Selective Impairment of Acetylcholine-Mediated Endothelium-Dependent Relaxation in Isolated Resistance Arteries of the Streptozotocin-Induced Diabetic Rat

1995 ◽  
Vol 88 (5) ◽  
pp. 519-524 ◽  
Author(s):  
P. D. Taylor ◽  
J. E. Graves ◽  
L. Poston
Keyword(s):  
Nitric Oxide ◽  
Sodium Nitroprusside ◽  
Vascular Complications ◽  
Signal Transduction Pathway ◽  
Diabetic Rats ◽  
Mesenteric Arteries ◽  
Diabetic Rat ◽  
Resistance Arteries ◽  
Significant Difference ◽  
Endothelium Dependent Relaxation

1. There is growing evidence that an impairment in the function of nitric oxide synthase may play a role in the vascular complications of diabetes mellitus. The relaxation of resistance arteries from the mesenteric and hindlimb circulations of streptozotocin-induced diabetic rats and age-matched controls were investigated using two endothelium-dependent vasodilators, bradykinin and acetylcholine, and the endothelium-independent vasodilator sodium nitroprusside. The contractile responses to the α1-adrenergic agonist phenylephrine were also studied. 2. Endothelium-dependent relaxation to acetylcholine was impaired in the diabetic rats in arteries from both mesenteric and hindlimb circulations (hindlimb pEC50, 7.93 ± 0.08 in the control compared with 7.38 ± 0.10 in the diabetic rat; mesenteric pEC50, 7.47 ± 0.04 in the control compared with 6.65 ± 0.06 in the diabetic rat; unpaired t-test P < 0.0001). Bradykinin elicited relaxation in only the mesenteric arteries, and this was not attenuated in the diabetic rats compared with controls. 3. Endothelium-independent relaxation to sodium nitroprusside was similar in the two circulations and was not abnormal in the diabetic rats. There was no significant difference in constrictor responses to phenylephrine between diabetic rats and controls in either the hindlimb or mesenteric arteries, in contrast to an earlier study in which we showed increased sensitivity to noradrenaline. 4. The diabetic rats therefore demonstrated a specific impairment of receptor-mediated endothelium-dependent relaxation to acetylcholine. These results suggest that, in this diabetic model, the ability of the endothelium to relax arteries via nitric oxide may involve a defect of a specific signal transduction pathway, leading to reduced production of nitric oxide.

scholarly journals Diabetes Attenuates the Contribution of Endogenous Nitric Oxide but Not Nitroxyl to Endothelium Dependent Relaxation of Rat Carotid Arteries

2021 ◽  
Vol 11 ◽  
Author(s):  
Jasmin Chendi Li ◽  
Anida Velagic ◽  
Cheng Xue Qin ◽  
Mandy Li ◽  
Chen Huei Leo ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Nitrogen Oxide ◽  
Carotid Arteries ◽  
Body Weight Gain ◽  
Vascular Complications ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Endothelium Dependent Relaxation

