Effects of Insulin on Coronary Blood Flow in Anesthetized Pigs

Molinari, Claudio; Battaglia, A; Grossini, Elena; Mary, D. A. S. G.; Bona, Gianni; Scott, Eleanor M.; Vacca, Giovanni

doi:10.1159/000067203

Cited by 10 publications

(15 citation statements)

References 29 publications

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“…Paradoxically, insulin induced a dose-dependent vasoconstriction in the absence of NO, suggesting that NO accounts for most of the vasodilation. Similar insulin-induced vasoconstriction was also observed in the presence of NOS inhibition and also phosphatidylinositol 3-kinase inhibition (12,13,32,43).…”

Section: Discussionsupporting

confidence: 67%

“…Other mechanisms, such as production of endothelium-derived hyperpolarizing factor and subsequent activation of Ca 2ϩ -activated K ϩ channels, are also known to contribute to insulin-induced vasodilation (21,22,37). Acute vasoconstrictor effects of insulin are attributed mainly to endothelin-1, a vasoconstrictor peptide produced by the endothelial cells (12,13,29,30,32,33,50). However, other mechanisms of insulin-induced acute vasoconstriction are less clear.…”

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confidence: 99%

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Impaired insulin-induced vasodilation in small coronary arteries of Zucker obese rats is mediated by reactive oxygen species

Katakam

Tulbert²,

Snipes³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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Impaired insulin-induced vasodilation in small coronary arteries of Zucker obese rats is mediated by reactive oxygen species. Am J Physiol Heart Circ Physiol 288: H854 -H860, 2005; doi:10.1152/ajpheart.00715. 2004.-Insulin resistance (IR) and associated hyperinsulinemia are major risk factors for coronary artery disease. Mechanisms linking hyperinsulinemia to coronary vascular dysfunction in IR are unclear. We evaluated insulin-induced vasodilation in isolated small coronary arteries (SCA; ϳ225 m) of Zucker obese (ZO) and control Zucker lean (ZL) rats. Vascular responses to insulin (0.1-100 ng/ml), ACh (10 Ϫ9 -10 Ϫ5 mol/l), and sodium nitroprusside (10 Ϫ8 -10 Ϫ4 mol/l) were assessed in SCA by measurement of intraluminal diameter using videomicroscopy. Insulin-induced dilation was decreased in ZO compared with ZL rats, whereas ACh and sodium nitroprusside elicited similar vasodilations. Pretreatment of arteries with SOD (200 U/ml), a scavenger of reactive oxygen species (ROS), restored the vasorelaxation response to insulin in ZO arteries, whereas ZL arteries were unaffected. Pretreatment of SCA with N-nitro-L-arginine methyl ester (100 mol/l), an inhibitor of endothelial nitric oxide (NO) synthase (eNOS), elicited a vasoconstrictor response to insulin that was greater in ZO than in ZL rats. This vasoconstrictor response was reversed to vasodilation in ZO and ZL rats by cotreatment of the SCA with SOD or apocynin (10 mol/l), a specific inhibitor of vascular NADPH oxidase. Lucigenin-enhanced chemiluminescence showed increased basal ROS levels as well as insulin (330 ng/ml)-stimulated production of ROS in ZO arteries that was sensitive to inhibition by apocynin. Western blot analysis revealed increased eNOS expression in ZO rats, whereas Mn SOD and Cu,Zn SOD expression were similar to ZL rats. Thus IR in ZO rats leads to decreased insulin-induced vasodilation, probably as a result of increased production of ROS by vascular NADPH oxidase, leading to decreased NO bioavailability, despite a compensatory increase in eNOS expression.superoxide; NADPH oxidase; hyperinsulinemia; endothelial nitric oxide synthase INSULIN RESISTANCE (IR) and accompanying hyperinsulinemia have been identified as independent risk factors for hypertension, coronary artery disease, and stroke (7, 39, 46, 48a). Vascular dysfunction in IR and type 2 diabetes [non-insulindependent diabetes mellitus (NIDDM)] has been characterized as a combination of an impaired ability to vasodilate and/or an enhanced sensitivity to vasoconstrictor agonists. Importantly, reactive oxygen species (ROS) and insulin are recognized as two key players in the pathogenesis of vascular dysfunction in IR and NIDDM (4,6,24,27,35,46). 1) ROS decreases the bioavailability of nitric oxide (NO) and impairs vasodilation. ROS, such as superoxide and its reactive nitrogen derivative peroxynitrite, are known vasoconstrictors in many vascular beds (34,36,38,42,51). 2) Insulin exhibits vasodilator and vasoconstrictor actions. Acute vasodilator effects of insulin have been shown to be...

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Section: Discussionsupporting

confidence: 67%

mentioning

confidence: 99%

Impaired insulin-induced vasodilation in small coronary arteries of Zucker obese rats is mediated by reactive oxygen species

Katakam

Tulbert²,

Snipes³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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“…The dose of 1 mg kg –1 of phentolamine has been shown in the same experimental model to abolish the reflex coronary vasoconstriction caused by distension of the gallbladder [27] and the reflex renal and iliac vasoconstriction caused by distension of the stomach [28] and has previously been used to block coronary, renal and iliac α-adrenergic receptors [see, for example, ref. [21, 22,29,30,31]. Similar doses of the blocking agents have been used in anesthetized pigs by other authors [32].…”

