icatibant and Diabetic-Neuropathies

The influence of an irreversible inhibitor of constitutive NO synthase (L-NOArg; 1.0 mg/kg ip), a relatively selective inhibitor of inducible NO synthase (L-NIL; 1.0 mg/kg ip) and a relatively specific inhibitor of neuronal NO synthase (7-NI; 0.1 mg/kg ip), on antihyperalgesic action of selective antagonists of B2 and B1 receptors: D-Arg-[Hyp3,Thi5,D-Tic7,Oic8] bradykinin (HOE 140; 70 nmol/kg ip) or des Arg10 HOE 140 (70 nmol/kg ip) respectively, in model of diabetic (streptozotocin-induced) and toxic (vincristine-induced) neuropathy was investigated.. The changes in pain thresholds were determined using mechanical stimuli--the modification of the classic paw withdrawal test described by Randall-Selitto.. The results of this paper confirm that inhibition of bradykinin receptors and inducible NO synthase but not neuronal NO synthase activity reduces diabetic hyperalgesia. Pretreatment with L-NOArg and L-NIL but not 7-NI, significantly increases antihyperalgesic activity both HOE 140 and des Arg10 HOE 140. It was also shown that both products of inducible NO synthase and neuronal NO synthase activation as well as bradykinin are involved in hyperalgesia produced by vincristine. Moreover, L-NOArg and 7-NI but not L-NIL intensify antihyperalgesic activity of HOE 140 or des-Arg10HOE 140 in toxic neuropathy.. Results of these studies suggest that B1 and B2 receptors are engaged in transmission of nociceptive stimuli in both diabetic and toxic neuropathy. In streptozotocin-induced hyperalgesia, inducible NO synthase participates in pronociceptive activity of bradykinin, whereas in vincristine-induced hyperalgesia bradykinin seemed to activate neuronal NO synthase pathway. Therefore, concomitant administration of small doses of bradykinin receptor antagonists and NO synthase inhibitors can be effective in alleviation of neuropathic pain, even in hospital care.

Topics: Animals; Bradykinin; Bradykinin Receptor Antagonists; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Drug Evaluation, Preclinical; Enzyme Inhibitors; Hyperalgesia; Hypoglycemic Agents; Indazoles; Lysine; Male; Nitric Oxide Synthase; Nitroarginine; Pain Measurement; Rats; Rats, Wistar; Receptors, Bradykinin; Streptozocin; Tetrahydroisoquinolines; Vincristine

The role of bradykinin receptor blockade in the development of neuropathies caused by diabetes mellitus and vincristine was examined. The effects of a potent and selective B(1) receptor antagonist (des-Arg(10)-HOE 140) as well as a specific antagonist of B(2) receptors (HOE 140) were investigated. Both agents significantly decreased hyperalgesia caused otherwise by vincristine. In a diabetic neuropathy model, both agents almost completely suppressed hyperalgesia in the first 10 days of the study. However, from day 11 after administration of streptozotocin, the action of des-Arg(10)-HOE 140 was significantly weaker than that of HOE 140. The results of the study suggest involvement of both B(1) and B(2) receptors in transmission of nociceptive stimuli in the vincristine-induced as well as diabetic neuropathy model.

Topics: Animals; Antineoplastic Agents; Bradykinin; Bradykinin Receptor Antagonists; Diabetic Neuropathies; Disease Models, Animal; Hyperalgesia; Male; Rats; Rats, Wistar; Receptors, Bradykinin; Streptozocin; Vincristine

Diabetic nephropathy (DN) can be delayed by the use of angiotensin-converting enzyme inhibitors (ACEi). The mechanisms of ACEi renal protection are not univocal. To investigate the impact of bradykinin B(2) receptor (B2R) activation during ACE inhibition, type II diabetic mice (C57BLKS db/db) received for 20 wk: 1) ACEi (ramipril) alone, 2) ACEi + HOE-140 (a specific B2R antagonist), 3) HOE-140 alone, or 4) no treatment. The development of DN, defined by an increase in albuminuria and glomerulosclerosis, was largely prevented by ACEi treatment (albuminuria: 980 +/- 130 vs. 2,160 +/- 330 mg/g creatinine; mesangial area: 22.5 +/- 0.5 vs. 27.6 +/- 0.3%). The protective effect of ramipril was markedly attenuated by B2R blockade (albuminuria: 2,790 +/- 680 mg/g creatinine; mesangial area: 30.4 +/- 1.1%), whereas HOE-140 alone significantly increased albuminuria. Despite such benefits, glomerular filtration rate remained unchanged, probably because of the combination of the hypotensive effect of diabetes in this model and the renal hemodynamic action of ramipril. Finally, the renal protective effect of ACEi was associated with a marked decrease in glomerular overexpression of insulin-like growth factor-1 (IGF-1) and transforming growth factor-beta pathways, but also in advanced glycation end product receptors and lipid peroxidation assessed by 4-hydroxy-2-nonenal (4-HNE) adducts. Concomitant blockade of B2R partly restored glomerular overexpression of IGF-1 receptor beta and 4-HNE complexes. These results support the critical role of B2R activation in the mediation of ACEi renal protection against DN and provide the rationale to examine the benefit of B2R activation by itself as a new therapeutic approach for DN.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Blotting, Western; Bradykinin; Bradykinin B2 Receptor Antagonists; Diabetic Neuropathies; Glomerular Filtration Rate; Kidney; Kidney Function Tests; Kidney Glomerulus; Mice; Mice, Inbred C57BL; Mice, Obese; Protective Agents; Ramipril; Signal Transduction