Enhanced Contractile Responses of Arteries from Diabetic Rats to α1-Adrenoceptor Stimulation in the Absence and Presence of Extracellular Calcium

Abebe, Worku; Harris, Kristin; MacLeod, Kathleen M.

doi:10.1097/00005344-199008000-00010

Cited by 120 publications

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“…In the latter study, the altered sensitivity to NA was no longer apparent after removal of endothelial cells. Abebe et al (1990) have recently reported that enhanced responses of arteries from 3 month STZ-treated rats to aadrenoceptor agonists are mediated by al-adrenoceptors and are largely dependent on the presence of extracellular calcium. It is possible that changes in responsiveness to NA of rat aortae are dependent on the duration of diabetes, since Mulhern & Docherty (1989), using aortae from 2-3 week STZ-treated rats found no change in responsiveness to NA.…”

Section: Discussionmentioning

confidence: 99%

“…It is possible that changes in responsiveness to NA of rat aortae are dependent on the duration of diabetes, since Mulhern & Docherty (1989), using aortae from 2-3 week STZ-treated rats found no change in responsiveness to NA. However, many previous studies have examined the responsiveness of isolated aortae to NA in the presence of a fladrenoceptor antagonist (Harris & MacLeod, 1988;Mulhern & Docherty, 1989;Abebe et al, 1990), since it is known that fl-adrenoceptors mediate relaxation in rat aortae and that diabetes may change the fJ-adrenoceptor-mediated response (Kamata et al, 1989). Nevertheless, the present study supports the findings of Mulhern & Docherty (1989), since after 2 weeks of diabetes, aortic responses to NA were not significantly different between STZ-treated and control rats.…”

Section: Discussionmentioning

confidence: 99%

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Attenuated responses to endothelin‐1, KCl and CaCl₂, but not noradrenaline, of aortae from rats with streptozotocin‐induced diabetes mellitus

Fulton

Hodgson

Sikorski

et al. 1991

British J Pharmacology

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1 This study investigated the responsiveness to vasoconstrictor agents (including endothelin-1, ET-1) of aortic rings from rats with two-week streptozotocin (STZ, 60mgkg-', i.v.)-induced diabetes and vehicletreated control rats. The basal tension was 10g, which was estimated to be more physiological than the tension of 1-2 g that has been previously used for most studies of aortic rings from diabetic rats. 2 Maximum responses to ET-1 (0.13-18 nM), KCl (2-20mM) or CaCl2 (1OpM-10mM) were reduced in aortae from STZ-treated rats compared to those from control rats. Such reductions were still evident after removal of the endothelium. 3 Responses to noradrenaline (NA, 0.1 nM-26pM) of aortae from STZ-treated rats were not significantly different from responses of aortae of control rats.4 Removal of endothelium resulted in a significant reduction in the EC50 values for NA of rings from both STZ-treated rats (6.90 + 0.13 and 8.17 + 0.35 (-logM) with and without endothelium, respectively, n = 5) and control rats (6.90 + 0.15 and 8.37 + 0.44 (-logM) with and without endothelium, respectively, n= 5).5 In calcium-free medium (with 1 mm EGTA), responses to NA and ET-1 were reduced compared with those in normal Krebs solution and maximum responses were less in rings from STZ-treated compared with control rats. 6 Indomethacin (5,UM) did not prevent the reduced maximum responsiveness to ET-1 in rings from STZ-treated rats compared with those from controls. 7 This study indicates that changes in vascular responsiveness to ET-1, KCI and CaCl2 (but not NA) occur in aortae of two-week STZ-treated rats. The endothelium does not appear to play a major role in mediating changes in responsiveness to ET-1.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Attenuated responses to endothelin‐1, KCl and CaCl₂, but not noradrenaline, of aortae from rats with streptozotocin‐induced diabetes mellitus

