lisinopril and Diabetic-Neuropathies

Thirteen diabetic patients with hypertension (mean diastolic blood pressure 96.2 +/- 1.1 mmHg) were included in a study to assess the effects of lisinopril (20 mg day-1) on measures of nerve function. Patients had nerve conduction velocity (NCV), temperature discrimination threshold (TDT), and vibration perception threshold (VPT) measurements. At the end of 12 weeks of treatment with lisinopril, there was a significant improvement in median motor NCV (mean change +/- SEM 2.7 +/- 0.6 m s-1, p < 0.0001), median sensory NCV (2.1 +/- 0.9 m s-1, p = 0.03), peroneal motor NCV (1.0 +/- 0.4 m s-1, p = 0.03), and sural sensory NCV (1.9 +/- 0.7 m s-1, p = 0.01) values. There were also significant improvements in warm TDT and VPT. Diastolic BP decreased significantly, but there was no significant change in HbA1. Double blind controlled studies are now needed to confirm the effect of lisinopril on measures of nerve function.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Discrimination, Psychological; Double-Blind Method; Humans; Hypertension; Lisinopril; Median Nerve; Middle Aged; Motor Neurons; Neural Conduction; Neurons, Afferent; Peroneal Nerve; Sensory Thresholds; Sural Nerve; Temperature; Vibration

To investigate the effects of lisinopril, an angiotensin-converting enzyme inhibitor, on diabetic peripheral neuropathy (DNP).. Twenty-five Wistar rats underwent intravenous injection of streptozocin to establish diabetes models and 10 rats were injected with sodium citrate solution as normal controls. The diabetic rats were randomly divided into 2 groups: lisinopril group treated with gastric perfusion of lisinopril daily for 8 weeks, and diabetic control group. The diabetic controls and normal controls were treated with gastric perfusion of water. Sciatic nerve electrode penetration method was used to measure the motor nerve conduction velocity (MNCV) and sensory nerve conduction velocity (SNCV). Light and heat pain measuring apparatus was used to measure the pain threshold. Then the sciatic nerves were isolated. Electron microscopy was used to observe the ultra-structure. The contents of superoxide dismutase (SOD) and malonyldialdehyde (MDA), and Na(+)K(+)-ATPase activity were detected by chemical colorimetry. Immunohistochemistry was used to detect the CD34 in the sciatic nerve. The capillary density of sciatic nerve was calculated.. The MNCV and SNCV levels of the lisinopril group were both lower than those of the 2 control groups (all P < 0.01). The potency of heat pain leg retraction response of the lisinopril group was significantly shorter than that pf the diabetic control group (P < 0.05). The pathological changes of the lisinopril group were milder than those of the other groups. The SOD level and the Na(+)K(+)-ATPase activity of the diabetic group were significantly lower than those of the normal control group, and the MDA of the diabetic group was significantly higher than those of the other 2 groups (all P < 0.05). And the SOD level and Na(+)K(+)-ATPase activity of the lisinopril group were significantly higher than those of the diabetic control group, and the MDA level of the lisinopril group was significantly lower than that of the diabetic control group. The capillary density of sciatic nerve of the diabetic control group was lower and the normal control group, and that of the lisinopril group was significantly higher than that of the diabetic control group (P < 0.01).. ACE inhibitors effectively prevent and treat DPN.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Lisinopril; Male; Malondialdehyde; Peroneal Nerve; Rats; Rats, Wistar; Sciatic Nerve; Sodium-Potassium-Exchanging ATPase; Superoxide Dismutase

Poly(ADP-ribose) polymerase (PARP) inhibition has recently been identified as a novel approach to treatment of experimental peripheral diabetic neuropathy (PDN). However, long-term inhibition of PARP, an enzyme involved in DNA repair, can potentially result in premature aging, loss of genome stability, and other side effects. This study evaluated potential synergistic interactions between low doses of the potent and specific PARP inhibitor 1,5-isoquinolinediol (ISO) and one of two vasodilators, the ACE inhibitor lisinopril (LIS) and the beta2-adrenoceptor agonist salbutamol (SAL) in the model of early PDN. Control and streptozotocin (STZ)-induced diabetic rats were treated with either ISO plus LIS or ISO plus SAL for 2 weeks after an initial 2 weeks without treatment. ISO (intraperitoneally) and LIS and SAL (both in the drinking water) were used in subtherapeutic doses, resulting in a minor correction of diabetes-associated sciatic motor and hind-limb digital sensory nerve conduction deficits when administered as monotherapies. Both combination treatments corrected endoneurial blood flow and vascular conductance deficits in STZ-induced diabetic rats. ISO plus SAL corrected all other changes of PDN, i.e., motor nerve conduction velocity (MNCV) and sensory nerve conduction velocity (SNCV) deficits as well as thermal and mechanical hyperalgesia. With ISO plus LIS, no significant correction of MNCV was observed, and the effect on thermal hyperalgesia was quite modest. SNCV and mechanical hyperalgesia were corrected. In vitro studies in human endothelial and Schwann cells showed early accumulation of poly(ADP-ribosyl)ated proteins (Western blot analysis) in response to high glucose, thus suggesting the importance of PARP activation in human PDN. In conclusion, low-dose PARP inhibitor-containing combination therapies may constitute a new approach for treatment of PDN.

