Hyperreactivity to Nitrovasodilators in Forearm Vasculature Is Related to Autonomic Dysfunction in Insulin-Dependent Diabetes Mellitus

Mäkimattila, Sari; Mäntysaari, Matti; Groop, Per‐Henrik; Summanen, Paula; Virkamäki, Antti; Schlenzka, A; Fagerudd, Johan; Yki-Järvinen, H

doi:10.1161/01.cir.95.3.618

Cited by 46 publications

(34 citation statements)

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“…Furthermore, the finding of increased NO-mediated, endothelium-dependent vasodilation in obesity or related hyperinsulinemic conditions such as diabetes, while infrequent, is not unique. Increased eNOS phosphorylation, activity, and NO-mediated vasodilation was reported in mesenteric arteries from rats with portal hypertension (33), and NOmediated vasodilation is also enhanced in the early stages of diabetes (30,42,52). In keeping with observations that NOS activity may be enhanced in the early, developing stages of diabetes but decreased with longer duration of the disease (52), it is quite possible that the duration of this well-characterized dietary model of obesity and observations reported in the study represent an intermediate or partial adaptive state in the response of the cremaster muscle artery to diet-induced obesity.…”

Section: Discussionmentioning

confidence: 99%

Dietary obesity increases NO and inhibits BK_Ca-mediated, endothelium-dependent dilation in rat cremaster muscle artery: association with caveolins and caveolae

Howitt

Grayson

Morris

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Howitt L, Grayson TH, Morris MJ, Sandow SL, Murphy TV. Dietary obesity increases NO and inhibits BK Ca-mediated, endothelium-dependent dilation in rat cremaster muscle artery: association with caveolins and caveolae. Am J Physiol Heart Circ Physiol 302: H2464 -H2476, 2012. First published April 6, 2012 doi:10.1152/ajpheart.00965.2011.-Obesity is a risk factor for hypertension and other vascular disease. The aim of this study was to examine the effect of diet-induced obesity on endothelium-dependent dilation of rat cremaster muscle arterioles. Male Sprague-Dawley rats (213 Ϯ 1 g) were fed a cafeteria-style high-fat or control diet for 16 -20 wk. Control rats weighed 558 Ϯ 7 g compared with obese rats 762 Ϯ 12 g (n ϭ 52-56; P Ͻ 0.05). Diet-induced obesity had no effect on acetylcholine (ACh)-induced dilation of isolated, pressurized (70 mmHg) arterioles, but sodium nitroprusside (SNP)-induced vasodilation was enhanced. ACh-induced dilation of arterioles from control rats was abolished by a combination of the KCa blockers apamin, 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34), and iberiotoxin (IBTX; all 0.1 mol/l), with no apparent role for nitric oxide (NO). In arterioles from obese rats, however, IBTX had no effect on responses to ACh while the NO synthase (NOS)/guanylate cyclase inhibitors N -nitro-L-arginine methyl ester (L-NAME; 100 mol/l)/1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 10 mol/l) partially inhibited ACh-induced dilation. Furthermore, NOS activity (but not endothelial NOS expression) was increased in arteries from obese rats. L-NAME/ODQ alone or removal of the endothelium constricted arterioles from obese but not control rats. Expression of caveolin-1 and -2 oligomers (but not monomers or caveolin-3) was increased in arterioles from obese rats. The number of caveolae was reduced in the endothelium of arteries, and caveolae density was increased at the ends of smooth muscle cells from obese rats. Dietinduced obesity abolished the contribution of large-conductance Ca 2ϩ -activated K ϩ channel to ACh-mediated endothelium-dependent dilation of rat cremaster muscle arterioles, while increasing NOS activity and inducing an NO-dependent component. (72). Many of these enzymes and channels are localized within caveolae, as cholesterol-rich invaginations of the plasma membrane (10). Caveolins, the structural proteins of caveolae, have an established role in modulating vascular signaling mechanisms including NO synthase (NOS) and BK Ca activity (1,13,20).Studies on the impact of obesity on endothelium-dependent vasodilation have focused on impaired NO-mediated responses and, in particular, the altered endothelial NOS (eNOS) activity and NO bioavailability associated with inflammatory mediators and oxidative stress (24, 53). Decreased NO-dependent vasodilation, as an apparent consequence of oxidative stress, has been observed in animal models of obesity (16,18,25,26). In smaller arteries and arterioles, however, particularly those in skeletal muscle (43), NO generally makes a relatively minor...

