Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we have investigated the vasodilator response to acetylcholine under diabetic conditions in isolated renal arteries of Wistar rats. The effect of nitric oxide synthase (NOS) inhibition on acetylcholine-induced vasodilator response was investigated. We have also examined the effects of two endothelium-dependent agonists which induce receptor-dependent and receptor-independent vasodilator responses. Acetylcholine (10(-10) to 10(-4)M) produced a cumulative concentration-response curve in the renal arteries of both control and diabetic rats. The EC(50) values and maximal responses to acetylcholine were reduced relative to diabetic conditions. The vasodilator response to sodium nitroprusside (SNP) (10(-10) to 10(-5)M) was also investigated. SNP produced a cumulative concentration-dependent vasodilator response, which was not affected under diabetic conditions. To confirm the nitric oxide component of acetylcholine-induced vasodilator response, L-nitro-methyl arginine ester (L-NAME) (10(-4)M) was added to the Krebs' solution. The maximal vasodilator response to acetylcholine was reduced in the presence of L-NAME (10(-4)M) in both control and diabetic renal preparations, with greater attenuation in the diabetic conditions. In order to examine the possible contribution of receptor dysfunction in diabetes, the vasodilator response to ADP (receptor-dependent agonist) and the calcium ionophore A23187 (receptor-independent agonist) were investigated. ADP (10(-10) to 10(-5)M) produced a concentration-dependent vasodilator response in preparations from both control and diabetic rats. The maximal vasodilator response to ADP was significantly reduced in the renal arteries from diabetic animals. However, A23187 (10(-10) to 10(-5)M); the receptor-independent agonist, produced a concentration-dependent vasodilator response in both control and diabetic rat preparations. There was no significant change in the EC(50) values or maximal vasodilator responses to A23187 under diabetic conditions. In conclusion, our results indicated that acetylcholine-induced vasodilatation in the isolated renal arteries of streptozotocin (STZ)-induced diabetic rats was attenuated under diabetic conditions. The reduction in acetylcholine-induced vasodilatation may be attributed to acetylcholine receptor dysfunction. This is based on the results from this study in which the vasodilator response to the receptor-independent agonist A23187 were maintained, while that of the receptor-dependent agonist ADP was attenuated under diabetic conditions.
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PMID:Diabetes differentially modulated receptor- and non-receptor-mediated relaxation in rat renal artery. 1286 Apr 50

Vascular complications associated with diabetes mellitus (DM) have been linked to activation of PKC-dependent signaling pathways in both human and animal models of DM. To determine whether aberrant PKC signaling mechanisms specifically impact the coronary circulation, we assessed isolated coronary artery (CA) responses after the induction of Type 1 DM. Male Sprague-Dawley rats were subjected to partial pancreatectomy (DM; n = 23) and compared with age-matched controls (CTL; n = 19). Vasoreactivity was assessed in single CAs ( approximately 250 microm internal diameter) after abluminal administration of the Gq-dependent vasoconstrictors endothelin (ET)-1 (10(-10)-10(-9) M) and U-44619 (10(-9)-10(-5) M) or the voltage-gated Ca2+ channel agonist BAY K 8644 (10(-9)-10(-5) M) with and without the PKC inhibitor bisindolylmaleimide (Bis; 10(-6) M). Dilator responses to ACh (10(-9)-10(-5) M) were also assessed. ET-1 resulted in significantly greater constriction in the DM versus CTL group (50 +/- 4% vs. 33 +/- 5%, P < 0.0001), whereas responses to U-44619 and BAY K 8644 were similar between groups. Importantly, inhibition of ET-1 and U-44619 constriction by Bis occurred in the DM but not CTL group (P < 0.05). Western blotting on isolated CAs revealed greater levels of PKC-alpha, PKC-beta I, and PKC-beta II by 22%, 15.3%, and 17.6%, respectively, in the DM versus CTL group (P < 0.05), whereas PKC-delta and PKC-epsilon protein levels were unchanged. DM was also associated with attenuated CA dilation after ACh treatment (P < 0.0566) and reductions in endothelial nitric oxide synthase protein levels versus CTL (P < 0.03). These data suggest that Ca2+-dependent PKC signaling pathways, particularly for ET-1, play a greater role in modulating CA vasoconstrictor responses in DM versus CTL. These data further suggest that aberrant CA constrictor and dilator responses are likely to contribute to the coronary vascular pathology associated with DM.
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PMID:Alterations in rat coronary vasoreactivity and vascular protein kinase C isoforms in Type 1 diabetes. 1291 31

