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

Abstract

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 microm) 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.

Impaired coronary flow reserve evaluated by echocardiography is associated with increased aortic stiffness in patients with metabolic syndrome: an observational study

“…Exact mechanisms underlying impaired pharmacologic coronary vasodilation in MetS have not been clearly defined, but are likely related to altered functional expression of receptors and ion channels, endothelial and vascular smooth muscle function, paracrine and neuroendocrine influences, structural remodeling of coronary arterioles and/or microvascular rarefaction (9). Coronary vasomotor dysfunction in the MetS is related to chronic activation of the renin-angiotensin and sympathetic nervous system that leads to augmented angiotensin II tip 1 and alpha 1-adrenoceptor mediated coronary vasoconstriction (5,32).…”

“…These factors contribute to a high incidence of cardiovascular disease in patients with MetS (2,3). MetS impairs the ability of the coronary circulation to regulate vascular resistance and balance myocardial oxygen supply and demand (4,5). Coronary microvascular dysfunction in MetS is evidenced by reduced coronary venous PO 2 , diminished vasodilation to endothelial-dependent and independent agonist and altered functional and reactive hyperemia (4)(5)(6)(7)(8)(9).…”

“…MetS impairs the ability of the coronary circulation to regulate vascular resistance and balance myocardial oxygen supply and demand (4,5). Coronary microvascular dysfunction in MetS is evidenced by reduced coronary venous PO 2 , diminished vasodilation to endothelial-dependent and independent agonist and altered functional and reactive hyperemia (4)(5)(6)(7)(8)(9). Alterations in coronary microvascular function could contributed to the increased cardiovascular morbidity and mortality observed in patients with MetS (10).…”

Perioperative management of the severely obese patient: a selective pathophysiological review

“…This enhanced response is partly mediated through upregulation of angiotensin receptors in the coronary circulation. 21 It is unclear if this increased vasoconstrictor potential has clinical implications for the perioperative use of agents with a predominant alpha-1 receptor agonist effect, e.g., phenylephrine. It is apparent, however, that there are abnormalities of coronary flow and flow reserve in severely obese patients that may not be evident on angiography but may become relevant during the perioperative period in response to perioperative stress or hypoxia.…”

Angiotensin II Type 1 Receptor Blockade Prevents Alcoholic Cardiomyopathy

“…The cDNA produced was amplified by polymerase chain reaction with the published primers for canine AT 1 (210 bp) and AT 2 (180 bp) receptor DNA fragments. 16 GAPDH was coamplified as an internal control. 14,16 Western Blot.…”