Introduction:Endothelial dysfunction is a major risk factor for several of the vascular complications of diabetes, including ischemic stroke. Nitroxyl (HNO), the one electron reduced and protonated form of nitric oxide (NO•), is resistant to scavenging by superoxide, but the role of HNO in diabetes mellitus associated endothelial dysfunction in the carotid artery remains unknown.Aim: To assess how diabetes affects the role of endogenous NO• and HNO in endothelium-dependent relaxation in rat isolated carotid arteries.Methods: Male Sprague Dawley rats were fed a high-fat-diet (HFD) for 2 weeks prior to administration of low dose streptozotocin (STZ; 35 mg/kg i. p./day) for 2 days. The HFD was continued for a further 12 weeks. Sham rats were fed standard chow and administered with citrate vehicle. After 14 weeks total, rats were anesthetized and carotid arteries collected to assess responses to the endothelium-dependent vasodilator, acetylcholine (ACh) by myography. The combination of calcium-activated potassium channel blockers, TRAM-34 (1 μmol/L) and apamin (1 μmol/L) was used to assess the contribution of endothelium-dependent hyperpolarization to relaxation. The corresponding contribution of NOS-derived nitrogen oxide species to relaxation was assessed using the combination of the NO• synthase inhibitor, L-NAME (200 μmol/L) and the soluble guanylate cyclase inhibitor ODQ (10 μmol/L). Lastly, L-cysteine (3 mmol/L), a selective HNO scavenger, and hydroxocobalamin (HXC; 100 μmol/L), a NO• scavenger, were used to distinguish between NO• and HNO-mediated relaxation.Results: At study end, diabetic rats exhibited significantly retarded body weight gain and elevated blood glucose levels compared to sham rats. The sensitivity and the maximal relaxation response to ACh was significantly impaired in carotid arteries from diabetic rats, indicating endothelial dysfunction. The vasorelaxation evoked by ACh was abolished by L-NAME plus ODQ, but not affected by the apamin plus TRAM-34 combination, indicating that NOS-derived nitrogen oxide species are the predominant endothelium-derived vasodilators in sham and diabetic rat carotid arteries. The maximum relaxation to ACh was significantly decreased by L-cysteine in both sham and diabetic rats, whereas HXC attenuated ACh-induced relaxation only in sham rats, suggesting that diabetes impaired the contribution of NO•, whereas HNO-mediated vasorelaxation remained intact.Conclusion: Both NO• and HNO contribute to endothelium-dependent relaxation in carotid arteries. In diabetes, NO•-mediated relaxation is impaired, whereas HNO-mediated relaxation was preserved. The potential for preserved HNO activity under pathological conditions that are associated with oxidative stress indicates that HNO donors may represent a viable therapeutic approach to the treatment of vascular dysfunction.

Losartan improves aortic endothelium-dependent relaxation via proline-rich tyrosine kinase 2/Src/Akt pathway in type 2 diabetic Goto-Kakizaki rats

2011 ◽  
Vol 301 (6) ◽  
pp. H2383-H2394 ◽  
Author(s):  
Shingo Nemoto ◽  
Tsuneo Kobayashi ◽  
Kumiko Taguchi ◽  
Takayuki Matsumoto ◽  
Katsuo Kamata
Keyword(s):  
Nitric Oxide ◽  
Tyrosine Kinase ◽  
Vascular Complications ◽  
Akt Pathway ◽  
Diabetic Rat ◽  
Tyrosine Kinase 2 ◽  
Endothelium Dependent Relaxation ◽  
Type 2 Diabetic ◽  
Losartan Treatment

In diabetic states, endothelial dysfunction is related to vascular complications. We hypothesized that insulin-induced relaxation and the associated proline-rich tyrosine kinase 2 (Pyk2)/Src/Akt pathway would be abnormal in aortas from the Goto-Kakizaki (GK) type 2 diabetic rat, which exhibits hyperglycemia/insulin resistance, and that losartan treatment of such rats (25 mg·kg−1·day−1 for 2 wk) would correct these abnormalities. Endothelium-dependent relaxation was by measuring isometric force in helical strips of aortas from four groups, each of 30 rats: normal Wistar (control), GK (diabetic), losartan-treated normal, and losartan-treated GK. Pyk2, Src, and Akt/endothelial nitric oxide synthase (eNOS) signaling-pathway protein levels and activities were assayed mainly by Western blotting and partly by immunohistochemistry. In GK (vs. age-matched control) aortas, various insulin-stimulated levels [nitric oxide production and the phosphorylations of eNOS at Ser1177, of Akt at Thr308, of phosphoinositide-dependent kinase-1 (PDK1) at Ser241, of Src at Tyr416, and of Pyk2 at Tyr579] were all significantly decreased and unaffected by either Src inhibitor (PP2) or Pyk2 inhibitor (AG17), while the insulin-stimulated levels of insulin receptor substrate (IRS)-1 phosphorylation at Ser307, total-eNOS, and total-Akt were significantly increased. Losartan treatment normalized these altered levels. The insulin-stimulated phosphorylation levels of Src/PDK1/Akt/eNOS, but not of Pyk2, were decreased by PP2 in control and losartan-treated GK, but not in GK, aortas. These results suggest that in the GK diabetic aorta increased phospho-IRS-1 (at Ser307) and decreased Pyk2/Src activity inhibit insulin-induced stimulation of the PDK/Akt/eNOS pathway. The observed increase in phospho-IRS-1 (at Ser307) may result from increased angiotensin II activity.

