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)

The discovery of atrial natriuretic peptide (ANP) has modified our current understanding of the regulation of sodium metabolism. This peptide, of which the second messenger is cyclic guanosine monophosphate (cyclic GMP), is released by the atrial myocytes in response to increased atrial stretch and has for essential function to diminish the venous return to the heart. Radioimmunoassays have demonstrated that plasma ANP and cyclic GMP levels are increased in various diseases such as congestive heart failure (CHF), renal insufficiency, and, to a lesser extent, diabetes mellitus and liver cirrhosis with ascites. Plasma ANP is of prognostic value in CHF and reflects the effective central volemia in renal failure so that its assay as well as that of plasma cyclic GMP seem of interest in these diseases. Further studies are needed to assess the pathophysiological significance of ANP in diabetes mellitus and cirrhosis, and to define the indications of the treatment by enkephalinase inhibitors which increase endogenous ANP levels by lowering the catabolism of this hormone.
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PMID:Current indications of plasma atrial natriuretic peptide measurements in human diseases. 215 73

Endothelin (ET) is a powerful vasoconstrictor peptide synthesized and secreted by the vascular endothelium. Significant amounts of ET are also produced by nonendothelial cells, mainly tubular-epithelial and mesangial cells. Large amounts of ET are found in the urine compared with the small amounts present in blood. Because most of the ET filtered from plasma is subject to degradation by neutral endopeptidase (EC 3.4.24.11) in the proximal tubule, urinary ET is probably of renal origin. The range of urinary ET excretion in healthy persons is 20 to 90 ng/day. The excretion of endothelin is modulated by several mechanical and chemical stimuli such as angiotensin II, phenylephrine, radiocontrast media, cyclosporine, and cis-platin. In addition, enhanced urinary ET excretion has been found in several forms of renal failure, both acute and chronic, and in diabetes mellitus. Thus, urinary ET has the potential of serving as a marker for renal disease.
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PMID:Urinary endothelin: a possible biological marker of renal damage. 813 95

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

It has been suggested that combined inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) may lower blood pressure more effectively than either treatment alone, independent of the degree of salt and volume status or the activity of the renin-angiotensin system. The effects of NEP inhibition in hypertension associated with diabetes mellitus are largely unknown. We therefore compared ACE inhibition, NEP inhibition, and dual NEP/ACE inhibition in diabetic hypertensive rats. Spontaneously hypertensive rats (SHR) aged 9 to 10 weeks were injected with either streptozotocin (45 mg/kg) or citrate buffer and randomized to receive either the ACE inhibitor captopril (25 mg/kg BID), the NEP inhibitor SCH 42495 (30 mg/kg BID), the dual NEP/ACE inhibitor S 21402 (25 or 50 mg/kg BID), or vehicle by gavage for 4 weeks. A group of diabetic SHR was also allocated to receive the combination of SCH 42495 (30 mg/kg BID) and captopril (25 mg/kg BID). The degree of renal NEP inhibition was determined by autoradiography, and plasma renin activity (PRA) was determined by radioimmunoassay. In diabetic SHR, the dual NEP/ACE inhibitor (50 mg/kg BID), as well as the combination of the NEP inhibitor and the ACE inhibitor, reduced systolic blood pressure more effectively than the ACE inhibitor (P<0.001) or the NEP inhibitor (P<0.001) alone. In nondiabetic SHR, the dual NEP/ACE inhibitor and the ACE inhibitor were equally effective, while the NEP inhibitor had only slight blood pressure lowering effects. Relative heart weight decreased in parallel to the changes in blood pressure. Renal NEP was clearly inhibited (70% to 92%; P<0.001) by both the NEP inhibitor and the dual NEP/ACE inhibitor. Both the ACE inhibitor and the dual NEP/ACE inhibitor increased PRA, but the stimulating effect of dual NEP/ACE inhibition on PRA was less than that observed with ACE inhibition alone (P<0.05). Albuminuria in diabetic SHR was lower during treatment with both the dual NEP/ACE inhibitor (50 mg/kg BID) and the combination of NEP inhibition and ACE inhibition compared with vehicle treatment (P<0.05). In conclusion, the present study shows that hypertension in SHR with streptozotocin-induced diabetes is modulated by natriuretic peptides and thus is sensitive to NEP inhibition. The increased efficacy of dual NEP/ACE inhibition on blood pressure in diabetic SHR, compared with ACE or NEP inhibition alone, suggests that this therapeutic approach may prove beneficial in the treatment of hypertension associated with diabetes mellitus and other forms of volume-dependent hypertension.
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PMID:Dual inhibition of neutral endopeptidase and angiotensin-converting enzyme in rats with hypertension and diabetes mellitus. 977 79

