(Hypertension. 2001;37:328.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Endothelin Antagonism Uncovers Insulin-Mediated Vasorelaxation In Vitro and In Vivo
From the Division of Pharmacology and Toxicology (L.Y., J.H.M.), Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, Canada; the Division of Cardiology (S.V., A.S.D., T.J.A.), Faculty of Medicine, The University of Calgary, Calgary, Canada; and the Division of Cardiology (S.V., D.J.S.), St Michael’s Hospital, The University of Toronto, Toronto, Canada.
Correspondence to Subodh Verma, Division of Cardiology, Foothills Hospital, 8th Floor, 1403-29th Street N.W., Calgary, AB, Canada, T2N 2T9. E-mail subodhverma{at}home.com
The endothelial actions of insulin remain an area of intense research because they relate to both insulin sensitivity and vascular tone. Physiological doses of insulin evoke endothelium-dependent vasorelaxation in humans; however, this remains a pharmacological phenomenon in rat aortas. Because insulin may stimulate the divergent production of both nitric oxide and endothelin-1, we hypothesized that the lack of insulin-induced vasorelaxation at low/subthreshold concentrations may be due to the concurrent production of endothelin-1, which in turn serves to inhibit nitric oxide-dependent, insulin-mediated dilation. To investigate this, we studied the effects of subthreshold concentrations of insulin (100 mU/L) on norepinephrine-induced contraction in rat aortas following short-term and long-term endothelin blockade. In addition, the effects of tetrahydrobiopterin inhibition (with diaminohydroxyprimidine) on norepinephrine-induced contraction in the presence of insulin and endothelin receptor blockade were investigated. Subthreshold concentrations of insulin failed to evoke vasorelaxation in rat aortas. Strikingly, short-term endothelin A/B receptor blockade with bosentan (10-2 mmol/L) uncovered insulin-mediated dilation; the percent maximum contraction and sensitivity of aortas to norepinephrine were attenuated (% maximum relaxation: bosentan+insulin 74±4%* versus bosentan 92±3%, insulin 107±5% P<0.002; pD2 values: bosentan+insulin 6.87±0.14* versus bosentan 7.40±0.15, insulin 7.63±0.11, *P<0.002). This effect was mediated through endothelin A receptors because bosentan and BQ-123 (10-2 mmol/L) attenuated norepinephrine-induced contraction to a similar degree. In addition, insulin evoked vasorelaxation in aortas isolated from rats after long-term bosentan treatment (100 mg · kg-1 · d-1, 3 weeks). The component of insulin-mediated vasorelaxation uncovered by endothelin receptor blockade was tetrahydrobiopterin-dependent because it was reversed by diaminohydroxyprimidine. These data demonstrate, for the first time, the functional interaction between insulin, endothelin-1, and tetrahydrobiopterin in modulating vascular tone in rat aortas in vitro and in vivo.
Key Words: insulin • endothelin • vasodilation • insulin resistance • hypertension • rat aorta • tetrahydrobiopterin • bosentan
This article has been cited by other articles:
 |
|
 |
|
  A. A. Lteif, A. D. Fulford, R. V. Considine, I. Gelfand, A. D. Baron, and K. J. Mather Hyperinsulinemia fails to augment ET-1 action in the skeletal muscle vascular bed in vivo in humans Am J Physiol Endocrinol Metab, December 1, 2008; 295(6): E1510 - E1517. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. G. Clark Impaired microvascular perfusion: a consequence of vascular dysfunction and a potential cause of insulin resistance in muscle Am J Physiol Endocrinol Metab, October 1, 2008; 295(4): E732 - E750. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. C. Eringa, C. D. A. Stehouwer, M. H. Roos, N. Westerhof, and P. Sipkema Selective resistance to vasoactive effects of insulin in muscle resistance arteries of obese Zucker (fa/fa) rats Am J Physiol Endocrinol Metab, November 1, 2007; 293(5): E1134 - E1139. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Muniyappa, M. Montagnani, K. K. Koh, and M. J. Quon Cardiovascular Actions of Insulin Endocr. Rev., August 1, 2007; 28(5): 463 - 491. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. A. Sarafidis and G. L. Bakris Insulin and Endothelin: An Interplay Contributing to Hypertension Development? J. Clin. Endocrinol. Metab., February 1, 2007; 92(2): 379 - 385. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. C. Eringa, C. D. A. Stehouwer, K. Walburg, A. D. Clark, G. P. van Nieuw Amerongen, N. Westerhof, and P. Sipkema Physiological Concentrations of Insulin Induce Endothelin-Dependent Vasoconstriction of Skeletal Muscle Resistance Arteries in the Presence of Tumor Necrosis Factor-{alpha} Dependence on c-Jun N-Terminal Kinase Arterioscler Thromb Vasc Biol, February 1, 2006; 26(2): 274 - 280. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Mather and S. Verma Function determines structure in the vasculature: lessons from insulin resistance Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2005; 289(2): R305 - R306. [Full Text] [PDF]
|
|
|
|
 |
|
 P. V. G. Katakam, C. D. Tulbert, J. A. Snipes, B. Erdos, A. W. Miller, and D. W. Busija Impaired insulin-induced vasodilation in small coronary arteries of Zucker obese rats is mediated by reactive oxygen species Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H854 - H860. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-C. Juan, Y.-W. Shen, Y. Chien, Y.-J. Lin, S.-F. Chang, and L.-T. Ho Insulin infusion induces endothelin-1-dependent hypertension in rats Am J Physiol Endocrinol Metab, November 1, 2004; 287(5): E948 - E954. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. C. Eringa, C. D. A. Stehouwer, G. P. van Nieuw Amerongen, L. Ouwehand, N. Westerhof, and P. Sipkema Vasoconstrictor effects of insulin in skeletal muscle arterioles are mediated by ERK1/2 activation in endothelium Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2043 - H2048. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M Gardiner, D. J. R. Nunez, P. G. Baer, K. K. Brown, and T. Bennett Regional Hemodynamic Effects of the N-(2-Benzoylphenyl)-L-tyrosine Peroxisome Proliferator-Activated Receptor-{gamma} Ligand, GI 262570 [(S)-2-(2-Benzoylphenylamino)-3-[4-[2-(5-methyl-2-phenyl-2-oxazol-4-yl)ethoxy]phenyl]propionic Acid], in Conscious Rats J. Pharmacol. Exp. Ther., September 1, 2004; 310(3): 1226 - 1233. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. He, C. Rask-Madsen, and G.L. King Mechanisms of cardiovascular complications in diabetes and potential new pharmacological therapies Eur. Heart J. Suppl., January 1, 2003; 5(suppl_B): B51 - B57. [Abstract] [PDF]
|
|
|
|
 |
|
 E. C. Eringa, C. D.A. Stehouwer, T. Merlijn, N. Westerhof, and P. Sipkema Physiological concentrations of insulin induce endothelin-mediated vasoconstriction during inhibition of NOS or PI3-kinase in skeletal muscle arterioles Cardiovasc Res, December 1, 2002; 56(3): 464 - 471. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Verma, A. W. Miller, and D. W. Busija Endothelin Antagonism and Insulin's Vascular Effects * Response: Endothelin Antagonism and Insulin's Vascular Effects Hypertension, December 1, 2002; 40 (6): e12 - e13. [Full Text] [PDF]
|
|