Age-related changes in endothelium-dependent relaxation in aorta from genetically diabetic WBN/Kob rats

1992 ◽  
Vol 262 (4) ◽  
pp. H1104-H1109 ◽  
Author(s):  
N. Miyata ◽  
K. Tsuchida ◽  
S. Okuyama ◽  
S. Otomo ◽  
K. Kamata ◽  
...  
Keyword(s):  
Sodium Nitroprusside ◽  
Matched Control ◽  
Vascular Complications ◽  
Diabetic Rats ◽  
Response Curves ◽  
Functional Changes ◽  
Age Related ◽  
Relaxation Responses ◽  
Effects Of Aging ◽  
Endothelium Dependent Relaxation

Experiments were designed to investigate the effects of aging and hyperglycemia on relaxation of the aorta for both endothelium-dependent and -independent agents in Wistar (control) and WBN/Kob (genetically diabetic) rats. The concentration of glucose in serum was elevated significantly in aged (90-92 wk) but not young (13-15 wk) WBN/Kob rats. Endothelium-dependent relaxations of both control and WBN/Kob rats to acetylcholine were reduced by aging. The relaxations induced by acetylcholine in aortic strips were significantly attenuated in both young (nondiabetic) and aged (diabetic) WBN/Kob rats, compared with those from age-matched control vessels, respectively. The concentration-response curves for sodium nitroprusside in aortic strips from both aged control and aged WBN/Kob rats were shifted to the left when compared with those from young rats, respectively. However, the maximal relaxation responses to sodium nitroprusside showed no difference among all vessels studied. The relaxations induced by sodium nitroprusside in aortic strips from both young and aged WBN/Kob rats were similar to those from age-matched control rats, respectively. The relaxations induced by atrial natriuretic peptide showed no difference among all vessels studied. In genetically diabetic rats, functional changes in endothelium occurred before elevation of the levels of glucose in the serum. Thus impaired endothelium-dependent relaxation may play an important role in the high incidence of vascular complications in diabetes mellitus.

Abstract P500: Activation of the Heterodimeric Erythropoietin /β-Common Receptor Impairs Acetylcholine Mediated Vasodilation in Mouse Mesenteric Arterioles

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Cody R Kilar ◽  
YanPeng Diao ◽  
Larysa Sautina ◽  
Sivakumar Sekharan ◽  
Shahar Keinan ◽  
...  
Keyword(s):  
Sodium Nitroprusside ◽  
Vascular Complications ◽  
Mesenteric Arteries ◽  
No Production ◽  
Resistance Arteries ◽  
Inhibitory Peptide ◽  
Receptor Complexes ◽  
Common Receptor ◽  
Potent Vasodilator ◽  
Selective Impairment