Fulton

Hodgson

Sikorski

et al. 1991

British J Pharmacology

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“…Both augmented smooth muscle contractility and endothelial dysfunction have been shown to underlie the abnormal vasoconstriction in arteries from diabetic and metabolic syndrome patients and animal models (16,18,19,28). The enhanced vascular smooth muscle contractile responses in diabetes have, in turn, been ascribed to increases in Ca 2ϩ entry and/or Ca 2ϩ release (1,6,16,36), although elevation in the Ca 2ϩ sensitivity of the contractile proteins has alternatively been proposed as the mechanism underlying the increased vascular contractility associated with diabetes (12,23,26).…”

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confidence: 99%

Impaired Ca²⁺ handling in penile arteries from prediabetic Zucker rats: involvement of Rho kinase

Villalba

Contreras

Hernández

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Diabetes is associated with an increased vascular tone usually involved in the pathogenesis of diabetic cardiovascular complications such as hypertension, stroke, coronary artery disease, or erectile dysfunction (ED). Enhanced contractility of penile erectile tissue has been associated with augmented activity of the RhoA/Rho kinase (RhoK) pathway in models of diabetes-associated ED. The present study assessed whether abnormal vasoconstriction in penile arteries from prediabetic obese Zucker rats (OZRs) is due to changes in the intracellular Ca2+ concentration ([Ca2+]i) and/or in myofilament Ca2+ sensitivity. Penile arteries from OZRs and lean Zucker rats (LZRs) were mounted on microvascular myographs for simultaneous measurements of [Ca2+]i and tension. The relationships between [Ca2+]i and contraction for the α1-adrenergic vasoconstrictor phenylephrine (PE) were left shifted and steeper in OZRs compared with LZRs, although the magnitude of the contraction was similar in both groups. In contrast, the vasoconstriction induced by the thromboxane A2 receptor agonist U-46619 was augmented in arteries from OZRs, and this increase was associated with an increase in both the sensitivity and maximum responses to Ca2+. The RhoK inhibitor Y-27632 (10 μM) reduced the vasoconstriction induced by PE to a greater extent in OZRs than in LZRs, without altering Ca2+. Y-27632 inhibited with a greater potency the contraction elicited by high KCl in arteries from OZRs compared with LZRs without changing [Ca2+]i. RhoK-II expression was augmented in arteries from OZRs. These results suggest receptor-specific changes in the Ca2+ handling of penile arteries under conditions of metabolic syndrome. Whereas augmented vasoconstriction upon activation of the thromboxane A2 receptor is coupled to enhanced Ca2+ entry, a RhoK-mediated enhancement of myofilament Ca2+ sensitivity is coupled with the α1-adrenergic vasoconstriction in penile arteries from OZRs.

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“…An association with intracellular calcium metabolism was also suggested in experimental diabetic models. It might be mediated by an alteration of calcium influx and/or calcium release from stores (Abebe et al, 1990;Pieper and Gross, 1990;Hattori et al, 1994). In diabetes, it is thought that the change in blood glucose level enhances PI turnover activity (Legan, 1989;Somlyo et al, 1999), which may lead to both high blood pressure and dysfunction in many types of tissue (Begum et al, 2000).…”

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confidence: 99%

Enhancement Effect under High-Glucose Conditions on U46619-Induced Spontaneous Phasic Contraction in Mouse Portal Vein

