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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We measured the sensitivity of glucose metabolism to insulin in soleus muscle preparations isolated from spontaneously hypertensive (SH) rats and normotensive age-matched Wistar-Kyoto (WKY) rats. SH rats were treated with the angiotensin-converting enzyme (ACE) inhibitor trandolapril (1 mg/kg) and/or a second antihypertensive drug, the calcium antagonist verapamil, alone (100 mg/kg) or as combination therapy (50 mg/kg). Treatment of SH rats with trandolapril or trandolapril in combination with verapamil for 6 weeks normalized the blood pressure. The estimated concentration of insulin required for half-maximal stimulation of glycogen synthesis (i.e., EC50 values) was approximately 500 microU/ml for muscles from both WKY and SH rats. This value is five times higher than the value obtained from soleus muscle preparations isolated from insulin-sensitive Wistar rats. This indicates that glycogen synthesis is insensitive to insulin in SH and WKY rat soleus muscle. Treatment of SH rats with trandolapril with or without verapamil improved the sensitivity of glycogen synthesis to insulin in soleus muscle. Further experiments investigated whether acute exposure (1 h) of insulin-sensitive skeletal muscle with either trandolaprilat (the active metabolite of trandolapril) or bradykinin (levels of which may be raised by ACE inhibition) could affect the insulin-stimulated rate of glucose metabolism. These results show that both trandolaprilat and bradykinin caused a small but significant increase in the rates of glucose metabolism. In conclusion, 1) SH and WKY rat skeletal muscle was insulin resistant, 2) chronic treatment of SH rats with trandolapril with or without verapamil normalized blood pressure and improved the response of glycogen metabolism to insulin, and 3) bradykinin and trandolaprilat acutely caused a small but significant increase in the rate of glycogen synthesis to a submaximal physiological concentration of insulin.
Diabetes 1996 Jan
PMID:Effects of treatment of spontaneously hypertensive rats with the angiotensin-converting enzyme inhibitor trandolapril and the calcium antagonist verapamil on the sensitivity of glucose metabolism to insulin in rat soleus muscle in vitro. 852 92

Insulin resistance of skeletal muscle glucose disposal underlies the pathogenesis of NIDDM and is associated with hypertension, obesity, and dyslipidemia. Angiotensin-converting enzyme (ACE) inhibitors are used primarily in antihypertensive therapy but also are known to improve whole-body insulin-mediated glucose disposal. However, the exact site of action is not well characterized. We have used the isolated epitrochlearis muscle from a well-established animal model of skeletal muscle insulin resistance, the obese Zucker rat, to test the effect of oral administration of ACE inhibitors on insulin-sensitive muscle glucose transport activity. Both acute and chronic administration of a sulfhydryl-containing ACE inhibitor (captopril) or a non-sulfhydryl-containing ACE inhibitor (tran-dolapril) significantly enhanced in vitro insulin-mediated muscle glucose transport activity. In addition, the acute effect of oral captopril administration was completely abolished by pretreatment of the animal with a bradykinin B2 receptor antagonist (HOE 140). These findings indicate that ACE inhibitors may improve whole-body glucose metabolism by acting on the insulin-sensitive skeletal muscle glucose transport system. In addition, bradykinin or one of its metabolites may be involved in the action of the ACE inhibitor captopril on insulin-resistant muscle.
Diabetes 1996 Jan
PMID:Glucose transport activity in insulin-resistant rat muscle. Effects of angiotensin-converting enzyme inhibitors and bradykinin antagonism. 852 93

Kallikrein-kininogen-kinin systems are now topics of widespread interest. The long-standing appreciation of their diverse pharmacological properties and biochemical characteristics is being supplemented by modern definitions of their cellular receptors' signal-transduction mechanisms and physiological and pathological roles. The assignment of important homeostatic responsibilities for kinins, including those in autocrine and paracrine signaling for skeletal and cardiac muscle energy metabolism, is now subject to definitive experimental evaluation via the availability of better kallikrein inhibitors, specific kinin receptor antagonists, and techniques of genetic manipulation.
Diabetes 1996 Jan
PMID:Kallikreins and kinins. Molecular characteristics and cellular and tissue responses. 852 94

