulative data indicate that insulin resistance and hyperinsulinemia alone are not sufficient to cause hypertension. However, this does not negate the notion that insulin resistance, under some circumstances, contributes to the pathogenesis of hypertension similar to other pathophysiological factors, such as salt, the SNS, and the renin-angiotensin system.Investigators have proposed the hypothesis that abnormalities in skeletal muscle vascular and sympathetic regulation/interaction underlie insulin resistance in essential hypertension and obesity.3240426165666784137 Accordingly, primary abnormalities could relate to hyperinsulinemia, activating the SNS, or to exaggerated activations of the SNS, causing insulin resistance. Several investigators32616592138 have conducted studies suggesting that insulin evokes an exaggerated muscle sympathetic response in essential hypertension, obesity, and type II diabetes, which is mediated by mechanisms involving the central nervous system. However, in carefully conducted studies, hyperinsulinemic type II diabetic patients displayed normal SNS responses to lower body negative pressure.139 Furthermore, insulin resistant/hyperinsulinemic obese persons have been reported to be normally responsive to sympathetic stimuli.140 In the studies conducted by Tack et al,139 SNS responses to hyperinsulinemia were not impaired. Thus, the role of SNS/hyperinsulinemia interactions in the pathogenesis of hypertension in these hyperinsulinemic conditions remains unresolved.There is also evidence that insulin and Ang II may interact to have hypertensinogenic actions. For example, euglycemic hyperinsulinemia has been reported to have a dose-related effect, ie, an increase in the blood pressure rise caused by Ang I infusion; insulin has been reported to increase mesangial cell responsiveness to Ang II141 ; and hyperinsulinemic/insulin-resistant Zucker obese rats have increased blood pressure sensitivity to Ang II.90 Recent studies conducted by Brands et al142 showed that ACE inhibition prevented the hypertension from developing insulin-induced hypertension, suggesting that a functional renin-angiotensin system is necessary for complete expression of insulin-induced hypertension in rats. The relevance of these observations in humans needs further exploration because many insulin-resistant hyperinsulinemic persons have low levels of plasma renin activity.1There is also considerable evidence that altered cardiovascular divalent cation metabolism may explain the relationship between insulin resistance and hypertension. Increased vascular resistance and vasoconstrictor responses to agonists occur in both insulinopenic and insulin-resistant conditions.1 In both of these conditions there are abnormalities in cardiovascular [Ca2+ ]i metabolism.143 For example, agonist-induced VSMC [Ca2+]i and vascular reactivity responses are exaggerated in the hyperinsulinemic/insulin-resistant Zucker rat.1690 Increased VSMC [Ca2+]i may be related, in part, to diminished activity of the membrane Na+,K+-ATPase pump (Fig 6).3738 Decreased activity of this pump has been observed in both insulin-resistant144145 and insulin-deficient states143146 in tissues in which glucose is modulated by insulin (ie, skeletal, cardiac, and vascular smooth muscle tissue). An isoform-specific reduction in the expression of the aortic α2 catalytic subunit of the pump,147 in conjunction with increased [Ca2+]i148 and vascular tone, has been observed in insulin-resistant spontaneously hypertensive rats.149 Elevated [Ca2+]i is associated with attenuated insulin-stimulated glucose transport in several insulin-sensitive tissues.150 Thus, altered VSMC [Ca2+]i regulatory mechanisms may represent a fundamental abnormality associated with both impaired VSMC insulin and IGF-1 action, increased VSMC [Ca2+]i, and enhanced vascular resistance.37384168Increased peripheral vascular resistance characteristic of hypertension associated with insulin resistance may also be related to abnormalities of intracellular [Mg2+]i metabolism.138151 Insulin increases cellular uptake of Mg2+,151 and in conditions of decreased cellular insulin action (ie, type I and type II diabetes), there is a reduction in [Mg2+]i.151152 Depletion of tissue [Mg2+]i contributes to decreased insulin-stimulated glucose uptake.152 Although the mechanism by which [Mg2+]i depletion leads to insulin resistance is unclear, decreases in [Mg2+]i may lead to an increase in [Ca2+]i,153 which has been shown to relate to insulin resistance.150 Furthermore, oral Mg2+ supplementation has been shown to improve insulin-mediated glucose uptake in type II diabetic patients.154 Recently, using nuclear magnetic techniques, our investigative group has shown that IGF-1, like insulin, increases tissue [Mg2+]i levels (Fig 6). These collective observations suggest that both elevations in [Ca2+]i and depletions in [Mg2+]i may contribute to resistance to vascular vasodilatory actions of insulin/IGF-1, leading to enhanced peripheral vascular resistance associated with insulin resistance.373839404168Data have been garnered suggesting that the ability of insulin and IGF-1 to modulate the vascular NO system may be decreased in states of insulin resistance, thereby contributing to the increased incidence of hypertension in obese persons, type II diabetic patients, and some persons with essential hypertension.3738394041 As previously noted, both insulin and IGF-1 stimulate production of NO by both endothelial cells and VSMCs,131437383940 by stimulating both cNOS and iNOS activity (Fig 6). Furthermore, resistance to the vascular actions of insulin and IGF-1 is induced by the NO synthesis inhibitor L-NMMA.3738394097106 Acute reduction of leg blood flow with