The preferred initial agents for the treatment of high blood pressure are low-dose thiazide diuretics, beta blockers, calcium antagonists, and angiotensin-converting enzyme (ACE) inhibitors. In high-risk patients, including those with diabetes, renal insufficiency, left ventricular dysfunction, and atherosclerosis, ACE inhibitors may have specific benefit in reducing cardiovascular morbidity and mortality. Omapatrilat, the prototypical vasopeptidase inhibitor, inhibits not only ACE but also neutral endopeptidase. Like conventional ACE inhibitors, omapatrilat causes extracellular volume reduction and vasodilatation; moreover, it increases levels of atrial and brain natriuretic peptides and bradykinin. Effective blood pressure control, especially in the high-risk patient, usually necessitates combination therapy. A recent study randomized 274 subjects with mild to severe hypertension (stages 1-3 diastolic blood pressure elevation) and confirmed the benefits of omapatrilat combined with hydrochlorothiazide in patients not controlled on hydrochlorothiazide alone. The frequencies of adverse events, serious adverse events, and discontinuation attributed to adverse events were similar for omapatrilat and placebo. Furthermore, there were no clinically significant changes in serum creatinine, potassium, or other laboratory parameters. Adding omapatrilat to the background of hydrochlorothiazide treatment produced statistically significant additional reductions in trough diastolic and systolic blood pressures at weeks 4 and 8.
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PMID:Advances in antihypertensive combination therapy: benefits of low-dose thiazide diuretics in conjunction with omapatrilat, a vasopeptidase inhibitor. 1158 9

Omapatrilat was designed to inhibit simultaneously angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The ubiquitous involvement of the renin-angiotensin-aldosterone system, originally conceived as an axis of sodium and fluid metabolism in inflammation, thrombosis and cardiac and smooth muscle hypertrophy, is a major factor in disease progression for conditions as diverse as hypertension, heart failure, coronary artery disease and diabetes. Interruption of angiotensin II generation and bradykinin degradation by ACE inhibition is a major therapeutic advance in the management of these diseases. NEP metabolizes both bradykinin and the natriuretic peptides (atrial natriuretic peptide, brain natriuretic peptide, c-type natriuretic peptide and adrenomedullin). These peptides counter the adverse effects of angiotensin II by their vasodilator, natriuretic, diuretic and autonomic neural actions; by their antitrophic effects; and by suppressing plasma renin activity. These two systems can be considered key components of a cardiorenal axis that maintains blood pressure and cardiopulmonary blood volume within a stable range. This balance is compromised in the setting of heart failure and primary hypertension. The combination of ACE and NEP inhibition should augment the beneficial hemodynamic and tissue effects of bradykinin and the natriuretic peptides. Vasopeptidase inhibition, therefore, is a novel approach to cardiovascular therapy, with implications for hypertension, heart failure, renal function and ischemic heart disease.
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PMID:Vasopeptidase inhibition: a novel approach to cardiovascular therapy. 1187 87

The renin-angiotensin system is initiate by numerous pathological situations which release the renal ischemia: heart failure, arterial hypertension, renal pathology with or without diabetes mellitus. Therapeutic possibilities in renin-angiotensin system control are offered by angiotensin-converting enzyme inhibitors, angiotensin II type-1 receptors antagonists, angiotensin converting enzyme inhibitors and neutral endopeptidase inhibitors and angiotensin II type 2 receptors agonists.
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PMID:[The renin-angiotensin system:implications, pathology, therapeutic possibilities, perspectives]. 1209 17