Erythropoietin (EPO) increases systemic vascular resistance and blood pressure. However, endothelial cells cultured in the presence of EPO demonstrate increased production of the potent vasodilator, nitric oxide (NO). The mechanism by which EPO causes vasoconstriction despite stimulating NO production may be dependent on its ability to differentially activate the two receptor complexes, the homodimeric EPO (EPOR 2 ) and the heterodimeric EPOR/β-common receptor (βCR). Objective: The purpose of this study was to investigate the contribution of the EPOR 2 and βCR receptor to the vasoactive properties of EPO. Methods: First order, mesenteric arteries isolated from 16-week old male C57BL/6 mice were cannulated and perfused using a pressure arteriography system. To determine the contribution of each receptor complex, arteries were incubated with EPO stimulating peptide (ESP) which binds and activates only the heterodimeric EPOR/βCR complex or EPO which activates both receptors, 20 min prior to evaluation of vasoconstrictor (phenylephrine and potassium chloride), endothelium-dependent (acetylcholine, bradykinin, A23187) and -independent (sodium nitroprusside) vasodilator responses. Additionally, we studied the effect of a novel βCR inhibitory peptide (βIP) which was developed in silico and validated by demonstrating that it selectively inhibits binding of ligands to the βCR. Results: Acetylcholine induced vasodilation was impaired in arteries pretreated with EPO or ESP by 100% and 60%, respectively. EPO and ESP did not affect endothelium-dependent vasodilation by Bradykinin or A23187, endothelium-independent vasodilation by sodium nitroprusside, or vasoconstriction by phenylephrine and KCl. The βIP prevented the impairment of acetylcholine-induced vasodilation by EPO and ESP. Conclusion: Together, our findings suggest that activation of the heterodimeric EPOR/βCR leads to selective impairment of ACh-mediated vasodilator response in mouse mesenteric resistance arteries. Thus the βCR might have a role in mediating hypertensive effects of EPO. Therapeutic inhibition of the βCR might prevent vascular complications of EPO without affecting erythropoiesis.

Impairment of endothelium-dependent relaxation of superior mesenteric artery in genetically diabetic WBN/Kob rats

1993 ◽  
Vol 71 (3-4) ◽  
pp. 297-300 ◽  
Author(s):  
Noriyuki Miyata ◽  
Hiroko Yamaura ◽  
Katsuharu Tsuchida ◽  
Shigeru Okuyama ◽  
Susumu Otomo ◽  
...  
Keyword(s):  
Sodium Nitroprusside ◽  
Superior Mesenteric Artery ◽  
Mesenteric Artery ◽  
Wistar Rats ◽  
Diabetic Rats ◽  
Mesenteric Arteries ◽  
Relaxing Factor ◽  
Endothelium Derived Relaxing Factor ◽  
Relaxation Responses ◽  
Endothelium Dependent Relaxation

The endothelium-dependent relaxation of superior mesenteric arteries of Wistar and genetically diabetic WBN/Kob rats was compared. Endothelium-dependent relaxation induced by acetylcholine (ACh) and A23187 was depressed in WBN/Kob rats. Relaxation induced by sodium nitroprusside, an endothelium-independent agent, in strips from WBN/Kob rats was similar to that in strips from Wistar rats. Indomethacin (5 × 10−6 M) enhanced the relaxation responses to ACh in strips from both WBN/Kob and Wistar rats; however, endothelium-dependent relaxation induced by ACh remained attenuated in WBN/Kob rats. These results show that endothelium-dependent relaxation is impaired not only in thoracic aorta but also in superior mesenteric arteries in genetically diabetic rats.Key words: acetylcholine, A23187, sodium nitroprusside, indomethacin, genetically diabetic rats, endothelium-derived relaxing factor.

Chronic stimulation of farnesoid X receptor impairs nitric oxide sensitivity of vascular smooth muscle

2009 ◽  
Vol 296 (1) ◽  
pp. H195-H201 ◽  
Author(s):  
Taiki Kida ◽  
Takahisa Murata ◽  
Masatoshi Hori ◽  
Hiroshi Ozaki
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Sodium Nitroprusside ◽  
Muscle Cells ◽  
Farnesoid X Receptor ◽  
Mesenteric Arteries ◽  
Chronic Stimulation ◽  
Endothelium Dependent Relaxation ◽  
Stimulation Of

