icatibant and omapatrilat

The kallikrein-kinin system is an endogenous metabolic cascade, triggering of which results in the release of vasoactive kinins (bradykinin-related peptides). This complex system includes the precursors of kinins known as kininogens and mainly tissue and plasma kallikreins. The pharmacologically active kinins, which are often considered as either proinflammatory or cardioprotective, are implicated in many physiological and pathological processes. The interest of the various components of this multi-protein system is explained in part by the multiplicity of its pharmacological activities, mediated not only by kinins and their receptors, but also by their precursors and their activators and the metallopeptidases and the antiproteases that limit their activities. The regulation of this system by serpins and the wide distribution of the different constituents add to the complexity of this system, as well as its multiple relationships with other important metabolic pathways such as the renin-angiotensin, coagulation, or complement pathways. The purpose of this review is to summarize the main properties of this kallikrein-kinin system and to address the multiple pharmacological interventions that modulate the functions of this system, restraining its proinflammatory effects or potentiating its cardiovascular properties.

Topics: Angioedema; Angiotensin-Converting Enzyme Inhibitors; Animals; Aprotinin; Bradykinin; Bradykinin B2 Receptor Antagonists; Cardiovascular Diseases; Complement C1 Inactivator Proteins; Complement C1 Inhibitor Protein; Humans; Inflammation; Kallikrein-Kinin System; Kallikreins; Kidney Diseases; Kinins; Neprilysin; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Pyridines; Randomized Controlled Trials as Topic; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Serpins; Thiazepines

The aim of the present study was to investigate whether pharmacological enhancement of the renal kallikrein-kinin system using the vasopeptidase inhibitor omapatrilat plays a direct role in modulating the fibrotic responses of human mesangial cells to injury. Treatment with 40 micromol/L omapatrilat was able to reduce macrophage-conditioned medium (MPCM)-induced fibronectin levels without affecting mRNA expression. MPCM injury also suppressed kallikrein and low molecular weight kininogen mRNA. Omapatrilat was able to attenuate this suppression. Bradykinin levels in contrast were increased by MPCM and treatment with omapatrilat further augmented levels. Co-incubation with the bradykinin B2 receptor antagonist HOE 140 attenuated the omapatrilat-induced lowering of fibronectin. Moreover, inhibition of cGMP release had a similar effect. Paradoxically, RT-PCR and Southern blotting demonstrated that bradykinin B2 receptor mRNA levels were down regulated in response to omapatrilat. Western blotting supported this data. Supernatant levels of tissue plasminogen activator (tPA), a product of bradykinin stimulation, were decreased by omapatrilat while cell associated tPA levels were increased. Matrix metalloproteinase-9 (MMP-9) mRNA expression was up regulated by omapatrilat treatment, although no difference in active zymogen levels was observed. In conclusion enhancement of kallikrein-kinin system appears to play a direct role in promoting anti-fibrotic responses in MPCM-injured human mesangial cells.

Topics: Bradykinin; Bradykinin B2 Receptor Antagonists; Culture Media, Conditioned; Fibronectins; Fibrosis; Humans; Kallikrein-Kinin System; Kallikreins; Kininogens; Macrophages; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Mesangial Cells; Protease Inhibitors; Pyridines; Receptor, Bradykinin B1; Receptor, Bradykinin B2; RNA, Messenger; Thiazepines; Tissue Plasminogen Activator

ACE inhibitors (ACEIs) improve insulin resistance and prevent type 2 diabetes, possibly mediated by inhibition of bradykinin (BK) degradation. The vasopeptidase inhibitor omapatrilat (OMA) raises BK to a greater extent than ACEIs by dual enzyme inhibition, whereas its insulin-sensitizing effects and mechanisms have not been investigated.. We compared the insulin-sensitizing effects of OMA, ramipril (an ACEI), losartan (an angiotensin II type 1 receptor blocker), and placebo by 2-step euglycemic hyperinsulinemic clamp in insulin-resistant Zucker fatty rats (n=6 to 7 in each group). OMA resulted in a lower rate of endogenous glucose production than placebo at baseline (35+/-5 versus 54+/-4 mmol x kg(-1) x min(-1), P<0.01), greater suppression of endogenous glucose production by low-dose insulin (73+/-11% versus 27+/-18%, P<0.05), and greater glucose disposal at high-dose insulin (135+/-5 versus 92+/-4 mmol x kg(-1) x min(-1), P<0.01). Ramipril tended to improve insulin sensitivity, but losartan did not. OMA significantly increased 2-deoxyglucose uptake by myocardium, fat, and skeletal muscle. Ramipril increased 2-deoxyglucose uptake only by some skeletal muscles, but losartan did not. The insulin-sensitizing effects of OMA were blocked significantly by HOE-140 (a BK, B2 receptor antagonist) and NG-nitro-L-arginine methyl ester (a nitric oxide synthase inhibitor) in all tissues except myocardium.. OMA induces profound insulin sensitization and increases myocardial glucose uptake in Zucker fatty rats. This effect is greater than that of ramipril and probably occurs at least in part via stimulation of the B2 receptor. OMA has the potential for greater type 2 diabetes prevention than ACEI.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Biological Transport; Blood Glucose; Bradykinin; Bradykinin Receptor Antagonists; Drug Synergism; Enzyme Inhibitors; Glucose; Glucose Clamp Technique; Insulin; Insulin Resistance; Losartan; Male; Myocardium; Neprilysin; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Protease Inhibitors; Pyridines; Ramipril; Rats; Rats, Zucker; Receptor, Angiotensin, Type 1; Receptor, Bradykinin B2; Thiazepines