Glucose-Dependent Enhancement of Spontaneous Phasic Contraction Is Suppressed in Diabetic Mouse Portal Vein: Association with Diacylglycerol-Protein Kinase C Pathway

The Journal of Pharmacology and Experimental Therapeutics

Miyatake²,

Sone³

et al. 2006

Self Cite

Vascular endothelial cells (ECs), which regulate vascular tonus, serve as a barrier at the interface of vascular tissue. It is generally believed that alteration of this barrier is correlated with diabetic complications; however, a detailed mechanism has not been elucidated. This study examined alteration of bovine arterial EC functions stimulated by a thromboxane A 2 analog (9,11-dideoxy-11␣,9␣-epoxymethano prostaglandin F 2␣ ; U46619) under normal and high-glucose (HG) conditions. U46619 treatment increased EC layer permeability in a timeand dose-dependent fashion. This response initially disrupted calcium-dependent EC-to-EC connections, namely, vascular endothelial cadherin (VE-CaD). Thereafter, EC force development in association with morphological changes was detected employing a reconstituted EC fiber technique, resulting in paracellular hole formation in the EC layer. Thus, we confirmed that U46619-induced enhancement of EC layer permeability involves these sequential steps. Similar trials were performed using a concentration twice that of normal glucose (22.2 mM glucose for 48 h). This treatment significantly enhanced U46619-induced EC layer permeability; furthermore, increases in both rate of VE-CaD disruption and EC fiber contraction were evident. Inhibition of calcium-independent protein kinase C and diacylglycerol kinase indicated that the glucose-dependent increase in VE-CaD disruption was mediated by a calcium-independent mechanism. Moreover, EC contraction was regulated by a typical calcium-independent pathway associated with rho kinase and actin stress fiber. Contraction was also enhanced under HG conditions. This investigation revealed that glucosedependent enhancement of EC layer permeability is related to increases in VE-CaD disruption and EC contraction. Increases in both parameters were mediated by alteration of a calciumindependent pathway.

Section: Alteration Of Ec Functions Under High-glucose Conditions 535supporting

confidence: 56%

mentioning

confidence: 99%

High-Glucose-Altered Endothelial Cell Function Involves Both Disruption of Cell-to-Cell Connection and Enhancement of Force Development

The Journal of Pharmacology and Experimental Therapeutics

Miyatake²,

Sone³

et al. 2006

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“…HG conditions were introduced in our previous study involving diabetic vascular smooth muscle measurement (Nobe et al, 2003(Nobe et al, , 2004. CCh-induced SD rat bladder contraction was significantly enhanced under HG conditions, but it was not evident in SHHR (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…These results suggested that suppression of glucose sensitivity in SHHR bladder is not correlated with activity of the rho-rho kinase pathway. We previously reported that enhancement of smooth muscle contraction under HG conditions involves the DG-PKC pathway in some vascular tissue as an additional regulatory factor of bladder contraction (Nobe et al, 2003(Nobe et al, , 2004. It is generally accepted that CCh-induced bladder smooth muscle contraction is mediated by phosphatidylinositolbisphosphate hydrolysis and DG formation in a manner similar to that of other types of excitable cells (Nord, 1996;Nofer et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Alterations of Glucose-Dependent and -Independent Bladder Smooth Muscle Contraction in Spontaneously Hypertensive and Hyperlipidemic Rat

The Journal of Pharmacology and Experimental Therapeutics

Yamazaki²,

Kumai³

et al. 2008

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Alteration of bladder contractility was examined in the spontaneously hypertensive and hyperlipidemic rat (SHHR; age, 9 months; systolic blood pressure, Ͼ150 mm Hg; plasma cholesterol, Ͼ150 mg/dl). Carbachol (CCh) induced time-and dose-dependent contractions in Sprague-Dawley (age-matched control) rats and SHHR; however, maximal levels differed significantly (13.3 Ϯ 2.2 and 5.4 Ϯ 1.9 N/mm 2 following 10 M CCh treatment, respectively; n ϭ 5). This difference, which was maintained in calciumreplaced physiological salt solution (PSS), was suppressed by pretreatment with rho kinase inhibitor, 1 M Y27632 [(R)-(ϩ)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide]; moreover, total activity of rho kinase was also reduced in SHHR bladder. Pretreatment of bladders under high-glucose (HG) conditions (22.2 mM glucose-contained PSS for 30 min) led to enhancement of CCh-induced contraction solely in control animals. Under HG conditions, both protein kinase C (PKC) activity and production of diacylglycerol (DG) derived from incorporated glucose declined in SHHR bladder; however, sustained elevation of plasma glucose level was not detected in SHHR. These results suggested that bladder contractility dysfunction in SHHR is attributable to alteration of rho kinase activity and the DG-PKC pathway. This dysfunction may occur prior to chronic hyperglycemia onset in progressive hypertension and hyperlipidemia.

“…In this study, the normal physiologic glucose concentration (11.1 mM) was defined as the NG condition. To understand the direct effects of extracellular glucose accumulation, a HG condition was established by pretreating the vascular tissues with HG-PSS (22.2 mM glucose in PSS) at 37°C for 30 minutes, as previously reported by our laboratory (Nobe et al, 2004).…”

Section: Methodsmentioning

confidence: 99%

Two Types of Overcontraction Are Involved in Intrarenal Artery Dysfunction in Type II Diabetic Mouse

The Journal of Pharmacology and Experimental Therapeutics

Takenouchi

Kasono

et al. 2014

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Contractile responses in small intrarenal arteries are associated with diabetic nephropathy. However, the mechanisms that induce and maintain altered small vessel contraction are not clearly understood. To further understand intrarenal artery dysfunction in diabetes, phenylephrine (PE)-induced force development was assessed in the intrarenal artery [interlobar artery (ILA)] in control (lean) and type II diabetic (ob/ob) mice. PE-induced dosedependent force development in the ILA was significantly greater in ob/ob mice than in lean mice (592.8 6 5.2 and 770.1 6 12.1 m/mm tissue, respectively, following administration of 30 mM PE, n 5 5). Under high-glucose conditions (twice the normal concentration of glucose), PE-induced force development in the ILA was only enhanced in ob/ob mice (946.0 6 18.2 mN/mm tissue; n 5 5). ILA dysfunction reduces blood flow to the glomerulus and may induce diabetic nephropathy. Basal overcontraction of the ILA in ob/ob mice under normal-glucose conditions was reduced by pretreatment with rottlerin, a calcium-independent protein kinase C (PKCd) inhibitor. Total PKC activity was also reduced by rottlerin. Under high-glucose conditions, the enhanced ILA contraction in diabetic mice was suppressed by rho A and rho kinase inhibitors. Our results indicate two types of ILA dysfunction in diabetes, as follows: 1) a basal increase in PE-induced contraction under normal-glucose conditions, and 2) extracellular glucose-dependent enhancement of PE-induced contraction. We believe that these dysfunctions are mediated by the activation of the PKCd and rho A-rho kinase pathways, respectively.