Farnesoid X receptor (FXR), a member of the nuclear receptor superfamily that is highly expressed in enterohepatic tissue, is implicated in bile acid, lipid, and glucose metabolisms. Although recent studies showed that FXR is also expressed in vascular endothelial cells and smooth muscle cells, its physiological and/or pathological roles in vasculature tissue remain unknown. The aim of this study is to examine the chronic effect of synthetic FXR agonist GW4064 on vascular contraction and endothelium-dependent relaxation using tissue culture procedure. In cultured rabbit mesenteric arteries, the treatment with 0.1–10 μM GW4064 for 7 days did not influence vascular contractility induced by high K+(15–65 mM), norepinephrine (0.1–100 μM), and endothelin-1 (0.1–100 nM). However, the chronic treatment with GW4064 (1–10 μM for 7 days) dose dependently impaired endothelium-dependent relaxation induced by substance P (0.1–30 nM). In hematoxylin-eosin cross sectioning and en face immunostaining, GW4064 had no effects on the morphology of endothelial and smooth muscle cells. In endothelium-denuded arteries treated with GW4064 (1–10 μM) for 7 days, 3 nM–100 μM sodium nitroprusside-induced vasorelaxation, but not membrane-permeable cGMP analog 8-bromoguanosine-cGMP (8-Br-cGMP; 1–100 μM)-induced vasorelaxation, was significantly impaired. In these GW4064-treated arteries, 1 μM sodium nitroprusside-induced intracellular cGMP elevations were impaired. In RT-PCR, any changes were detected in mRNA expression level of α1- and β1-subunit of soluble guanylyl cyclase. These results suggest that chronic stimulation of FXR impairs endothelium-dependent relaxation, which is due to decreased sensitivity of smooth muscle cells to nitric oxide.

Effects of Volatile Anesthetics on Acetylcholine-induced Relaxation in the Rabbit Mesenteric Resistance Artery 

1995 ◽  
Vol 82 (1) ◽  
pp. 188-204 ◽  
Author(s):  
Takashi Akata ◽  
Mikio Nakashima ◽  
Kenji Kodama ◽  
Walter A. Boyle ◽  
Shosuke Takahashi
Keyword(s):  
Endothelial Function ◽  
Sodium Nitroprusside ◽  
Volatile Anesthetic ◽  
Volatile Anesthetics ◽  
Mesenteric Arteries ◽  
K Channel ◽  
Resistance Arteries ◽  
Anesthetic Action ◽  
Endothelium Dependent Relaxation

Background Vascular endothelium plays an important role in the regulation of vascular tone. Volatile anesthetics have been shown to attenuate endothelium-mediated relaxation in conductance arteries, such as aorta. However, significant differences in volatile anesthetic pharmacology between these large vessels and the small vessels that regulate systemic vascular resistance and blood flow have been documented, yet little is known about volatile anesthetic action on endothelial function in resistance arteries. Furthermore, endothelium-dependent relaxation mediated by factors other than endothelium-derived relaxing factor (EDRF) has recently been recognized, and there is no information available regarding volatile anesthetic action on non-EDRF-mediated endothelium-dependent relaxation. Methods Employing isometric tension recording and microelectrode methods, the authors first characterized the endothelium-dependent relaxing and hyperpolarizing actions of acetylcholine (ACh) in rabbit small mesenteric arteries, and tested the sensitivities of these actions to EDRF pathway inhibitors and K+ channel blockers. They then examined the effects of the volatile anesthetics isoflurane, enflurane, and sevoflurane on ACh-induced endothelium-dependent relaxation that was sensitive to EDRF inhibitors and that which was resistant to the EDRF inhibitors but sensitive to blockers of ACh-induced hyperpolarization. The effects of the volatile anesthetics on endothelium-independent sodium nitroprusside (SNP)-induced relaxation were also studied. Results Acetylcholine concentration-dependently caused both endothelium-dependent relaxation and hyperpolarization of vascular smooth muscle. The relaxation elicited by low concentrations of ACh (&lt; or = 0.1 microM) was almost completely abolished by the EDRF inhibitors NG-nitro-L-arginine (LNNA), oxyhemoglobin (HbO2), and methylene blue (MB). The relaxation elicited by higher concentrations of ACh (&gt; or = 0.3 microM) was only attenuated by the EDRF inhibitors. The remaining relaxation, as well as the ACh-induced hyperpolarization that was also resistant to EDRF inhibitors, were both specifically blocked by tetraethylammonium (TEA &gt; or = 10 mM). Sodium nitroprusside, a NO donor, produced dose-dependent relaxation, but not hyperpolarization, in the endothelium-denuded (E[-]) strips, and the relaxation was inhibited by MB and HbO2, but not TEA (&gt; or = 10 mM). One MAC isoflurane, enflurane, and sevoflurane inhibited both ACh relaxation that was sensitive to the EDRF inhibitors and the ACh relaxation resistant to the EDRF inhibitors and sensitive to TEA, but not SNP relaxation (in the E[-] strips). An additional finding was that the anesthetics all significantly inhibited norepinephrine (NE) contractions in the presence and absence of the endothelium or after exposure to the EDRF inhibitors. Conclusions The results confirm that ACh has a hyperpolarizing action in rabbit small mesenteric resistance arteries that is independent of EDRF inhibitors but blocked by the K+ channel blocker TEA. The ACh relaxation in these resistance arteries thus appears to consist of distinct EDRF-mediated and hyperpolarization-mediated components. Isoflurane, enflurane, and sevoflurane inhibited both components of the ACh-induced relaxation in these small arteries, indicating a more global depression of endothelial function or ACh signaling in endothelial cells, rather than a specific effect on the EDRF pathway. All these anesthetics exerted vasodilating action in the presence of NE, the primary neurotransmitter of the sympathetic nervous system, which plays a major role in maintaining vasomotor tone in vivo. This strongly indicates that the vasodilating action of these anesthetics probably dominates over their inhibitory action on the EDRF pathway and, presumably, contributes to their known hypotensive effects in vivo. Finally, the vasodilating action of these anesthetics is, at least in part, independent from endothelium.