(1) The aim of the present study was to investigate the causal relationship between peroxisome proliferator-activated receptor (PPAR) and endothelium-dependent relaxation in streptozotocin (STZ)-induced diabetic rats. (2) Acetylcholine (ACh)-induced endothelium-dependent relaxation was significantly weaker in diabetic rats than in age-matched controls. The decreased relaxation in diabetes was improved by the chronic administration of bezafibrate (30 mg kg-1, p.o., 4 weeks). (3) The expressions of the mRNAs for PPARalpha and PPARgamma were significantly decreased in STZ-induced diabetic rats (compared with the controls) and this decrease was restored partially, but not completely, by the chronic administration of bezafibrate. (4) Superoxide dismutase activity in the aorta was not significantly different between diabetic rats and bezafibrate-treated diabetic rats. (5) The expression of the mRNA for the p22phox subunit of NAD(P)H oxidase was significantly higher in diabetics than in controls, but it was lower in bezafibrate-treated diabetic rats than in nontreated diabetic rats. Although the expression of the mRNA for prepro ET-1 (ppET-1) was markedly increased in diabetic rats (compared with controls), this increase was prevented to a significant extent by the chronic administration of bezafibrate. (6) These results suggest that downregulations of PPARalpha and PPARgamma may lead to an increased expression of ppET-1 mRNA in diabetic states and this increment may trigger endothelial dysfunction.
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PMID:Relationship between peroxisome proliferator-activated receptors (PPAR alpha and PPAR gamma) and endothelium-dependent relaxation in streptozotocin-induced diabetic rats. 1296 31

Obesity is associated with many comorbid conditions including diabetes, hyperlipidemia, and gallstones. However, the interaction among these modalities remains unclear. We recently demonstrated that both leptin-deficient and leptin-resistant obese mice have impaired biliary motility. These obese mice also are diabetic and hyperlipidemic. Therefore, we tested the hypothesis that serum glucose, insulin, cholesterol, and triglyceride levels would correlate with gallbladder contractility. Thirty-four lean control, 10 lean heterozygous leptin-deficient, 18 obese homozygous leptin-deficient, and 12 obese homozygous leptin-resistant mice were fed a nonlithogenic chow diet while nine lean control and nine obese homozygous leptin-deficient mice were fed a high-cholesterol diet for 4 weeks. In vitro gallbladder responses to cholecystokinin (CCK; 10(-8) mol/L), acetylcholine (ACh; 10(-5) mol/L), and neuropeptide Y (NPY; 10(-6) mol/L) were measured. Serum glucose, insulin, cholesterol, and triglyceride levels were measured from pooled serum from an additional 704 animals. Gallbladder responses were greatest for CCK, intermediate for ACh, and least for NPY. Serum glucose, insulin, cholesterol, and triglyceride levels and body weight all correlated similarly, negatively, and significantly (P<0.001) with gallbladder contractility. Hyperglycemia, insulin-resistance, hyperlipidemia, and body weight in obese mice with leptin dysfunction are associated with poor gallbladder contractility, which in turn may contribute to the association between obesity and gallstone formation.
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PMID:Diabetes and hyperlipidemia correlate with gallbladder contractility in leptin-related murine obesity. 1459 58

Acetylcholine release from cholinergic nerves in the gastrointestinal tract is limited by neuronal M(2) muscarinic receptors. In diabetic animals, M(2) muscarinic receptor function in the ileum is increased, leading to decreased acetylcholine release and smooth muscle contraction in response to nerve stimulation. The mechanisms responsible for increased M(2) muscarinic receptor function are unknown but may contribute to the gastrointestinal dysmotility that occurs frequently in diabetics. In this study, we investigated whether insulin modulates M(2) muscarinic receptor function in the gastrointestinal tract of diabetic rats. M(2) muscarinic receptor function was tested by measuring the ability of an agonist, pilocarpine, to inhibit and an antagonist, methoctramine, to potentiate electrical field stimulation (EFS)-induced contraction of ileum in vitro. Insulin administration (0.2, 0.6, and 2 U s.c. daily for 7 days) reversed the diabetes-induced increase in M(2) muscarinic receptor function and restored normal contractions to EFS. Insulin had no effect on the function of postjunctional M(3) muscarinic receptors, determined by measuring contractile responses to acetylcholine. These data suggest that insulin tonically inhibits neuronal M(2) muscarinic receptors. Thus, loss of insulin removes this inhibition and increases M(2) muscarinic receptor function leading to decreased acetylcholine release and contraction to EFS. In nondiabetic rats, there was a trend that higher insulin doses (0.6 and 2 U) increased M(2) muscarinic receptor function, suggesting a bell-shaped concentration-response relationship for insulin. In conclusion, lack of insulin or excess insulin increases M(2) muscarinic receptor function in rat ileum. This mechanism may contribute to decreased acetylcholine release in the gastrointestinal tract of diabetics, resulting in dysmotility.
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PMID:Insulin regulates neuronal M2 muscarinic receptor function in the ileum of diabetic rats. 1461 Feb 35

