Alterations in EDHF-type relaxation and phosphodiesterase activity in mesenteric arteries from diabetic rats

Abstract

Matsumoto, Takayuki, Tsuneo Kobayashi, and Katsuo Kamata. Alterations in EDHF-type relaxation and phosphodiesterase activity in mesenteric arteries from diabetic rats. Am J Physiol Heart Circ Physiol 285: H283-H291, 2003; 10.1152/ajpheart.00954.2002.-In isolated superior mesenteric artery rings from age-matched control rats and streptozotocin (STZ)-induced diabetic rats, we investigated the role of cAMP in endothelium-derived hyperpolarizing factor (EDHF)-type relaxation. The ACh-induced EDHFtype relaxation was significantly weaker in STZ-induced diabetic rats than in control rats, and in both groups of rats it was attenuated by 18␣-glycyrrhetinic acid (18␣-GA), an inhibitor of gap junctions, and enhanced by IBMX, a cAMP-phosphodiesterase (PDE) inhibitor. These enhanced EDHF-type responses were very similar in magnitude between diabetic and age-matched control rats. The EDHF-type relaxation was enhanced by cilostamide, a PDE3-selective inhibitor, but not by Ro 20-1724, a PDE4-selective inhibitor. The expression levels of the mRNAs and proteins for two cAMP PDEs (PDE3A, PDE3B) were significantly increased in STZ-induced diabetic rats, but those for PDE4D were not. We conclude that the impairment of EDHF-type relaxations in STZ-induced diabetic rats may be attributed to a reduction in the action of cAMP via increased PDE activity. endothelium-derived hyperpolarizing factor; adenosine 3Ј,5Ј-cyclic monophosphate; streptozotocin THE ENDOTHELIUM PLAYS a major role in the regulation of vascular tone. It is capable of exerting a profound relaxing influence on the underlying smooth muscle, an effect mediated by at least three different factors, depending on the vascular bed. These factors include nitric oxide (NO) and prostacyclin, both diffusible factors (24,31,47,52,57). In addition, after blockade of NO and prostacyclin synthesis, stimulation of the endothelium is capable of evoking a vascular smooth muscle relaxation that has been attributed to a third factor, endothelium-derived hyperpolarizing factor (EDHF) (8,21,25,67).Although the identity of EDHF is still controversial (46), there is evidence that EDHF-type relaxations involve the transfer of a mediator from the endothelium to the smooth muscle via myoendothelial gap junctions (6,20,59). Indeed, EDHF-type responses are attenuated by connexin-mimetic peptides (6,17,30) and by 18␣-and 18␤-glycyrrhetinic acids (GA), aglycones that disrupt gap junction plaques at points of cell-to-cell contact (12,66,69).It was recently reported that cAMP facilitates EDHF-type relaxation in conduit arteries by enhancing electrotonic conduction via gap junctions (26). In fact, EDHF-type relaxations are potentiated when cAMP hydrolysis is inhibited by the phosphodiesterase (PDE) inhibitor IBMX but remain susceptible to a combination of apamin plus charybdotoxin (65). In accord with such a role for gap junctions, the EDHFtype relaxations and cAMP accumulation evoked by ACh are inhibited by synthetic connexin-mimetic peptides, which interrupt intercellular communication in a connexin-s...

Acetylcholine-induced vasodilation in the perfused kidney of the streptozotocin-induced diabetic rat: role of prostacyclin

“…4), and 5) ACh increased the level of 6-keto-prostaglandin F1α in the effluent from the perfused kidneys of diabetic rats (Kamata and Hosokawa, 1997b). In the present study, an impairment of ACh-induced vasodilation was seen in the perfused kidneys of STZ-induced diabetic rats, as previously reported for other vessels in this diabetic model (Kamata et al, 1989;Kamata and Kobayashi, 1996;De Vriese et al, 2000b;Kobayashi et al, 2000;Matsumoto et al, 2003aMatsumoto et al, , 2004bKamata et al, 2005). This is in agreement with previous reports both by us (Kamata and Hosokawa, 1997b;Kamata and Hayashi, 1999;Kamata and Yamashita, 1999) and by others (Dai et al, 1993;Yousif, 2003), but in contrast to reports by Bhardwaj and Moore (1988), Gebremedhin et al (1989) and Alabadi et al (2001) who reported enhanced endothelium-dependent vasodilation of the renal vascular bed to ACh in experimentally induced diabetes.…”