The kallikrein-kinin system has been implicated in the inflammatory process, blood pressure regulation, renal homeostasis, and glucose utilization. The effects of kallikrein and kinin on glucose uptake by the skeletal muscle are well established; however, the occurrence and the cellular distribution of the kinin receptor(s) mediating these effects in the striated muscle are unknown. Using anti-peptide antibodies raised against the predicted intra- and extracellular domains of the B2 receptor and the peroxidase/antiperoxidase system, we have been able to detect the B2 receptor on the plasma membrane of striated skeletal muscle cells of the rat hindlimb. A strong immunostaining appeared as a rim of immunoreactive material located on the periphery of striated muscle cells. Cross-sectioned and longitudinally sectioned cells revealed a similar staining pattern. Alternatively, the immunostaining with specific antibodies to tissue kallikrein and to T-kininogen did not yield a significant staining of the striated muscle cells. Localization of the B2 receptor on the surface of striated muscle cells provides a structural basis for the hypothesized physiological functions of the kinin system in the skeletal muscle.
Diabetes 1996 Jan
PMID:Immunolocalization of bradykinin B2 receptors on skeletal muscle cells. 852 96

To determine the presence of bradykinin receptors in skeletal muscle, we examined in both displacement and saturation studies the binding of [125I-Tyr8]bradykinin or [3H]bradykinin in three types of skeletal muscle preparations: membrane fractions from guinea pig hindlimb quadriceps, dog semimembranosus and semitendinosus muscles, and L8 rat skeletal muscle myoblasts. Scatchard analysis of [125I-Tyr8]bradykinin x bradykinin competition binding demonstrated specific bradykinin binding of 4.9 and 3.2 fmol/mg protein in dog and guinea pig skeletal muscle preparations, respectively. Unlabeled bradykinin specifically displaced [125I-Tyr8]bradykinin with IC50 values of 36.5 +/- 6 and 118.0 +/- 16.0 pmol/l from dog and guinea pig muscle membranes, respectively. The B2 bradykinin receptor antagonist HOE 140 and the B1 bradykinin receptor antagonist des-Arg9[Leu8]bradykinin displaced the binding of [3H]bradykinin from dog membranes with IC50 values of 0.38 and 217.3 nmol/l, respectively, suggesting that bradykinin binds to a B2-type receptor. In addition, unlabeled bradykinin competed with [3H]bradykinin for binding to dog skeletal muscle membrane preparations in a biphasic manner. To assess whether this represents multiple bradykinin receptor subtypes present in skeletal muscle homogenates or several affinity states of a single binding site, we examined bradykinin receptors on a pure skeletal muscle system, the L8 neonatal rat skeletal muscle myoblast cell line. These myoblasts also contain specific [3H]bradykinin-binding sites with a Bmax of 271 fmol/mg protein and a Kd of 0.83 nmol/l. Competitive agonist binding curves were biphasic (high-affinity IC50 = 3.9 pmol/l, low-affinity IC50 = 22.6 nmol/l) in the absence of guanosine 5'-O-(3-thio-trisphosphate) (GTP gamma S); they shifted to a model of one affinity (8.1 nmol/l) in the presence of GTP gamma S. Because the enzyme neutral endopeptidase 24.11 is an important kininase in skeletal muscle, we examined the effect of the neutral endopeptidase inhibitor phosphoramidon on the binding of bradykinin to dog skeletal muscle membranes. We found that phosphoramidon decreased the apparent Bmax from 7.3 to 5.8 fmol/mg protein. In addition, in this cell line we investigated the action of bradykinin on phosphoinositide hydrolysis. Inositol 1,4,5-trisphosphate (IP3) was measured with a radioreceptor assay. Bradykinin (0.1 nmol/l to 1 mumol/l) induced IP3 formation in a dose-dependent manner (EC50 = 1.42 nmol/l) from a basal level of 72.8 +/- 16 pmol/mg protein to 433 +/- 35.5 at the highest (1 mumol/l) concentration. We conclude that bradykinin B2 receptors are expressed in skeletal muscle. Phosphoinositide hydrolysis upon stimulation of this receptor is an indicator of intracellular signal transduction. Part of the bradykinin binding in skeletal muscle is due to interaction with the enzyme neutral endopeptidase.
Diabetes 1996 Jan
PMID:Bradykinin B2 receptors on skeletal muscle are coupled to inositol 1,4,5-trisphosphate formation. 852 97