1. The functional changes in mesenteric arterioles of streptozotocin-induced diabetes were investigated by intravital microscopy. The mesentery was exteriorized from anesthetized rats, spread in a chamber, and superfused with Tyrode solution. All drugs tested were applied to the superfusing Tyrode solution. 2. Compared with age-matched controls, the diabetic rats showed enhanced vascular sensitivity to phenylephrine, an alpha(1)-adrenoceptor agonist. The preincubation of the mesentery with N(G)-nitro-l-arginine (l-NNA), a nitric oxide synthase (NOS) inhibitor, shifted the phenylephrine-concentration-response curves to the left in both the diabetic and control rats. Even in the presence of l-NNA, the sensitivity to phenylephrine was higher in the diabetic rats than in the control. 3. Acetylcholine relaxed the mesenteric arterioles in both groups, but to a significantly greater extent in the control than in the diabetic rats. However, the l-NNA-induced constriction of arterioles did not differ significantly between the groups. In contrast, the amplitude of the constrictions of mesenteric arterioles induced by S-ethylisothiourea, an inducible NOS (iNOS) inhibitor, was significantly greater in the diabetic rats than in the control. 4. Immunostaining of the mesentery with a specific antibody for iNOS revealed iNOS in the microvessels of only the diabetic rats. 5. These results suggest that constrictor responses to alpha(1)-adrenoceptor stimulation are sensitized in the mesenteric arterioles of STZ-diabetic rats, and that iNOS expressed in the arteriolar smooth muscle plays a role in suppressing the basal tone and the reactivity of the arterioles in STZ-diabetic rats.
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PMID:Contribution of nitric oxide produced by inducible nitric oxide synthase to vascular responses of mesenteric arterioles in streptozotocin-diabetic rats. 1470 30

We hypothesized that resistance arteries from diabetic patients with controlled hypertension have less remodeling than vessels from untreated hypertensive subjects. Eight normotensive subjects (aged 44+/-3 years, 3 men; values are mean+/-SEM), 19 untreated hypertensive subjects (46+/-2 years, 9 men), and 23 hypertensive subjects with type 2 diabetes mellitus under antihypertensive treatment (58+/-1 years, 15 men) were studied. Resistance arteries dissected from gluteal subcutaneous tissue were assessed on a pressurized myograph. Most diabetic patients (70%) were being treated with angiotensin-converting enzyme inhibitors. Although systolic blood pressure was still above the normotensive range in these patients (144+/-2 versus 150+/-3 mm Hg in hypertensive and 114+/-4 mm Hg in normotensive subjects), diastolic blood pressure was well controlled (83+/-2 mm Hg) and significantly lower compared with that in untreated hypertensives (100+/-1 mm Hg; P<0.001) but higher than in normotensives (76+/-3 mm Hg; P<0.05). Thus, pulse pressure was higher in diabetic patients (P<0.05). The media-to-lumen ratio of resistance arteries was greater in hypertensives (0.083+/-0.002) compared with normotensive controls (0.059+/-0.003; P<0.05) and was even higher in diabetic hypertensive subjects (0.105+/-0.004; P<0.001 versus normotensive controls). The medial cross-sectional area was greater in diabetic and hypertensive patients compared with normotensive controls (P<0.001). Acetylcholine-induced relaxation was impaired in vessels from hypertensive patients and from patients with both diabetes mellitus and hypertension (P<0.05 versus normotensive controls), whereas endothelium-independent vasorelaxation was similar in all groups. Despite effective antihypertensive treatment, resistance arteries from hypertensive diabetic patients showed marked remodeling, greater than that of vessels from untreated, nondiabetic, hypertensive subjects, in agreement with the high cardiovascular risk of subjects suffering from both diabetes and hypertension.
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PMID:Persistent remodeling of resistance arteries in type 2 diabetic patients on antihypertensive treatment. 1470 58

