Impaired AV Nodal Conduction due to AV Nodal ischemia in patients with right coronary artery stenosis (original) (raw)
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Acute effects of glucose and insulin on vascular endothelium
Diabetologia, 2004
Aims/hypothesis. Chronic exposure to high concentrations of glucose has consistently been demonstrated to impair endothelium-dependent, nitric oxide (NO)-mediated vasodilation. In contrast, several clinical investigations have reported that acute exposure to high glucose, alone or in combination with insulin, triggers vasodilation. The aim of this study was to examine whether elevated glucose itself stimulates endothelial NO formation or enhances insulin-mediated endothelial NO release. Methods. We measured NO release and vessel tone ex vivo in porcine coronary conduit arteries (PCAs). Intracellular Ca 2+ was monitored in porcine aortic endothelial cells (PAECs) by fura-2 fluorescence. Expression of the Na + /glucose cotransporter-1 (SGLT-1) was assayed in PAECs and PCA endothelium by RT-PCR. Results. Stimulation of PCAs with D-glucose, but not the osmotic control L-glucose, induced a transient increase in NO release (EC 50 ≈10 mmol/l), mediated by a rise in intracellular Ca 2+ levels due to an influx from the extracellular space. This effect was abolished by inhibitors of the plasmalemmal Na + /Ca 2+ exchanger (dichlorobenzamil) and the SGLT-1 (phlorizin), which was found to be expressed in aortic and coronary endothelium. Alone, D-glucose did not relax PCA, but did augment the effect of insulin on NO release and vasodilation. Conclusions/interpretation. An increased supply of extracellular D-glucose appears to enhance the activity of the endothelial isoform of nitric oxide synthase by increasing intracellular Na + concentrations via SGLT-1, which in turn stimulates an extracellular Ca 2+ influx through the Na + /Ca 2+ exchanger. This mechanism may be responsible for glucose-enhanced, insulin-dependent increases in tissue perfusion (including coronary blood-flow), thus accelerating glucose extraction from the blood circulation to limit the adverse vascular effects of prolonged hyperglycaemia.
Circulation journal, 2003
pproximately 10-20% of patients with typical angina pectoris have normal coronary arteries, 1 and most of these patients are concluded to have syndrome X. 2 However, syndrome X is a heterogeneous group that includes slow coronary flow (SCF), 3,4 which is characterized by late opacification of the epicardial coronary arteries without occlusive disease. 5 SCF was first described by Tambe et al in 1972 6 and the exact etiopathogenesis is still unknown. Endothelial and vasomotor dysfunction, microvascular dysfunction, and occlusive disease of small coronary arteries have been suggested. 6-10 Endothelin-1 (ET-1) is the strongest known vasoconstrictor peptide and has significant effects on the cardiovascular system. It increases coronary vascular resistance and has positive inotropic effects on cardiomyocytes and is mitogenic for smooth muscle cells. 11,12 Because of these properties, it contributes to the progression of atherosclerosis. 13 Recent studies have indicated that peripheral immunoreactive ET-1 concentrations are also elevated in patients with chest pain and angiographically patent coronary arteries (syndrome X patients). 14,15 Furthermore, Lubov et al found that ET-1 is indeed released during exercise and is related to the severity of the ischemia as reflected by perfusion defects on single photon emission computerized tomography (SPECT) sestamibi. 16 It has also been suggested that abnormalities in nitric oxide (NO)-mediated endothelium dependent dilation of small coronary arteries may play a role in the pathogenesis of syndrome X. 17,18 In the present study, we aimed to investigated plasma ET-1 and NO concentrations of SCF patients during myocardial ischemia induced by exercise testing because, to our knowledge, there is not an existing study that has evaluated ET-1 and NO concentrations at rest and their response to exercise in SCF patients. Methods Forty-nine patients who underwent coronary angiography because of typical and quasi-typical symptoms of angina between January 2001 and June 2002 were diagnosed with SCF. All of them had angiographically normal coronary arteries without luminal irregularities. Of them, only 25 were suitable for the study and accepted the study procedures (11 females (44%); aged 56.7±9.8 years). Patients who suffered from one of the following diseases or associated disorders were excluded: myocardial and/or valvular heart disease, diabetes mellitus, hypertension, left
Forearm nitric oxide balance, vascular relaxation, and glucose metabolism in NIDDM patients
Diabetes, 1997
Endothelium-dependent and-independent vascular responses were assessed in 10 NIDDM patients and 6 normal subjects with no evidence of atherosclerotic disease. Changes in forearm blood flow and arteriovenous (AV) serum nitrite/nitrate (NO 2 7NO 3~) concentrations were measured in response to intra-arterial infusion of acetylcholine (ACh) (7.5, 15, 30 ug/min, endothelium-dependent response) and sodium nitroprusside (SNP) (0.3, 3, 10 ug/min, endothelium-independent response). Insulin sensitivity (determined by minimal model intravenous glucose tolerance test) was lower in NIDDM patients (0.82 ± 0.20 vs. 2.97 ± 0.29 10 4 min • uU" 1 • ml" 1 ; P < 0.01). Baseline forearm blood flow (4.8 ± 0.3 vs. 4.4 ± 0.3 ml • 100 ml 1 tissue • min 1 ; NS), mean blood pressure (100 ± 4 vs. 92 ± 4 mmHg; NS), and vascular resistance (21 ± 1 vs. 21 ± 1 units; NS), as well as their