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Coronary arteriolar vasoconstriction to angiotensin II is augmented in prediabetic metabolic syndrome via activation of AT₁ receptors

¹Department of Medical Physiology, Cardiovascular Research Institute, College of Medicine, Texas A&M University System Health Science Center, Temple; and ²Department of Integrative Physiology, University of North Texas Health Science Center, Fort Worth, Texas; and ³Department of Physiology, ⁴Department of Anesthesiology, and ⁵Department of Surgery, Louisiana State University Health Sciences Center, New Orleans, Louisiana

Submitted 24 September 2004 ; accepted in final form 10 January 2005

The metabolic syndrome is associated with activation of the renin-angiotensin system. However, whether the coronary vascular response to ANG II is altered under this condition is unknown. Experiments were conducted in control and chronically high-fat-fed dogs with the prediabetic metabolic syndrome both in vitro (isolated coronary arterioles, 60–110 µm) and in vivo (anesthetized and conscious). We found that plasma renin activity and ANG II levels are elevated in high-fat-fed dogs and that this increase in ANG II is associated with a significant increase in ANG II-mediated coronary vasoconstriction in isolated coronary arterioles and in anesthetized open-chest dogs. The vasoconstriction to ANG II is abolished by ANG II type 1 (AT₁) receptor blockade. In conscious chronically instrumented dogs, AT₁ receptor blockade with telmisartan improved the balance between coronary blood flow and myocardial oxygen consumption in the high-fat-fed dogs but not in normal control dogs, i.e., the relationship between coronary venous PO₂ and myocardial oxygen consumption was shifted upward, toward normal control values. Quantitative assessment of coronary arteriolar AT₁ and ANG II type 2 (AT₂) receptor mRNA levels by real-time PCR revealed no significant difference between normal control and high-fat-fed dogs; however, Western blot analysis showed a significant increase in AT₁ receptor protein level with no change in AT₂ receptor protein density. These findings indicate that AT₁ receptor-mediated coronary constriction is augmented in the prediabetic metabolic syndrome and contributes to impaired control of coronary blood flow via increases in circulating ANG II and/or coronary arteriolar AT₁ receptor density.

obesity; microcirculation; blood flow; exercise

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