Pharmacological Agents Designed To Lower The Plasma Levels Of Bradykinin In

Pharmacological agents designed to lower the plasma levels of bradykinin in this condition may be suitable treatment agents. There is evidence from animal models that the injection of endotoxins (lipopolysaccharide (LPS) from E. Coli into the dorsal skin of rats caused a dose-dependent increase in vascular permeability and this increase caused by LPS was attenuated by pretreatment with the B2R antagonist HOE 140 (42). The role of bradykinin receptors in the pathophysiology of this condition is thus highlighted.
Body substrates for ACE are numerous and they are widely distribution throughout the human body; this perhaps is an indicator that this enzyme may be involved in additional physiologic processes such as atherosclerosis and inflammation, in addition to an important role in cardiovascular homeostasis (5, 43). It is a scientific fact that the formation of Ang II from Ang I through the action of ACE will initiates a cascade of events producing high levels free radicals and promotes vascular smooth muscle cell proliferation (44). However bradykinin is more readily hydrolyzed by ACE than Ang I, it is thus logical to suppose that the hydrolysis of bradykinin may also contribute to the pathophysiology of these disorders (45). The inhibition of ACE activity is reported to improve endothelial function and to stimulate vascular remodeling, as well as attenuate the progression of arteriosclerosis and the occurrence of cardiovascular events in humans (5, 46, 47). The introduction of many second-generation ACE inhibitors, with improved pharmacokinetic properties relative to captopril (a first-generation ACE inhibitor) has led to numerous multi-center outcome trials that have established the clinical effectiveness of ACE inhibitors for the treatment cardiovascular diseases. An appreciation of the role of bradykinin and the kallikrein-kinin system is therefore fundamental to the development of better pharmacological lead molecules.
Neutral endopeptidase (NEP) is the main enzyme responsible for the metabolism of kinins in the kidney; it regulates the degradation of natriuretic peptides (48) and plays an important role in the metabolism of bradykinin at the endothelium. NEP also inactivates other peptides like enkephalins, neurokinins, and amyloid-ß peptide, a marker for Alzheimer disease of the CNS (49). NEP is thus a potential target for the disorders marked by an aberration in the levels of these endogenous substances.
Bradykinin administration reproduces two of the cardinal signs of inflammation (rubor, calor) through the activation of B2R that causes vasodilatation due to endothelial Nitric oxide synthase and phospholipase A2 stimulation leading to Nitric oxide and prostaglandin I2 production by vascular endothelial cells (Figure 5).