Nobe

Sakata²,

Nobe³

et al. 2002

J Pharmacol Exp Ther

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The effect of the thromboxane A 2 analog 9,11-dideoxy-11␣, 9␣-epoxymethanoprostaglandin F 2␣ (U46619) on spontaneous phasic contractions in the mouse portal vein was studied. U46619 induced concentration-dependent (1-100 nM) increases in amplitude, frequency, and contractile period (ONtime) of the contraction. Both amplitude and ON-time were enhanced significantly under high-glucose (HG; 4-fold greater than normal) conditions. This hyperactivation may be associated with portal vein dysfunction in diabetes. However, the mechanisms remain unclear. HG enhanced the U46619-induced accumulation of endogenous diacylglycerol (DG). Phospholipase C inhibition suppressed accumulation under normal conditions; however, this suppression was not observed under HG conditions. The HG-induced enhancement of U46619-induced contraction was inhibited by protein kinase C (PKC)inhibition. This finding indicated that accumulated DG might increase PKC activity. Activated PKC stimulated DG kinase activation as a feedback mechanism. DG kinase inhibition also suppressed the HG-induced enhancement of contraction. Increased myo-inositol incorporation was detected under HG conditions, indicating an acceleration of phosphatidylinositol (PI) turnover. This acceleration was inhibited by PKC and DG kinase inhibitors. These findings indicated that HG treatments increased DG synthesis derived from incorporated glucose, PKC, and DG kinase activation. These responses induce hyperactivation of the amplitude and contractile period of contraction mediated by acceleration of PI turnover. This series of responses may be involved in the dysfunction of the portal vein under the HG conditions occurring with diabetes.The portal vein functions as the main transfer vessel from the digestive organs to the liver. To effect highly efficient transfer, the portal vein exhibits spontaneous, intermittent rhythmic contractions (Miwa et al., 1997). Dysfunction of this tissue leads not only to reduction in blood supply to the liver but also to serious diseases such as varix mediated by reflux of blood (MacMathuna, 1992). An understanding of the basic mechanisms modulating these spontaneous contractions is a prerequisite for investigation of potential pathophysiological processes. Calcium and potassium channel activity is associated with spontaneous contraction (Loirand et al., 1990;Helliwell and Large, 1997). Regulation of calcium channels is believed to occur via plasma membrane potential and/or intracellular signaling systems. However, the mechanisms involved in increased mechanical activity mediated by receptor stimulation and their related intracellular factors are poorly understood.We have previously reported that receptor-mediated contractile responses in vascular smooth muscle are altered in diabetes and the mechanisms involved change in phosphatidylinositol (PI) turnover (Nobe et al., 2002). Phosphatidylinositols, diacylglycerol (DG), protein kinase C (PKC), and DG kinase are key elements of PI turnover. Increased contractility in many smooth muscle cell ...

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Enhanced Contractile Responses of Arteries from Diabetic Rats to α1-Adrenoceptor Stimulation in the Absence and Presence of Extracellular Calcium

Cited by 120 publications

References 0 publications

Attenuated responses to endothelin‐1, KCl and CaCl₂, but not noradrenaline, of aortae from rats with streptozotocin‐induced diabetes mellitus

Attenuated responses to endothelin‐1, KCl and CaCl₂, but not noradrenaline, of aortae from rats with streptozotocin‐induced diabetes mellitus

Impaired Ca²⁺ handling in penile arteries from prediabetic Zucker rats: involvement of Rho kinase

Enhancement Effect under High-Glucose Conditions on U46619-Induced Spontaneous Phasic Contraction in Mouse Portal Vein

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Enhanced Contractile Responses of Arteries from Diabetic Rats to α1-Adrenoceptor Stimulation in the Absence and Presence of Extracellular Calcium

Cited by 120 publications

References 0 publications

Attenuated responses to endothelin‐1, KCl and CaCl2, but not noradrenaline, of aortae from rats with streptozotocin‐induced diabetes mellitus

Attenuated responses to endothelin‐1, KCl and CaCl2, but not noradrenaline, of aortae from rats with streptozotocin‐induced diabetes mellitus

Impaired Ca2+ handling in penile arteries from prediabetic Zucker rats: involvement of Rho kinase

Enhancement Effect under High-Glucose Conditions on U46619-Induced Spontaneous Phasic Contraction in Mouse Portal Vein

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Resources

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Attenuated responses to endothelin‐1, KCl and CaCl₂, but not noradrenaline, of aortae from rats with streptozotocin‐induced diabetes mellitus

Attenuated responses to endothelin‐1, KCl and CaCl₂, but not noradrenaline, of aortae from rats with streptozotocin‐induced diabetes mellitus

Impaired Ca²⁺ handling in penile arteries from prediabetic Zucker rats: involvement of Rho kinase