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Section: Discussionmentioning

confidence: 99%

Dietary obesity increases NO and inhibits BK_Ca-mediated, endothelium-dependent dilation in rat cremaster muscle artery: association with caveolins and caveolae

Howitt

Grayson

Morris

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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“…The reason for the divergent findings between studies is not clear, but could be related to confounding factors that were not controlled for, such as glycaemic control (82), dyslipidaemia (52), dysautonomia (78,79), long-term complications of NIDDM and differences in the techniques and pharmacological agents used to assess endothelial function.…”

Section: Physiology: Interplay Between Nitric Oxide and The Sympathetmentioning

confidence: 99%

Defective nitric oxide synthesis: a link between metabolic insulin resistance, sympathetic overactivity and cardiovascular morbidity

Scherrer

Sartori

2000

European Journal of Endocrinology

107

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Epidemiological studies demonstrate an association between insulin resistance, hypertension and cardiovascular morbidity. In addition to its metabolic effects, insulin also has important cardiovascular actions. The sympathetic nervous system and the nitric oxide-L-arginine pathway have emerged as central players in the mediation of these actions. Over the past decade, the underlying mechanisms and the factors that may govern the interaction between insulin and these two major cardiovascular regulatory systems have been studied extensively in healthy people and insulinresistant individuals. Here we summarize the current understanding and gaps in knowledge on these interactions. We propose that a genetic and/or acquired defect of nitric oxide synthesis could represent a central defect triggering many of the metabolic, vascular and sympathetic abnormalities characteristic of insulin-resistant states, all of which may predispose to cardiovascular disease.

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“…Thus, in blood vessels from type I diabetic rats, the relaxation to acetylcholine is reported to be normal [aorta (Head et al, 1987;Harris and MacLeod, 1988;Mulhern and Docherty, 1989), mesenteric artery (Harris and MacLeod, 1988)], blunted [aorta (Vallejo et al, 2000), mesenteric artery (Heygate et al, 1995;Vallejo et al, 2000)], or augmented [aorta (Altan et al, 1989)]. Likewise, in type I diabetic patients, endothelium-dependent di-latations have been reported to be normal (Huvers et al, 1999), impaired (Makimattila et al, 1996), or enhanced (Makimattila et al, 1997).…”

mentioning

confidence: 99%

Augmented Endothelium-Derived Hyperpolarizing Factor-Mediated Relaxations Attenuate Endothelial Dysfunction in Femoral and Mesenteric, but Not in Carotid Arteries from Type I Diabetic Rats