increments during ACh and SNP, infusion were similar in both groups. No difference existed in baseline NO 2 7NO 3-concentrations (4.09 ± 0.33 [NIDDM patients] vs. 5.00 ± 0.48 umol/1 [control subjects]; NS), their forearm net balance (0.31 ± 0.08 [NIDDM patients] vs. 0.26 ± 0.08 umol/1 • 100 ml" 1 tissue • min" 1 ; NS), and baseline forearm glucose uptake. During ACh infusion, both NO 2~ and NO 3 " concentrations and net balance significantly increased in both groups, whereas glucose uptake increased only in control subjects. When data from NIDDM and control groups were pooled together, a correlation was found between the forearm AV NO 2 " and NO 3 " differences and blood flow (r = 0.494, P = 0.024). On the contrary, no correlation was evident between NO 2 " and NO 3 " concentrations or net balance and insulin sensitivity. In summary, i) no difference existed in basal and ACh-stimulated NO generation and endothelium-dependent relaxation between uncomplicated NIDDM patients and control subjects; 2*) in both NIDDM and control groups, forearm NO 2 " and NO 3 " net balance following ACh stimulation was related to changes in the forearm blood flow; and S) ACh-induced increase in forearm blood flow was associated with an increase in glucose uptake only in control subjects but not in NIDDM patients. In conclu
Compromised Arterial Function in Human Type 2 Diabetic Patients
Diabetes, 2005
Diabetes is associated with a perturbation of signaling pathways in vascular tissue, which causes vasomotor dysfunction such as hypertension and accelerated atherosclerosis. In the present study, the mechanisms of vasomotor dysfunction, Akt (Thr 308 and Ser 473) phosphorylation and expression of endothelial NO (nitric oxide) synthase, and inducible NO synthase were investigated in human diabetic internal mammary arteries. The phospho-Akt (Thr 308) level in arteries from diabetic patients was reduced to about one-half of the level in nondiabetic patients, suggesting impaired insulin signaling in human diabetic vascular tissue. Augmented vasoconstriction was observed in diabetic arteries, due in part to deficiency of basal and stimulated NO production. This correlated with decreased endothelial NO synthase expression and activity in diabetic vessels. The sensitivity of diabetic vessels to the NO donor, sodium nitroprusside, was reduced as well, suggesting that NO breakdown and/or decreased sensitivity of smooth muscle to NO are also responsible for abnormal vasoconstriction. In addition, the abnormal vasoconstriction in diabetic vessels was not completely abolished in the presence of N-nitro-L-arginine methyl ester, revealing that NO-independent mechanisms also contribute to vasomotor dysfunction in diabetes. In conclusion, diabetes downregulates the Akt-signaling pathway and compromises human arterial function through a decrease in NO availability as well as through NO-independent mechanisms.
Insulin resistance in microvascular angina (syndrome X)
The Lancet, 1993
136 9 Magness RR, Rosenfeld CR. Local and systemic estradiol-17 beta: effects on uterine and systemic vasodilation. Am J Physiol 1989; 256: E536-42. 10 Jiang C, Sarrel PM, Poole-Wilson PA, Collins P. Acute effect of 17&bgr;-estradiol on rabbit coronary artery contractile responses to endothelin-1. Am J Physiol 1992; 263: H271-75. 11 Jiang C, Poole-Wilson PA, Sarrel PM, Mochizuki S, Collins P, MacLeod KT. Effect of 17&bgr;-oestradiol on contraction, Ca2+ current and intracellular free Ca2+ in guinea-pig isolated cardiac myocytes. Br J Pharmacol 1992; 106: 739-45. 12 Jiang C, Sarrel PM, Lindsay DC, Poole-Wilson PA, Collins P. Endothelium-independent relaxation of rabbit coronary artery by 17&bgr;-oestradiol in vitro. Br J Pharmacol 1991; 104: 1033-37. 13 Collins P, Rosano GMC, Jiang C, Lindsay D, Sarrel PM, Poole-Wilson PA. Cardiovascular protection by oestrogen-a calcium antagonist effect? Lancet 1993; 341: 1264-65. 14 Danahy DT, Burwell DT, Aronow WS, Prakash R. Sustained hemodynamic and antianginal effect of high dose oral isosorbide dinitrate. Circulation 1977; 55: 381-87. 15 Rosano GMC, Clarke D, Sarrel PM, Collins P. Estradiol 17 beta improves ischemia in postmenopausal women with coronary heart disease. Circulation 1992; 86 (suppl I): I-537 (abstr). 16 Adams MR, Clarkson TB, Kaplan JR, Koritnik DR. Ovarian secretions and atherosclerosis. In: Naftolin F, Gutmann JN, DeCherney AH, Sarrel PM, eds. Ovarian secretions and cardiovascular and neurological function. New York: Raven Press, 1990: 151-59. 17 Williams JK, Adams MR, Klopfenstein HS,. Estrogen modulates responses of atherosclerotic coronary arteries. Circ Res 1990; 81: 1680-87. 18 Williams JK, Adams MR, Herrington DM, Clarkson TB. Short-term administration of estrogen and vascular responses of atherosclerotic coronary arteries. JACC 1992; 20: 452-57. 19 Gisclard V, Miller VM, Vanhoutte PM. Effect of 17beta-oestradiol on endothelial responses in the rabbit. J Pharmacol Exp Ther 1988; 244: 19-22. 20 Sarrel PM. Effects of ovarian steroids on the cardiovascular system. In: Ginsberg J, ed. Circulation in the female. Carnforth, Lancashire: Parthenon, 1989: 117-41. 21 Ginsberg J, Hardiman P, O'Reilly B. Peripheral blood flow in menopausal women who have hot flushes and in those who do not. BMJ 1989; 298: 1488-90. 22 Chelsky R, Wilson RA, Morton MJ, et al. Rapid alteration of ascending aortic compliance following treatment with pergonal. Circulation 1990; 82: III-126. 23 Brass LM, Kisiel D, Sarrel PM. A correlation between estrogen and middle cerebral artery blood velocity at different times in the menstrual cycle in women with catamenial migraines.