Because of the importance of bradykinin in improving heart function in some conditions or in enhancing glucose uptake by skeletal muscle, we investigated kininases in these tissues. In P3 fraction of the heart and skeletal muscles, angiotensin I-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP) are the major kininases, as determined first with specific substrates and second with bradykinin. ACE activity was highest in guinea pig heart (2.7 +/- 0.07 mumol.h-1.mg protein-1) but decreased in other species in this order: dog atrium, rat heart, dog ventricle, and human atrium. The specific activity of NEP was lower: 0.45 mumol.h-1.mg protein-1 in cultured neonatal cardiac myocytes and varying between 0.12 and 0.05 mumol.h-1.mg protein-1 in human, dog, rat, and guinea pig heart. In the skeletal muscle P3, ACE was most active in guinea pig and rat (1.2 and 1.1 mumol.h-1.mg protein-1, respectively) but less so in dog (0.09 mumol.h-1.mg protein-1). NEP activity was higher in dog P3 (0.28 mumol.h-1.mg protein-1) but lower in rat and guinea pig (0.19 and 0.1 mumol.h-1.mg protein-1, respectively). Continuous density gradient centrifugation enriched NEP activity in dog and rat (from 0.3 to 1.0 and 0.49 mumol.h-1.mg protein-1, respectively). Immunoprecipitation with antiserum to purified NEP proved the specificity of the rat enzyme. Bradykinin (0.1 mmol/l) was inactivated in the presence and absence of inhibitors by rat skeletal muscle NEP, as measured by high-performance liquid chromatography. Here, 36% of the activity was caused by NEP and 19% by ACE. In radioimmunoassay (bradykinin 10 nmol/l), 46 and 55% of kininase in rat and dog skeletal muscle P3, respectively, was due to ACE; 36 and 28%, respectively, was due to NEP. Aside from these enzymes, an aminopeptidase in rat P3 also inactivates bradykinin. Thus, in conclusion, heart and skeletal muscle membranes contain kininase II-type enzymes, but their activity depends on the species.
Diabetes 1996 Jan
PMID:Kininase II-type enzymes. Their putative role in muscle energy metabolism. 852 98

Receptors for bradykinin (BK) were characterized in primary cultures of beating neonatal rat cardiomyocytes using [3H]BK was radioligand. Degradation studies demonstrated that [3H]BK was stable for at least 2 h when incubated with cardiomyocytes at 2 and 37 degrees C in the presence of bacitracin in combination with captopril or ramiprilat. Without these inhibitors, > 80% of the [3H]BK was degraded within 2 h at 37 degrees C. This indicates that angiotensin-converting enzyme (ACE) is responsible for the main BK-degrading activity in cardiomyocytes. Scatchard plots were linear and gave a Kd of 1.5 +/- 0.8 nmol/l (mean +/- SD, n = 4) and a maximum binding capacity of 55-125 fmol/mg protein. Association and dissociation studies showed that binding of [3H]BK was saturable and reversible. Binding of [3H]BK at 37 degrees C led to internalization of the ligand. Competition studies with B1 and B2 agonists and antagonists were consistent with a B2 subtype of receptor. Addition of BK to beating cardiomyocytes (> 1 nmol/l) at 37 degrees C gave a strong but transient negative chronotropic effect. This response was paralleled by changes in the pulsation amplitude, which indicated a simultaneous negative inotropic effect of BK. These results provide a basis for the hypothesis that ACE inhibition exerts its cardioprotective effect at the level of a population of cardiomyocytes by virtue of kinin receptor-mediated mechanisms.
Diabetes 1996 Jan
PMID:B2 bradykinin receptors in cultured neonatal rat cardiomyocytes mediate a negative chronotropic and negative inotropic response. 852

In ischemia, the heart generates and releases kinins as mediators that seem to have cardioprotective actions. Kinin-generating pathways are present in the heart. Kininogen, kininogenases, kinins, and B2 kinin receptors can be measured in cardiac tissue. Kinins are released under conditions of ischemia. In anesthetized rats and dogs with coronary artery ligation and in human patients with myocardial infarction, kinin plasma levels are increased. In isolated rat hearts, the outflow of kinins is enhanced during ischemia but markedly attenuated after deendothelialization, pointing to the coronary vascular endothelium as the main possible source. Kinins administered locally exert beneficial cardiac effects. In isolated rat hearts with ischemia-reperfusion injuries, perfusion with bradykinin (BK) reduces the duration and incidence of ventricular fibrillation, improves cardiodynamics, reduces release of cytosolic enzymes, and preserves energy-rich phosphates and glycogen stores. In anesthetized animals, intracoronary BK is followed by comparable beneficial changes and limits infarct size. Inhibition of breakdown of BK and related peptides induces beneficial cardiac effects. Treatment with ACE inhibitors such as ramipril increases cardiac kinin levels and reduces post-ischemic reperfusion injuries in isolated rat hearts and infarct size in anesthetized animals. The importance of an intact endothelium that continuously generates kinins is supported by observations that basal and ramipril-induced release of kinins and PGI2 is markedly reduced after deendothelialization of isolated hearts. Blockade of B2 kinin receptors increases ischemia-induced effects. Endothelial formation of NO and PGI2 by ACE inhibition is prevented by the specific B2 kinin receptor antagonist icatibant. In isolated hearts, ischemia-reperfusion injuries deteriorate with icatibant, which also abolishes the cardioprotective effects of ACE inhibitors and of exogenous BK. Infarct size reduction by ACE inhibitors and by BK in anesthetized animals is reversed by icatibant. Kinins contribute to the cardioprotective effects associated with ischemic preconditioning because preconditioning or BK-induced antiarrhythmic and infarct size-limiting effects are attenuated by icatibant. In conclusion, kinins may act as mediators of endogenous cardioprotective mechanisms. Kinins are generated and released during ischemia, with subsequent formation of PGI2 and NO probably derived mainly from the coronary vascular endothelium. Their cardioprotective profile resembles that of ACE inhibitors.
Diabetes 1996 Jan
PMID:Role of kinins in the pathophysiology of myocardial ischemia. In vitro and in vivo studies. 852 1

