Published online before print October 21, 2002, doi: 10.1161/01.HYP.0000038359.74702.B4
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(Hypertension. 2002;40:e12.)
© 2002 American Heart Association, Inc.
Letters to the Editor |
Endothelin Antagonism and Insulin’s Vascular Effects
Division of Cardiac Surgery, Toronto, Canada, E-mail subodh.verma@sympatico.ca
To the Editor:
I read with interest the paper entitled "Enhanced Endothelin Activity Prevents Vasodilation to Insulin in Insulin Resistance."1 The authors report that insulin-mediated vasodilatation is absent in mesenteric arteries from insulin-resistant rats, confirming the presence of vascular insulin resistance in this model.2,3 Furthermore, the authors provide evidence that vascular insulin resistance in this model is secondary to increased endothelin-1 (ET-1) action, because ETA receptor blockade restored insulin-mediated vasorelaxation.
We are surprised that the authors omitted discussion of 3 key papers, highly relevant to the material published in their paper. A recent paper in Hypertension4 defined the dual nature of insulin to synchronously stimulate ET-1 and nitric oxide (NO) and demonstrated that, at subthreshold concentrations of insulin, the absence of insulin-mediated vasorelaxation is due to simultaneous stimulation of ET-1. Both in vivo and in vitro studies were done in control rat aortae, which suggested that insulin-mediated vasorelaxation could be augmented during ET receptor blockade, whether physiological or pharmacological concentrations of insulin are employed. Miller et al1 do not discuss the lack of effect of ET blockade on insulin-mediated vasorelaxation in control mesenteric arteries; neither do they discuss this paper addressing the functional interaction between insulin, ET-1, and NO in rat aortae.
We are also puzzled that the authors do not address an area of controversy surrounding the vascular actions of insulin in mesenteric arteries. We have previously demonstrated that insulin-mediated exaggeration of norepinephrine responses in perfused mesenteric arteries is further augmented in insulin-resistant, fructose-hypertensive rats.5 These observations are in opposition to the results presented by Miller et al. Additionally, previous studies in mesenteric arteries from fructose-hypertensive rats have demonstrated an augmented contractile response to ET-1,6 and this should be discussed in the context of the data presented.1
Finally, the interrelationship between insulin, NO, and ET-1 has now been demonstrated clinically. In a recent paper in Circulation,7 the relative contributions of NO and ET-1 to forearm blood flow were determined under control conditions and following euglycemia hyperinsulinemia. ET blockade without concurrent hyperinsulinemia had little effect on forearm blood flow but allowed expression of a marked vasodilatory effect of insulin. This augmented flow was entirely blocked by the subsequent addition of a nitric oxide synthase inhibitor, confirming the relevance of NO in insulin-induced vasodilatation.
The findings to date clearly suggest that insulin, at doses within and above the physiological range, can engender the production of ET-1, with effects on vascular function and insulin sensitivity. Recent evidence also supports the concept that ET antagonism may prevent diabetes-induced cardiovascular dysfunction8,9 and may attenuate endothelial dysfunction following coronary artery bypass graft surgery in diabetes.10 Understanding the functional relationship between insulin, ET-1, and NO may uncover strategies aimed at improving vascular function in insulin resistance.
References
1. Miller AW, Tulbert C, Puskar M, Busiia DW. Enhanced endothelin activity prevents vasodilation to insulin in insulin resistance. Hypertension. 2002; 40: 78–82.
2. Verma S, Bhanot S, Yao L, McNeill JH. Vascular insulin resistance in fructose-hypertensive rats. Eur J Pharmacol. 1997; 322: R1–R2.[CrossRef][Medline] [Order article via Infotrieve]
3. Mather K, Anderson TJ, Verma S. Insulin action in the vasculature: physiology and pathophysiology. J Vasc Res. 2001; 38: 415–422.[CrossRef][Medline] [Order article via Infotrieve]
4. Verma S, Yao L, Stewart DJ, Dumont AS, Anderson TJ, McNeill JH. Endothelin antagonism uncovers insulin-mediated vasorelaxation in vitro and in vivo. Hypertension. 2001; 37: 328–333.
5. Verma S, McNeill JH. Insulin resistance and hypertension: pharmacological and mechanistic studies. Can J Diabetes Care. 1999; 23 (suppl 2): 23–42.
6. Verma S, Skarsgard P, Bhanot S, Yao L, Laher I, McNeill JH. Reactivity of mesenteric arteries from fructose hypertensive rats to endothelin-1. Am J Hypertens. 1997; 10 (pt 1): 1010–1019.[CrossRef][Medline] [Order article via Infotrieve]
7. Cardillo C, Nambi SS, Kilcoyne CM, Choucair WK, Katz A, Quon MJ, Panza JA. Insulin stimulates both endothelin and nitric oxide activity in the human forearm. Circulation. 1999; 100: 820–825.