“…Thus, evidence has accrued to suggest Correspondence to: Katsuo Kamata, Ph.D., Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan Phone: that EDRFs other than NO may contribute to the vascular actions of ACh (Triggle et al, 2003;Matsumoto et al, 2004a;Tanaka et al, 2004). It is well appreciated that ACh stimulates the endothelial production of vasodilatory prostaglandins (Salom et al, 1991;Majid and Navar, 1992;Vizioli et al, 2005), and current evidence suggests that an endothelium-derived hyperpolarizing factor (EDHF) may also contribute to the vasodilator actions of ACh (Busse et al, 2002;Chen et al, 1988;Matsumoto et al, 2003aMatsumoto et al, , 2003bMatsumoto et al, , 2005Matsumoto et al, , 2006aMatsumoto et al, , 2006bTakano et al, 2005;Yamamoto and Suzuki, 2005). Thus, EDRFs distinct from NO may mediate part of the ACh-induced vasodilation.…”

The PI3-K/Akt pathway: roles related to alterations in vasomotor responses in diabetic models

“…Although an accumulating body of evidence indicates that endothelium-dependent relaxation is weaker both in a type I diabetic model, namely the streptozotocin (STZ)-induced rat (Oyama et al, 1986;Kamata et al, 1989aKamata et al, , b, 1996aKamata et al, ,b,c, 1997Abiru et al, 1990a, b;Miyata et al, 1992a,b;Tomlinson et al, 1992;Poston and Taylor, 1995;Pieper, 1998;De Vriese et al, 2000;Makino et al, 2000Makino et al, , 2002Matsumoto et al, 2003Matsumoto et al, , 2004Kobayashi et al, 2004c), and in type II diabetic rats (Sakamoto et al, 1998;Walker et al, 1999;Kagota et al, 2000;Sandu et al, 2000;Kim et al, 2002;Witte et al, 2002;Matsumoto et al, 2004;Kobayashi et al, 2004c), we and others have noted an augmented or unaltered endothelium-dependent relaxation at an early stage in STZdiabetes (Brands and Fitzgerald, 1998;Pieper, 1999, Kobayashi and Kamata, 1999a, Kobayashi et al, 2005b. Moreover, there is some clinical and experimental evidence of augmented blood flow at early stages of diabetes (Jaap and Tooke, 1995;Cipolla et al, 1996; Abbreviations: ACh, acetylcholine; Ang II, angiotensin II; L-Arg, L-arginine; BH4, tetrahydrobiopterin; DOCA, deoxycorticosterone acetate; eNOS, endothelial NO synthase; ET-1, endothelin-1; GSK, glycogen synthase kinase; HDL, high density lipoprotein; HSP, heat-shock protein; IGF-1, insulin-like growth factor 1; IP3, inositol 1,4,5,-triphosphate; IRS-1, insulin receptor substrate-1; LDL, low density lipoprotein; NE, norepinephrine; NO, nitric oxide; NOS, NO synthase; PDK, PI-dependent kinase; PI3-K, phosphatidylinositol 3-kinase; PIP3, phosphatidylinositol-3,4,5-trisphosphate; PTEN, phosphatase and tensin homolog; STZ, streptozotocin; VEGF, vascular endothelial growth factor.…”

Reduced EDHF responses and connexin activity in mesenteric arteries from the insulin-resistant obese Zucker rat

“…Cell cultures exposed to high glucose levels have been used to study gap junctions and specific connexins in isolation, with results showing attenuation of gap junction activity in bovine aortic endothelial and smooth muscle cells [22,23]. Furthermore, investigations using animal models of type 1 diabetes have shown attenuation of EDHF-mediated responses [24] and gap junction activity in mesenteric [25] arteries from streptozotocin (STZ)-induced diabetic rats. To our knowledge, no studies in insulin-resistant or type 2 diabetic animal models have studied changes in gap junction and connexin activity.…”