American journal of physiology. Endocrinology and metabolism, 2003
We examined the effects of inhibiting nitric oxide synthase with Nomega-nitro-l-arginine-methyl ester (l-NAME) on total hindlimb blood flow, muscle microvascular recruitment, and hindlimb glucose uptake during euglycemic hyperinsulinemia in vivo in the rat. We used two independent methods to measure microvascular perfusion. In one group of animals, microvascular recruitment was measured using the metabolism of exogenously infused 1-methylxanthine (1-MX), and in a second group contrast-enhanced ultrasound (CEU) was used. Limb glucose uptake was measured by arterial-venous concentration differences after 2 h of insulin infusion. Saline alone did not alter femoral artery flow, glucose uptake, or 1-MX metabolism. Insulin (10 mU.min-1.kg-1) significantly increased hindlimb total blood flow (0.69 +/- 0.02 to 1.22 +/- 0.11 ml/min, P < 0.05), glucose uptake (0.27 +/- 0.05 to 0.95 +/- 0.08 micromol/min, P < 0.05), 1-MX uptake (5.0 +/- 0.5 to 8.5 +/- 1.0 nmol/min, P < 0.05), and skel...
Life Sciences, 2003
To analyze the effects of diabetes mellitus on the vascular responsiveness to nitric oxide and thromboxane receptor stimulation, 2 mm long segments of basilar, coronary, renal and tail arteries from male and female, control (normoglycemic) and streptozotocin-induced diabetic rats, were prepared for isometric tension recording. In the segments at basal resting tension, the thromboxane analog U46619 (10 À 9 -10 À 5 M) produced concentrationdependent contraction, which was similar in arteries from male and female rats, and was reduced by diabetes in coronary arteries from male and in tail arteries from female rats. In the vascular segments precontracted with endothelin-1 (10 À 9 M), acetylcholine (10 À 9 -3 Â 10 À 5 M) produced concentration-dependent relaxation which was similar in all arteries from normoglycemic male and female rats, and was increased by diabetes in tail arteries from female, but not in those from male rats. In precontracted segments the nitric oxide donor sodium nitroprusside (10 À 10 -10 À 5 M) also produced concentration-dependent relaxation, which was higher in basilar arteries from normoglycemic females compared with males, and was increased by diabetes in tail arteries from female but not from male rats. These results suggest that diabetes may increase the relaxation to nitric oxide in tail arteries, and may reduce the contraction to thromboxane receptor activation in coronary and tail arteries in a gender-dependent way. These changes in vascular reactivity may be adaptative to the vascular alterations produced by diabetes. D
The responses of the iliac artery to insulin: direct delayed nitric oxide-mediated dilatation
The British Journal of Diabetes & Vascular Disease, 2011
T he aim of the study was to determine the effect of insulin on a conduit artery. In a closed-off test segment of iliac artery in vivo in anaethetised pigs, pressure was kept constant. During the first 10 minutes of exposure to hyperinsulinaemic blood, the test segment diameter was 3.63±0.64 mm (mean ± SD). Dilatation occurred after 10 minutes when the test segment diameter increased to 3.80±0.62 mm (mean ± SD), p=0.0006, n=10. The increase in diameter with the vehicle for insulin in blood was -0.0775±0.116 mm (mean ± SD, n=6) and with hyperinsulin in blood was 0.165±0.124 mm (mean ± SD, n=10), p=0.0024. Dilatation with hyperinsulin was 0.229±0.116 mm (mean ± SD) versus insulin plus 250 µg/ml of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester hydrochloride (L-NAME), 0.041±0.026 mm (mean ± SD), p=0.0313, n=6. No evidence of arterial constriction was observed in the presence of L-NAME. We conclude that insulin has a direct relaxing effect on the smooth muscle in the wall of conduit artery, mediated by nitric oxide. Br J Diabetes Vasc Dis 2011;11:130-136.