8. Arikawa E, Verma S, Dumont AS, McNeill JH. Chronic bosentan treatment improves renal artery vascular function in diabetes. J Hypertens. 2001; 19: 803–812.[CrossRef][Medline] [Order article via Infotrieve]
9. Verma S, Arikawa E, McNeill JH. Long-term endothelin receptor blockade improves cardiovascular function in diabetes. Am J Hypertens. 2001; 14 (pt 1): 679–687.[CrossRef][Medline] [Order article via Infotrieve]
10. Verma S, Maitland A, Weisel RD, Fedak PW, Li SH, Mickle DA, Li RK, Ko L, Rao V. Increased endothelin-1 production in diabetic patients after cardioplegic arrest and reperfusion impairs coronary vascular reactivity: reversal by means of endothelin antagonism. J Thorac Cardiovasc Surg. 2002; 123: 1114–1119.
Response: Endothelin Antagonism and Insulin’s Vascular Effects
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, E-mail amiller@wfubmc.edu
We appreciate the interest of Dr Verma in our recently published paper, "Enhanced Endothelin Activity Prevents Vasodilation to Insulin in Insulin Resistance."1 However, we believe that his comments concerning our omission of references are misdirected. First, some of the references that he mentions are inappropriate for citation in our paper because they are not germane to the subject matter, or they represent redundant information available from other papers. Second, the space limitations of Hypertension mandate that we make critical choices concerning which publications we discuss. We should also note that nowhere in his letter does Dr Verma challenge the conclusions of our study.
In our experiments, we studied small fourth-order arteries, which are considered resistance vessels in the mesenteric circulation. However, in the first2 and third3 papers that Dr. Verma mentions, data included were only from conduit arteries. Given the differences in the regulation of dilator mechanisms between resistance and conduit arteries, we do not believe that inclusion of these references is justified in our paper.
Moreover, we evaluated the role of endothelium in concentration-dependent dilator response to insulin. In contrast, the first2 study that Dr Verma mentions used only a single concentration of insulin in examining the norepinephrine concentration response relationship in the aorta. Thus, it appears inappropriate to include this citation in our Discussion. On the other hand, we cited another paper with similar results, which was performed in the mesenteric circulation.4
Dr Verma, in his third paragraph, complains that we did not cite a specific paper in which he shows in mesenteric arteries from fructose-fed rats that the response to norepinephrine is augmented by insulin.5 We admit that we did not initially locate this paper, published in a supplement to the Canadian Journal of Diabetes Care, until after receiving Dr Verma’s letter. However, we discussed 3 other papers6–8 showing similar results in arteries from both fructose-fed and Zucker obese rat models. Thus, we believe that we adequately covered this topic.
Finally, Dr Verma rebukes us for not referencing his paper, which showed that the response to endothelin-1 was increased in the superior mesenteric artery of the fructose-fed rat.9 However, we did not believe that citation of his paper was warranted because we have shown (and referenced) similar results in the appropriate vascular segment from the mesentery in a previous paper.10
In summary, we agree with Dr Verma that endothelin is an important component in the vascular actions of insulin. However, we strongly believe that the discussion of the relevant literature in our manuscript was appropriately inclusive and balanced and that the citations discussed adhered to the stated limitations of the journal and accepted academic standards.
References
1. Miller AW, Tulbert C, Puskar M, Busija DW. Enhanced endothelin activity prevents vasodilation to insulin in insulin resistance. Hypertension. 2002; 40: 78–82.
2. Verma S, Yao L, Stewart DJ, Dumont AS, Anderson TJ, McNeill JH. Endothelin antagonism uncovers insulin-mediated vasorelaxation in vitro and in vivo. Hypertension. 2001; 37: 328–333.
3. Cardillo C, Nambi SS, Kilcoyne CM, Choucair WK, Katz A, Quon MJ, Panza JA. Insulin stimulates both endothelin and nitric oxide activity in the human forearm. Circulation. 1999; 100: 820–825.
4. Misurski D, Wu S, McNeill R, Wilson T, Gopalakrishnan V. Insulin-induced biphasic responses in rat mesenteric vascular bed: role of endothelin. Hypertension. 2001; 37: 1298–1302.
5. Verma S, McNeill JH. Insulin resistance and hypertension: pharmacological and mechanistic studies. Can J Diabetes Care. 1999; 23 (suppl 2): 23–42.
6. Walsh MF, Ali SS, Sowers JR. Vascular insulin/insulin like growth factor-1 resistance in female obese Zucker rats. Metabolism. 2001; 5: 607–612.
7. Walker AB, Dores J, Buckingham RE, Savage MW, Williams G. Impaired insulin induced attenuation of noradrenaline-mediated vasoconstriction in insulin-resistant obese Zucker rats. Clin Sci. 1997; 93: 235–241.[Medline] [Order article via Infotrieve]
8. Verma S, Bhanot S, Yao L, McNeill JH. Vascular insulin resistance in fructose hypertensive rats. Eur J Pharmacol. 1997; 322: R1–R2.[CrossRef][Medline] [Order article via Infotrieve]
9. Verma S, Skarsgard P, Bhanot S, Yao L, Laher I, McNeill JH. Reactivity of mesenteric arteries from fructose hypertensive rats to endothelin-1. Am J Hypertension. 1997; 10: 1010–1019.[CrossRef][Medline] [Order article via Infotrieve]
10. Katakam PV, Pollock JS, Pollock DM, Ujhelyi MR, Miller AW. Enhanced endothelin-1 response in small mesenteric arteries of insulin-resistant rats. Am J Physiol: Heart Circ Physiol. 2001; 280: H522–H527.
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