dihydropyridines and Diabetes-Mellitus--Type-1

Angiotensin-converting enzyme inhibitors plus dihydropyridine calcium channel blockers or low-dose thiazide diuretics are considered first-line therapies in hypertensive diabetic patients as glucose metabolism is not relevantly affected. Most diabetic patients require at least two different drug classes to achieve the recommended target blood pressure of 130/85 mmHg. This controlled clinical trial investigated the calcium channel blocker lercanidipine versus hydrochlorothiazide (HCTZ) as add-on in diabetic patients with uncontrolled hypertension on enalapril monotherapy.. Overall, 174 patients (18-80 years old, well-controlled diabetes type 1 or 2, mild to moderate hypertension) were included in a 2-week placebo run-in followed by 4 weeks on enalapril 20 mg. Subsequently, 135 non-responders (90 mmHg < or = mean sitting diastolic blood pressure < or = 109 mmHg) were randomized to 20 weeks of double-blind add-on therapy to enalapril with either lercanidipine 10 mg (n = 69) or HCTZ 12.5 mg (n = 66). The primary study objective was to prove non-inferiority of lercanidipine add-on versus HCTZ add-on in reducing sitting diastolic blood pressure; response rates and tolerability data were also observed.. Both add-on treatments clearly decreased diastolic blood pressure to a greater extent than enalapril monotherapy (mean +/- SD changes at study end: lercanidipine, -9.3 mmHg; HCTZ, -7.4 mmHg); non-inferiority of lercanidipine versus HCTZ was formally proven. Blood pressure response rates reached 69.6% on enalapril plus lercanidipine as compared with 53.6% on enalapril plus HCTZ (difference between treatments, P > 0.05). Blood pressure of 130/85 mmHg or less was achieved in 30.4% of patients on lercanidipine add-on and in 23.2% of those randomized to HCTZ add-on (P > 0.05). Both treatment regimens were well tolerated.. Lercanidipine add-on showed comparable efficacy to HCTZ add-on in diabetic patients with hypertension badly controlled on angiotensin-converting enzyme inhibitor monotherapy. The blood pressure response rates seemed to be somewhat higher following enalapril plus lercanidipine than enalapril plus HCTZ.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dihydropyridines; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Single-Blind Method

Impaired degradation of proteins by the ubiquitin-proteasome system (UPS) is observed in numerous pathologies including diabetes mellitus (DM) and its complications. Dysregulation of proteasomal degradation might be because of altered expression of genes and proteins involved in the UPS. The search for novel compounds able to normalize expression of the UPS appears to be a topical problem. A novel group of 1,4-dihydropyridine (1,4-DHP) derivatives lacking Ca2+-antagonists activities, but capable to produce antidiabetic, antioxidant and DNA repair enhancing effects, were tested for ability to modify Psma6 mRNA expression levels in rat kidneys and blood in healthy animals and in rats with streptozotocin (STZ) induced DM. Psma6 gene was chosen for the study, as polymorphisms of its human analogue are associated with DM and cardiovascular diseases. 1,4-DHP derivatives (metcarbatone, etcarbatone, glutapyrone, J-9-125 and AV-153-Na) were administered per os for three days (0.05 mg/kg and/or 0.5 mg/kg). Psma6 gene expression levels were evaluated by quantitative PCR. Psma6 expression was higher in kidneys compared to blood. Induction of diabetes caused increase of Psma6 expression in kidneys, although it was not changed in blood. Several 1,4-DHP derivatives increased expression of the gene both in kidneys and blood of control and model animals, but greater impact was observed in kidneys. The observed effect might reflect coupling of antioxidant and proteolysis-promoting activities of the compounds.

Topics: Animals; Diabetes Mellitus, Type 1; Dihydropyridines; Female; Humans; Kidney; Male; Proteasome Endopeptidase Complex; Rats; Up-Regulation

We investigated the protective effect of benidipine, by testing the changes of the activity of Rho kinase and transdifferentiation of renal tubular epithelium cells in vivo. Wistar rats were randomly divided into two groups: normal (N) and diabetes. STZ were used to make the rats type 1 diabetic and were randomly assigned as diabetes without treatment (D), diabetes treated with benidipine (B), and diabetes treated with fasudil (F) and treated for 3 months. Immunohistochemistry and western blotting were for protein expressions of ROCK1, α-SMA, and E-cadherin and real-time PCR for the mRNA quantification of ROCK1. Compared with N group, D group had significant proliferation of glomerular mesangial matrix, increased cell number, thickened basement membrane, widely infiltrated by inflammatory cells and fibrosis in the renal interstitial, and dilated tubular. Those presentations in F and B groups were milder. Compared with N group, D group showed elevated MYPT1 phosphorylation, increased expression of ROCK1, α-SMA protein, and ROCK1 mRNA and decreased expression of E-cadherin protein. B group showed attenuated MYPT1 phosphorylation, decreased ROCK1, α-SMA protein, and ROCK1 mRNA expression and increased expression of E-cadherin protein. In conclusion, benidipine reduces the epithelium-mesenchymal transdifferentiation and renal interstitial fibrosis in diabetic kidney by inhibiting ROCK1 activity.