Left ventricular hypertrophy is considered to be an independent risk factor giving rise to ischemia, arrhythmias, and left ventricular dysfunction. Slow movement of intracellular calcium contributes to the impaired contraction and relaxation function of hypertrophied myocardium. Myofibril content may also be shifted to fetal-type isoforms with decreased contraction and relaxation properties in left ventricular hypertrophy. Myocyte hypertrophy and interstitial fibrosis are regulated independently by mechanical and neurohumoral mechanisms. In severely hypertrophied myocardium, capillary density is reduced, the diffusion distance for oxygen, nutrients, and metabolites is increased, and the ratio of energy-production sites to energy-consumption sites is decreased. The metabolic state of severely hypertrophied myocardium is anaerobic, as indicated by the shift of lactate dehydrogenase marker enzymes. Therefore, the hypertrophied myocardium is more vulnerable to ischemic events. As a compensatory response to severe cardiac hypertrophy and congestive heart failure, the ADP/ATP carrier is activated and atrial natriuretic peptide is released to increase high-energy phosphate production and reduce cardiac energy consumption by vasodilation and sodium and fluid elimination. However, in severely hypertrophied and failing myocardium, vasoconstrictor and sodium- and fluid-retaining factors, such as the renin-angiotensin system, aldosterone, and sympathetic nerve activity, play an overwhelming role. Angiotensin-converting enzyme inhibitors (ACEIs) are able to prevent cardiac hypertrophy and improve cardiac function and metabolism. Under experimental conditions, these beneficial effects can be ascribed mainly to bradykinin potentiation, although a contribution of the ACEI-induced angiotensin II reduction cannot be excluded.
Diabetes 1996 Jan
PMID:Substrate metabolism, hormone interaction, and angiotensin-converting enzyme inhibitors in left ventricular hypertrophy. 852 2

The effect of bradykinin on glucose transporter translocation in isolated rat heart was compared with the effect of insulin. Hearts from male obese (fa/fa) Zucker rats were perfused under normoxic conditions and constant pressure in a classic Langendorff preparation with 12 mmol/l glucose as substrate, and a set of functional parameters was measured simultaneously. Bradykinin was administered at a concentration (10(-11) mmol/l) that did not increase coronary flow. Insulin was used at a concentration (8 x 10(-8) mmol/l) known to maximally stimulate glucose transport in this model. After 15 min of perfusion with insulin or bradykinin, subcellular membrane fractions of the heart were prepared, and distribution of glucose transporter protein (GLUT1 and GLUT4) in fractions enriched with surface membranes (transverse tubules [TTs] and sarcolemmal membranes [PMs]) and with low-density microsomal membranes (LDMs) were determined by immunoblotting with the respective antibodies. Both glucose transporter isoforms were translocated after stimulation with insulin (increased transporter protein content in the PM+TT-enriched fraction with a concomitant decrease in the LDM-enriched fraction) and, to a smaller extent, also with bradykinin. These data suggest that in hearts of insulin-resistant obese (fa/fa) Zucker rats, bradykinin interacts with or facilitates the translocation process of both GLUT1 and GLUT4.
Diabetes 1996 Jan
PMID:Insulin-induced glucose transporter (GLUT1 and GLUT4) translocation in cardiac muscle tissue is mimicked by bradykinin. 852 3


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