Circulating and vascular endothelin-1 (ET-1) levels are elevated in diabetes, but the molecular components of the enzymatic activation of ET-1 in the vasculature remains unknown. Furthermore, the distribution of ET receptors favors a contractile phenotype in African Americans with diabetes. Whether there is any difference in local ET-1 activation in this population is unknown. This study examined the expression and activity of ET converting enzyme-1 subisoforms (ECE-1) in the internal mammary artery specimens obtained from patients undergoing coronary artery bypass grafting. The study groups included African-American (AA) and Caucasian (CA), nondiabetic (ND) and diabetic (D) patients: AAND N = 10, CAND N = 9, AAD N = 9, and CAD N = 11. The expression of ECE-1 a, ECE-1 b and ECE-1c subisoforms was studied by RT-PCR. ECE-1 a was upregulated 2- and 4-fold in the CAD and MD groups, respectively (P < .05). In African-American patient groups, ECE-1 activity (fmol/ mg protein.h) was augmented from 2,804 +/- 185 in nondiabetic tissue samples to 6,857 +/- 393 in the diabetic tissue (P < .05). There was a similar increase in the CAD group, which did not significantly differ from AA diabetics. ECE-1 inhibitors, phosphoramidon and FR-901533, inhibited vascular ECE-1 activity by more than 80%. While neutral endopeptidase (NEP) and matrix metalloproteinase-2 (MMP-2) are able to process big ET-1, inhibitors of NEP (thiorphan) and MMP (batimistat) did not affect ECE-1 activity. In conclusion, the enzymatic pathway essential for generating vascular ET-1 is activated in the vasculature of both AA and CA diabetic patients and this activation is highly specific for ECE-1.
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PMID:Vascular endothelin converting enzyme-1 expression and activity is upregulated in clinical diabetes. 1247 47

Cutaneous sensory nerves mediate inflammation and wound healing by releasing neuropeptides, such as substance P, which stimulates pro-inflammatory responses by keratinocytes, fibroblasts, and endothelial cells. The cell surface enzyme, neutral endopeptidase, degrades substance P, thereby regulating its biologic actions. We hypothesized that neutral endopeptidase enzymatic activity is increased in chronic wounds and skin from subjects with diabetes. We compared cutaneous neutral endopeptidase expression and enzymatic activity between normal controls and diabetic subjects with neuropathy and chronic wounds. Skin samples from subjects with diabetes were taken at the time of amputation for nonhealing ulcers. Skin taken from the ulcer margin, 1 cm from the ulcer (adjacent), and from the most proximal region of the amputated leg were studied. Skin biopsies from the leg of healthy control subjects were also studied. Neutral endopeptidase was localized by immunohistochemistry in all tissue sections. Neutral endopeptidase activity was measured using a fluorimetric assay. The median neutral endopeptidase activity of the ulcer margin was 1.21 x higher (p>0.2) than adjacent skin, 5.26 (p<0.001) than proximal skin, and 15.22 x higher (p<0.001) than control skin. Adjacent skin had a median neutral endopeptidase activity 4.34 x higher (p<0.001) than proximal skin and 12.58 x higher (p<0.001) than control skin. The median neutral endopeptidase activity of proximal skin was 2.90 x higher (p<0.001) than control skin. This elevated neutral endopeptidase activity in the skin and chronic ulcers of subjects with diabetes combined with peripheral neuropathy may contribute to deficient neuroinflammatory signaling and may impair wound healing in subjects with diabetes.
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PMID:Neutral endopeptidase activity is increased in the skin of subjects with diabetic ulcers. 1248 46

Diabetes mellitus impairs the cardiac kallikrein-kinin system by reducing cardiac kallikrein (KLK) and kininogen levels, a mechanism that may contribute to the deleterious outcome of cardiac ischemia in this disease. We studied left ventricular (LV) function and bradykinin (BK) coronary outflow in buffer-perfused, isolated working hearts (n = 7) of controls and streptozotocin (STZ)-induced diabetic rats before and after global ischemia. With the use of selective kininase inhibitors, the activities of angiotensin I-converting enzyme, aminopeptidase P, and neutral endopeptidase were determined by analyzing the degradation kinetics of exogenously administered BK during sequential coronary passages. Basal LV function and coronary flow were impaired in STZ-induced diabetic rats. Neither basal nor postischemic coronary BK outflow differed between control and diabetic hearts. Reperfusion after 15 min of ischemia induced a peak in coronary BK outflow that was of the same extent and duration in both groups. In diabetic hearts, total cardiac kininase activity was reduced by 41.4% with an unchanged relative kininase contribution compared with controls. In conclusion, despite reduced cardiac KLK synthesis, STZ-induced diabetic hearts are able to maintain kinin liberation under basal and ischemic conditions because of a primary impairment or a secondary downregulation of kinin-degrading enzymes.
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PMID:Cardiac kinin level in experimental diabetes mellitus: role of kininases. 1263 59


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