Topics: Animals; Calcium Channel Blockers; Cell Transdifferentiation; Cytoprotection; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Dihydropyridines; Epithelial-Mesenchymal Transition; Fibrosis; Kidney; Male; Rats; Rats, Wistar; rho-Associated Kinases

Autonomic neuropathy, including gastrointestinal dysfunction, is a common complication of type 1 diabetes; however, its cause is uncertain. This study aimed to test whether functional autoantibodies cause the gastrointestinal dysfunction.. We used isolated mouse colon undergoing colonic migrating motor complex (MMC) activity to test for autoantibodies that disrupt colonic motility. Purified immunoglobulin G (IgG) from patients with type 1 diabetes or from controls was tested either in vitro or after passive transfer. Pharmacological studies of the interaction between the IgG and L-type calcium channel activator (Bay K8644) and inhibitors (nicardipine and verapamil) were performed. The effect of IgG on nerve-evoked contraction of the vas deferens longitudinal smooth muscle was also assessed.. MMC activity was disrupted by IgG (0.2 mg/mL) from 8 of 16 patients with type 1 diabetes but not by control IgG. Passive transfer of diabetic IgG to mice also disrupted MMCs, showing access to the antigen in vivo. The acute effect of the autoantibody was mimicked by the dihydropyridine agonist, Bay K8644 (2-10 nmol/L), and both Bay K8644 and the autoantibody competitively inhibited the effect on MMC contraction of the dihydropyridine antagonist, nicardipine. Diabetic IgG, but not control IgG, altered the nerve-evoked contractile activity of vas deferens smooth muscle effects mimicked by Bay K8644.. A novel functional autoantibody that activates smooth muscle L-type calcium channels at the dihydropyridine binding site is produced specifically by patients with type 1 diabetes and may mediate gastrointestinal and autonomic dysfunction in these patients.

Topics: Adult; Aged; Animals; Autoantibodies; Binding Sites; Calcium Channel Agonists; Calcium Channel Blockers; Calcium Channels, L-Type; Colon; Diabetes Mellitus, Type 1; Dihydropyridines; Female; Gastrointestinal Motility; Humans; Intestinal Diseases; Male; Mice; Middle Aged; Myoelectric Complex, Migrating; Vas Deferens

The effects of the calcium channel blocker, isradipine, on BP, urinary albumin excretion, plasma lipoproteins and natriuresis in albuminuric Type 1 (insulin-dependent) diabetic patients were assessed. Fifteen Type 1 diabetic patients aged 22-52 years were studied. All had elevated urinary albumin excretion (more than 30 mg/24h) based on several 24 h urine collections, and BP was normal (below 140/90 mmHg). After a placebo treatment period of eight weeks the patients were randomly assigned to two groups for a double-blind crossover study. Each patient received either 2.5 mg isradipine twice daily or placebo for eight weeks. Then, after 4 weeks (the wash-out period), each patient received the drug he or she had not taken before for another 8 weeks. Systolic blood pressure was lowered by 8 mmHg from 127 (114-139) mmHg (P less than 0.01) and diastolic by 5 mmHg from 81 (70-87) mmHg (P less than 0.03) during isradipine treatment. The 24 h urinary sodium excretion increased and no signs of volume expansion were observed during treatment with isradipine. Urinary albumin excretion and total body exchangeable sodium remained unchanged. During isradipine treatment the plasma concentrations of VLDL cholesterol and triglyceride decreased significantly (P less than 0.01) and the level of HDL cholesterol increased, but not significantly (P = 0.08). In conclusion, treatment of Type 1 diabetic patients, at risk of progressive clinical nephropathy, with the calcium channel blocker, isradipine, had beneficial effects on plasma lipoprotein levels and resulted in a reduction in BP. We did not find any effect of isradipine on urinary albumin excretion.

Topics: Albuminuria; Blood Pressure; Calcium Channel Blockers; Cholesterol; Diabetes Mellitus, Type 1; Dihydropyridines; Humans; Isradipine; Natriuresis; Reference Values