Our goal was to examine whether exercise training alleviates impaired nitric oxide synthase (NOS)-dependent dilatation of the basilar artery in Type 1 diabetic rats. To test this hypothesis, we measured in vivo diameter of the basilar artery in sedentary and exercised nondiabetic and diabetic rats in response to NOS-dependent (acetylcholine) and -independent (nitroglycerin) agonists. To determine the potential role for nitric oxide in vasodilatation in sedentary and exercised nondiabetic and diabetic rats, we examined responses after NG-monomethyl-l-arginine (l-NMMA). We found that acetylcholine produced dilatation of the basilar artery that was similar in sedentary and exercised nondiabetic rats. Acetylcholine produced only minimal vasodilatation in sedentary diabetic rats. However, exercise alleviated impaired acetylcholine-induced vasodilatation in diabetic rats. Nitroglycerin produced dilatation of the basilar artery that was similar in sedentary and exercised nondiabetic and diabetic rats. l-NMMA produced similar inhibition of acetylcholine-induced dilatation of the basilar artery in sedentary and exercised nondiabetic and diabetic rats. Finally, we found that endothelial NOS (eNOS) protein in the basilar artery was higher in diabetic compared with nondiabetic rats and that exercise increased eNOS protein in the basilar artery of nondiabetic and diabetic rats. We conclude that 1) exercise can alleviate impaired NOS-dependent dilatation of the basilar artery during diabetes mellitus, 2) the synthesis and release of nitric oxide accounts for dilatation of the basilar artery to acetylcholine in sedentary and exercised nondiabetic and diabetic rats, and 3) exercise may exert its affect on cerebrovascular reactivity during diabetes by altering levels of eNOS protein in the basilar artery.
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PMID:Influence of exercise on dilatation of the basilar artery during diabetes mellitus. 1472 30

Endothelial cell dysfunction (ECD) is emerging as the common denominator for diverse and highly prevalent cardiovascular diseases. Recently, an increased number of procoagulant circulating endothelial microparticles (EMPs) has been identified in patients with acute myocardial ischemia, preeclampsia, and diabetes, which suggests that these particles represent a surrogate marker of ECD. Our previous studies showed procoagulant potential of endothelial microparticles and mobilization of microparticles by PAI-1. The aim of this study was to test the effects of isolated EMPs on the vascular endothelium. EMPs impaired ACh-induced vasorelaxation and nitric oxide production by aortic rings obtained from Sprague-Dawley rats in a concentration-dependent manner. This effect was accompanied by increased superoxide production by aortic rings and cultured endothelial cells that were coincubated with EMPs and was inhibited by a SOD mimetic and blunted by an endothelial nitric oxide synthase inhibitor. Superoxide was also produced by isolated EMP. In addition, p22(phox) subunit of NADPH-oxidase was detected in EMP. Our data strongly suggest that circulating EMPs directly affect the endothelium and thus not only act as a marker for ECD but also aggravate preexisting ECD.
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PMID:Endothelium-derived microparticles impair endothelial function in vitro. 1507 74

The aim of the present study was to compare vascular dysfunction between the early (12 wk old) and later (36 wk old) stages of spontaneous diabetes in Goto-Kakizaki (GK) rats. We also evaluated the aortic expression of the alpha(2D)-adrenoceptor and endothelial nitric oxide synthase (eNOS). Vascular reactivity was assessed in thoracic aortas from age-matched control rats and 12- and 36-wk GK rats. Using RT-PCR and immunoblots, we also examined the changes in expression of the alpha(2D-)adrenoceptor and eNOS. In aortas from GK rats (vs. those from age-matched control rats): 1) the relaxation response to ACh was enhanced at 12 wk but decreased at 36 wk; 2) the relaxation response to sodium nitroprusside was decreased at both 12 and 36 wk, 3) norepinephrine (NE)-induced contractility was decreased at 12 wk but not at 36 wk, 4) the expressions of alpha(1B)- and alpha(1D)-adrenoceptors were unaffected, whereas those of alpha(2D)-adrenoceptor and eNOS mRNAs were increased at both 12 and 36 wk; and 5) NE- and ACh-stimulated NO(x) (nitrite and nitrate) levels were increased at 12 wk, although at 36 wk ACh-stimulated NO(x) was lower, whereas NE-stimulated NO(x) showed no change. These results clearly demonstrate that enhanced ACh-induced relaxation and impaired NE-induced contraction, due to NO overproduction via eNOS and increased alpha(2D)-adrenoceptor expression, occur in early-stage GK rats and that the impaired ACh-induced relaxation in later-stage GK rats is due to reductions in both NO production and NO responsiveness (but not in eNOS expression).
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PMID:Differential expression of alpha2D-adrenoceptor and eNOS in aortas from early and later stages of diabetes in Goto-Kakizaki rats. 1513 Aug 81


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