L-NMMA results in a 25% reduction in insulin-mediated leg glucose uptake, an effect independent of changes in insulin or glucose concentrations or adrenergic interaction.40 We have recently observed that hyperglycemia tends to attenuate both IGF-1–stimulated and estradiol-stimulated NO production in cultured endothelial cells (Fig 1). Thus, impairment of insulin/IGF-1–mediated vasodilation in states of insulin resistance could contribute to both elevated blood pressures and reduced glucose uptake in insulin-sensitive tissues in these patients.Role of Hyperinsulinemia/Insulin Resistance in Pathogenesis of Atherosclerotic DiseaseFour large prospective studies have shown that hyperinsulinemia is a predictor of CAD,434483155 with a few prospective reports not demonstrating such a relationship.156157 The greatest association of hyperinsulinemia with CAD has been found in Finland, in a population with a very high frequency of CAD.43 A recent report83 of a prospective investigation of 2103 men from Quebec clearly showed that high fasting insulin concentrations are an independent predictor of CAD. This important study used an insulin assay without cross-reactivity with proinsulin, thus avoiding that confounding influence.54 Several recent studies have shown a relationship between carotid wall atherosclerotic lesions and insulin levels/resistance.7576777880 Thus, hyperinsulinemia does appear to be a predictor for the development of CAD and stroke.We have observed the role of cyclic and sustained stretch in VSMC IGF-1 and NO expression. Cyclic stretch causes VSMC thymidine uptake and IGF-1 and NO production secretion. Addition of IGF-1 antibodies to the growth medium inhibits stretch-induced growth (Fig 7). However, the role of PDGF in VSMC autocrine growth cannot be overlooked, since other investigators have demonstrated that similar stretch paradigms induced PDGF expression/secretion. Blocking PDGF action with anti-PDGF antibodies attenuates, but does not abolish, stretch-induced growth. Given that PDGF increases VSMC IGF-1 expression, it is becoming increasingly clear that autocrine VSMC growth is under the control of several locally produced factors, including IGF-1 and NO (ie, stimulation/inhibition). Thus, it is likely that many of the growth and atherosclerotic effects that have been attributed to insulin are mediated through an IGF-1 receptor either directly by IGF-1 or indirectly by high concentrations of insulin.Selected Abbreviations and AcronymsAng I, Ang II=angiotensin I and IICAD=coronary artery diseasecNOS, iNOS=constitutive, inducible NOSIGF-1=insulin-like growth factor IL-NAME=NG-nitro-l-arginine methyl esterL-NMMA=NG-monomethyl-l-arginineNO=nitric oxideNOS=NO synthasePDGF=platelet-derived growth factorSMBF=skeletal muscle blood flowSNS=sympathetic nervous systemVSMC=vascular smooth muscle cellDownload figureDownload PowerPoint Figure 1. Effects of estradiol (bE2) and IGF-1 on endothelial cell NO production under normal (5 mmol/L) and high (20 mmol/L) glucose concentration.Download figureDownload PowerPoint Figure 2. A, In vitro contractility 90 minutes after in vivo IGF-1. Responses to both KCl (top) and norepinephrine (bottom) were attenuated. B, Dose responses to KCl (top) and norepinephrine (bottom) 90 minutes after in vitro preincubation with 100 nmol/L IGF-1.39 *indicates P<.001.Download figureDownload PowerPoint Figure 3. Coincubation with L-NAME (100 μmol/L) and IGF-1 (100 nmol/L) for 90 minutes reversed the IGF-1 induced inhibition for both KCl and for norepinephrine.39Download figureDownload PowerPoint Figure 4. Nitrite/nitrate accumulation as an index of NO production in control and IGF-1–exposed aortas after 90 minutes of incubation.39 *indicates P<.05.Download figureDownload PowerPoint Figure 5. Effects of insulin and IGF-1 on VSMC [Ca2+]i and [Mg2+]i and associated VSMC contractility as mediated through modulation of both endothelial and VSMC NO production. AII indicates Ang II.Download figureDownload PowerPoint Figure 6. Mechanisms regulating divalent cation metabolism and contraction in vascular smooth muscle cells and proposed targets of insulin and IGF-1 action. Pivotal steps in regulation of divalent cation metabolism are indicated by circled numbers.1 IP3 indicates inositol tris-phosphate; DAG, diacylglycerol.Download figureDownload PowerPoint Figure 7. Effects of IGF-1 antibody (anti–IGF-1) stretch-induced increases in DNA synthesis rate. In association with cyclic stretch, we have observed increases in VSMC IGF-1 and NO in conjunction with thymidine incorporation.41This work was supported by a VA research grant, National Institutes of Health grant R01-HD-24497-06, and the American Heart Association. The author wishes to thank Paddy McGowan for preparation of this manuscript.This presentation and publication is one of a long-standing Clinical Conference Series supported by an educational grant-in-aid from the Health Sciences Service of Merck & Co and Astra-Merck Pharmaceuticals.FootnotesCorrespondence to James R. Sowers, MD, Director, Division of Endocrinology, Metabolism, and Hypertension, Wayne State University School of Medicine, 4201 St Antoine, UHC-4H, Detroit, MI 48201. E-mail [email protected] References 1 Sowers JR, Epstein M. Diabetes mellitus and associated hypertension, vascular disease, and nephropathy: an update. Hypertension.1995; 26:869-879.CrossrefMedlineGoogle Scholar2 Yagi S, Takata S, Kiyokawa H, Yamamoto M, Noto Y, Ikeda M, Hattori N. Effects of insulin on vasoconstrictive responses to norepinephrine and angiotensin II in rabbit femoral artery and vein. Diabetes.1988; 37:1064-1067.CrossrefMedlineGoogle Scholar3 Reddy S, Shehin S, Sowers JR. 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