Section: Discussionmentioning

confidence: 98%

Human Placental Lactogen Decreases Regional Blood Flow in Anesthetized Pigs

Grossini

Molinari²,

Battaglia³

et al. 2006

J Vasc Res

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In 22 pigs anesthetized with sodium pentobarbitone, changes in blood flow caused by infusion of human placental lactogen into the left renal, external iliac, and anterior descending coronary arteries were assessed using electromagnetic flowmeters. In 17 pigs, infusion of human placental lactogen whilst keeping the heart rate and arterial pressure constant decreased coronary, renal and iliac flow. In 5 additional pigs, increasing the dose of human placental lactogen produced a dose-related decrease in regional blood flow. The mechanisms of the above response were studied in 15 of the 17 pigs by repeating the experiment of infusion. The human placental lactogen-induced decrease in regional blood flow was not affected by blockade of cholinergic receptors (5 pigs) or of α-adrenergic receptors (5 pigs), but it was abolished by blockade of β₂-adrenergic receptors (5 pigs). The present study showed that intra-arterial infusion of human placental lactogen primarily decreased coronary, renal and iliac blood flow. The mechanism of this response was shown to be due to the inhibition of a vasodilatory β₂-adrenergic receptor-mediated effect.

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“…In addition, the effects of gastrin, secretin and human chorionic gonadotropin on coronary circulation and cardiac function could be prevented by the blockade of ␤-adrenoceptors and NOS (25)(26)(27), whereas intracoronary genistein and melatonin acutely increased coronary blood flow through ␤-adrenergic-mediated NO release (28,29). Finally, the administration of insulin induced a coronary vasoconstriction, which could be considered as the net result of sympathetic ␣-adrenergic activation and increased release of NO (48).…”

Section: Discussionmentioning

confidence: 99%

Intracoronary Des-Acyl Ghrelin Acutely Increases Cardiac Perfusion Through a Nitric Oxide-Related Mechanism in Female Anesthetized Pigs

Grossini¹,

Raina²,

Farruggio³

et al. 2016

Endocrinology

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Des-acyl ghrelin (DAG), the most abundant form of ghrelin in humans, has been found to reduce arterial blood pressure and prevent cardiac and endothelial cell apoptosis. Despite this, data regarding its direct effect on cardiac function and coronary blood flow, as well as the related involvement of autonomic nervous system and nitric oxide (NO), are scarce. We therefore examined these issues using both in vivo and in vitro studies. In 20 anesthetized pigs, intracoronary 100 pmol/mL DAG infusion with a constant heart rate and aortic blood pressure, increased coronary blood flow and NO release, whereas reducing coronary vascular resistances (P Ͻ .05). Dose responses to DAG were evaluated in five pigs. No effects on cardiac contractility/relaxation or myocardial oxygen consumption were observed. Moreover, whereas the blockade of muscarinic cholinoceptors (n ϭ 5) or ␣-and ␤-adrenoceptors (n ϭ 5 each) did not abolish the observed responses, NO synthase inhibition (n ϭ 5) prevented the effects of DAG on coronary blood flow and NO release. In coronary artery endothelial cells, DAG dose dependently increased NO release through cAMP signaling and ERK1/2, Akt, and p38 MAPK involvement as well as the phosphorylation of endothelial NO synthase. In conclusion, in anesthetized pigs, DAG primarily increased cardiac perfusion through the involvement of NO release. Moreover, the phosphorylation of ERK1/2 and Akt appears to play roles in eliciting the observed NO production in coronary artery endothelial cells. (Endocrinology 157: 2403-2415, 2016) T he ghrelin-related peptides, acylated ghrelin and desacylated ghrelin, are gastrointestinal hormones that have been reported to exert variable effects on the cardiovascular system. Apart from being able to stimulate food intake and adiposity (1-4), ghrelin has been found to reduce arterial and pulmonary blood pressure (BP) (5-8), to increase myocardial contractility (5, 9), and to exert opposite effects on different vascular beds (10 -13). For example, ghrelin has been shown to increase human forearm blood flow and dilate human mammary and rat mesenteric arteries, whereas in rats and pigs, it caused coronary vasoconstriction.The deacylated form of ghrelin, des-acyl ghrelin, is far more abundant in circulation than ghrelin and is devoid of any endocrine activity (1, 2, 4, 14), although several authors strongly suggest that des-acyl ghrelin has intrinsic and specific actions in many physiological and pathophysiological conditions, mainly as a functional antagonist of ghrelin (15). To date, however, the function of des-acyl ghrelin is currently unknown, with the few studies exam- Abbreviations: BP, blood pressure; CEC, coronary artery endothelial cell; DAG, des-acyl ghrelin; dP/dt max , maximum rate of change of LV systolic pressure; eNOS, endothelial NO synthase; GHSR, GH secretagogue receptor; LAD, left anterior descending coronary artery; L-NAME, N-nitro-L arginine methyl ester; LV, left ventricular; NO, nitric oxide; NOS, NO synthase; PKA, protein kinase A; PLC, phospholipase C; PO 2...

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Effects of Insulin on Coronary Blood Flow in Anesthetized Pigs

Cited by 10 publications

References 29 publications

Impaired insulin-induced vasodilation in small coronary arteries of Zucker obese rats is mediated by reactive oxygen species

Impaired insulin-induced vasodilation in small coronary arteries of Zucker obese rats is mediated by reactive oxygen species

Human Placental Lactogen Decreases Regional Blood Flow in Anesthetized Pigs

Intracoronary Des-Acyl Ghrelin Acutely Increases Cardiac Perfusion Through a Nitric Oxide-Related Mechanism in Female Anesthetized Pigs

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