Shi

Ku²,

Man³

et al. 2006

J Pharmacol Exp Ther

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Individual vascular beds exhibit differences in vascular reactivity. The present study investigates the effects of streptozotocininduced type I diabetes on endothelium-dependent responses of rat carotid, femoral, and mesenteric arteries. Rings with and without endothelium, suspended in organ chambers for isometric tension recording, were contracted with phenylephrine and exposed to increasing concentrations of acetylcholine. In carotid and femoral arteries, acetylcholine produced concentration-and endothelium-dependent relaxations that were abolished by N -nitro-L-arginine methyl ester (L-NAME; specific nitric-oxide synthase inhibitor) and were impaired slightly in preparations from streptozotocin-treated rats (STZ-rats). This impairment could be prevented by L-arginine. In femoral arteries incubated with L-NAME, acetylcholine caused endotheliumdependent contractions that were abolished by 3-[(6-amino-(4-chlorobenzensulfonyl)-2-methyl-5,6,7,8-tetrahydronapht]-1-yl) propionic acid (S18886) (antagonist of thromboxane A 2 /prostaglandins H 2 -receptors) and reversed to relaxation by indomethacin (inhibitor of cyclooxygenase). The latter relaxation was inhibited by charybdotoxin plus apamin, suggesting a role of endothelium-dependent hyperpolarizing factor (EDHF). This EDHF-mediated component was augmented slightly in arteries from STZ-rats. In mesenteric arteries, relaxations to acetylcholine were only partially inhibited by L-NAME, and the L-NAMEresistant component was abolished by charybdotoxin plus apamin. In the mesenteric arteries from STZ-rats, L-NAME-sensitive relaxations to acetylcholine were reduced and the EDHFcomponent was augmented. These findings demonstrate a marked heterogeneity in endothelium-dependent responses in rat arteries and their differential adaptation in the course of type I diabetes. In particular, the EDHF-mediated component not only compensates for the reduced bioavailability of nitric oxide in the femoral and mesenteric artery but also counteracts the augmented endothelium-dependent contractions in the former.The endothelial cells release both endothelium-derived relaxing factors and endothelium-derived contracting factors (EDCFs), which control the tone of the underlying smooth muscle. Endothelium-derived relaxing factors include NO, prostacyclin, and several endothelium-derived hyperpolarizing factors (EDHFs). Different vascular beds, exposed to varying local and neurohumoral influences, exhibit a marked heterogeneity in vascular responsiveness (Vanhoutte, 1978;Lü scher and Vanhoutte, 1990;Feletou and Vanhoutte, 2006). NO is a major contributor to endothelium-dependent relaxations in large conduit arteries, whereas endothelium-derived hyperpolarizing factor(s) play a predominant role in small arteries (Nagao et al., 1992;Shimokawa et al., 1996). Diabetes mellitus is characterized by hyperglycemia resulting from a defective secretion and/or action of insulin. Data on the impairment of endothelial function caused by type I diabetes are controversial. Thus, in blood vessels from...

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Hyperreactivity to Nitrovasodilators in Forearm Vasculature Is Related to Autonomic Dysfunction in Insulin-Dependent Diabetes Mellitus

Abstract: These data are consistent with idea that altered neurotransmission is an important determinant of vascular reactivity of diabetic blood vessels to nitrovasodilators in vivo.

Cited by 46 publications

References 35 publications

Dietary obesity increases NO and inhibits BK_Ca-mediated, endothelium-dependent dilation in rat cremaster muscle artery: association with caveolins and caveolae

Dietary obesity increases NO and inhibits BK_Ca-mediated, endothelium-dependent dilation in rat cremaster muscle artery: association with caveolins and caveolae

Defective nitric oxide synthesis: a link between metabolic insulin resistance, sympathetic overactivity and cardiovascular morbidity

Augmented Endothelium-Derived Hyperpolarizing Factor-Mediated Relaxations Attenuate Endothelial Dysfunction in Femoral and Mesenteric, but Not in Carotid Arteries from Type I Diabetic Rats

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Hyperreactivity to Nitrovasodilators in Forearm Vasculature Is Related to Autonomic Dysfunction in Insulin-Dependent Diabetes Mellitus

Abstract: These data are consistent with idea that altered neurotransmission is an important determinant of vascular reactivity of diabetic blood vessels to nitrovasodilators in vivo.

Cited by 46 publications

References 35 publications

Dietary obesity increases NO and inhibits BKCa-mediated, endothelium-dependent dilation in rat cremaster muscle artery: association with caveolins and caveolae

Dietary obesity increases NO and inhibits BKCa-mediated, endothelium-dependent dilation in rat cremaster muscle artery: association with caveolins and caveolae

Defective nitric oxide synthesis: a link between metabolic insulin resistance, sympathetic overactivity and cardiovascular morbidity

Augmented Endothelium-Derived Hyperpolarizing Factor-Mediated Relaxations Attenuate Endothelial Dysfunction in Femoral and Mesenteric, but Not in Carotid Arteries from Type I Diabetic Rats

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Dietary obesity increases NO and inhibits BK_Ca-mediated, endothelium-dependent dilation in rat cremaster muscle artery: association with caveolins and caveolae

Dietary obesity increases NO and inhibits BK_Ca-mediated, endothelium-dependent dilation in rat cremaster muscle artery: association with caveolins and caveolae