Topics: Albuterol; Animals; Cells, Cultured; Diabetic Neuropathies; Drug Therapy, Combination; Endothelium, Vascular; Enzyme Inhibitors; Humans; Lisinopril; Male; Motor Neurons; Neural Conduction; Poly(ADP-ribose) Polymerase Inhibitors; Rats; Rats, Wistar; Regional Blood Flow; Schwann Cells

Streptozotocin (STZ)-induced diabetic neuropathy in rats was monitored by measuring the motor nerve conduction velocity (MNCV) and histopathology of the tibial nerve. Pretreatment with lisinopril (2 mg/kg p.o., 5 days prior to STZ and continued for 10 weeks) significantly (p < 0.01) prevented deterioration of MNCV as compared to STZ-diabetic animals. Nerve sections from the lisinopril pretreated group revealed less structural damage as compared to STZ-diabetic rats. However lisinopril had no effect on blood sugar, i.e., it did not alter the diabetic state. It is concluded that lisinopril prevents the development of experimental diabetic neuropathy in STZ-induced diabetic rats.

Topics: Administration, Oral; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Electric Stimulation; Female; Insulin; Lisinopril; Male; Motor Neurons; Neural Conduction; Neurons, Afferent; Rats; Rats, Inbred Strains; Sciatic Nerve; Tibial Nerve; Time Factors

The effect of treatment of rats with the angiotensin converting enzyme inhibitor lisinopril after 5 weeks of untreated streptozotocin-diabetes was examined by daily monitoring of sciatic motor conduction velocity to tibialis anterior muscle. Diabetes produced a 31.5% decrease in conduction velocity (P < 0.001). Lisinopril treatment caused a progressive improvement which was significant after 3 days (P = 0.002), full normalization being achieved by 6 days (P < 0.0001). After 7 days of treatment there followed a 7-day washout period in which no lisinopril was given. During this time conduction velocity declined to untreated diabetic levels over 3 days. A subsequent treatment period resulted in complete normalization of conduction velocity within 2 days (P < 0.0001). Thus, the marked functional effects seen for vasodilator treatment with lisinopril suggest that angiotension converting enzyme inhibitors may have potential therapeutic value in the treatment of diabetic neuropathy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Dipeptides; Lisinopril; Male; Motor Neurons; Neural Conduction; Peroneal Nerve; Rats; Rats, Sprague-Dawley; Sciatic Nerve

The effects of the angiotensin converting enzyme inhibitor lisinopril on slow and fast twitch muscle contractile properties, nerve conduction and hypoxic resistance, and muscle and nerve capillary density were examined in streptozotocin-diabetic rats. Prolongation of soleus contraction and relaxation were partially prevented by treatment (p less than 0.01). A 22% deficit in fast twitch extensor digitorum longus tetanic tension production was also ameliorated (p less than 0.01). Sciatic motor and sensory conduction velocity, 25% and 12% reduced by diabetes respectively, were 75% normalized by lisinopril (p less than 0.01). There was a 47% increase in resistance to hypoxic conduction block with diabetes (p less than 0.01). Lisinopril treatment resulted in normal hypoxic resistance. Capillarization of nerve and muscle was little affected by diabetes; however, there was a 17% increase in capillary density in sciatic nerve, and a 40% increase in extensor digitorum longus muscle with lisinopril (p less than 0.01). For soleus, a smaller treatment-induced increase in capillary density led to an elevated capillary/muscle fibre ratio (p less than 0.01). These results suggest that lisinopril promoted angiogenesis. It was concluded that the beneficial effect of preventive lisinopril treatment is likely to depend upon a reduction of peripheral vascular resistance and improvement of tissue blood flow, which implicates relative hypoxia as an important factor in the development of myopathy and neuropathy in experimental diabetes.

Topics: Action Potentials; Angiotensin-Converting Enzyme Inhibitors; Animals; Capillaries; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Enalapril; Lisinopril; Male; Muscle Contraction; Muscles; Neovascularization, Pathologic; Neural Conduction; Rats; Rats, Inbred Strains; Reference Values; Regression Analysis; Sciatic Nerve