Superoxide dismutase recovers altered endothelium-dependent relaxation in diabetic rat aorta

1991 ◽  
Vol 261 (4) ◽  
pp. H1086-H1094 ◽  
Author(s):  
Y. Hattori ◽  
H. Kawasaki ◽  
K. Abe ◽  
M. Kanno
Keyword(s):  
Superoxide Dismutase ◽  
Superoxide Anion ◽  
Rat Aorta ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Transient Nature ◽  
Significant Difference ◽  
Time Courses ◽  
And Control ◽  
Endothelium Dependent Relaxation

Experiments were designed to characterize endothelium-dependent relaxation in thoracic aortic rings obtained from streptozotocin-induced diabetic rats. When the degree of the peak relaxation was compared, the endothelium-dependent relaxant responses to acetylcholine, histamine, or ADP in precontracted aortic rings showed that there was no significant difference between diabetic and control vessels. However, the time courses appeared quite different. The endothelium-dependent relaxant responses in diabetic vessels were more transient than those in control vessels. In addition, the rapid fade of the endothelium-dependent responses observed in diabetic vessels was significantly suppressed by pretreatment with superoxide dismutase. Pretreatment with catalase, deferoxamine, allopurinol, or indomethacin did not prevent the rapid fade of the endothelium-dependent relaxation. The endothelium-independent relaxation induced by nitric oxide also faded more quickly in diabetic vessels; this impairment was less pronounced in the presence of superoxide dismutase. These results suggest that the transient nature of the endothelium-dependent relaxation is more marked in diabetic rat aorta as a result of an enhanced accumulation of superoxide anion.

Endothelial Function in Subcutaneous Resistance Arteries from Elderly Hypertensive and Normotensive Subjects

1997 ◽  
Vol 92 (2) ◽  
pp. 139-145 ◽  
Author(s):  
Martin A. James ◽  
Pamela A. C. Watt ◽  
John F. Potter ◽  
Herbert Thurston ◽  
John D. Swales
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Sodium Nitroprusside ◽  
Elderly Subjects ◽  
Resistance Arteries ◽  
Elderly Hypertensive ◽  
Normotensive Subjects ◽  
Relaxation Responses ◽  
Oxide Synthase ◽  
Endothelium Dependent Relaxation

1. Previous studies have indicated that younger hypertensive subjects may have abnormal endothelium-dependent relaxation, which could contribute to the elevated peripheral resistance seen in established hypertension. This study was designed to examine the functional behaviour of the endothelium of small arteries from elderly hypertensive and normotensive subjects. 2. Resistance arteries were obtained from gluteal biopsies taken under local anaesthesia in 28 subjects of mean age 70 (range 60–76) years, and studied in an isometric myograph. Eighteen subjects had untreated essential hypertension, and 10 were normotensive. 3. After measurement of the contractile response to noradrenaline, relaxation responses to a variety of endothelium-dependent (acetylcholine and bradykinin) and endothelium-independent (iloprost and sodium nitroprusside) mechanisms were assessed in vessels precontracted with noradrenaline. Endothelium-dependent responses were also studied after incubation with NG-nitro-l-arginine to inhibit nitric oxide synthase. 4. There were no significant differences in the contraction or relaxation responses between elderly subjects with or without high blood pressure. Inhibition of nitric oxide synthase prevented any relaxation with acetylcholine and significantly attenuated the relaxation with bradykinin. Near-complete relaxation was however achieved with the endothelium-independent vasodilator sodium nitroprusside. 5. Hypertension in elderly subjects is not associated with a reduction in endothelial vasodilating function in the subcutaneous vessels of the gluteal region compared with age-matched normotensive controls. The results of this study do not support the hypothesis of a defect of resistance artery endothelium-dependent relaxation in the pathophysiology of hypertension in the elderly.

Functional changes in adenylyl cyclases and associated decreases in relaxation responses in mesenteric arteries from diabetic rats

2005 ◽  
Vol 289 (5) ◽  
pp. H2234-H2243 ◽  
Author(s):  
Takayuki Matsumoto ◽  
Kentaro Wakabayashi ◽  
Tsuneo Kobayashi ◽  
Katsuo Kamata
Keyword(s):  
Mesenteric Artery ◽  
Diabetic Rats ◽  
Functional Change ◽  
Water Soluble ◽  
Mesenteric Arteries ◽  
Diabetic Rat ◽  
Adenylyl Cyclases ◽  
Camp Production ◽  
Functional Changes ◽  
Rat Mesenteric Artery

To assess the functional change in adenylyl cyclases (AC) associated with the diabetic state, we investigated AC-mediated relaxations and cAMP production in mesenteric arteries from rats with streptozotocin (STZ)-induced diabetes. The relaxations induced by the water-soluble forskolin (FSK) analog NKH477, which is a putative AC5 activator, but not by the β-adrenoceptor agonist isoproterenol (Iso) and the AC activator FSK, were reduced in intact diabetic mesenteric artery. In diabetic rats, however, Iso-, FSK-, and NKH477-induced relaxations were attenuated in the presence of inhibitors of nitric oxide synthase and cyclooxygenase. To exclude the influence of phosphodiesterase (PDE), we also examined the relaxations induced by several AC activators in the presence of 3-isobutyl-1-methylxanthine (IBMX; a PDE inhibitor). Under these conditions, the relaxation induced by Iso was greatly impaired in STZ-diabetic rats. This Iso-induced relaxation was significantly attenuated by pretreatment with SQ-22536, an AC inhibitor, in mesenteric rings from age-matched controls but not in those from STZ-diabetic rats. Under the same conditions, the relaxations induced by FSK or NKH477 were impaired in STZ-diabetic rats. Neither FSK- nor A-23187 (a Ca2+ ionophore)-induced cAMP production was significantly different between diabetics and controls. However, cAMP production induced by Iso or NKH477 was significantly impaired in diabetic mesenteric arteries. Expression of mRNAs and proteins for AC5/6 was lower in diabetic mesenteric arteries than in controls. These results suggest that AC-mediated relaxation is impaired in the STZ-diabetic rat mesenteric artery, perhaps reflecting a reduction in AC5/6 activity.

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