kallidin and Atherosclerosis

The kinin B(1) receptor plays an important role in mediating the inflammatory effects of the kallikrein-kinin pathway. The recent development of orally available non-peptidic antagonists and genetically modified mice deficient in B(1) receptor expression have demonstrated that the receptor plays a pivotal role in the cellular, particularly neutrophil, recruitment associated with an acute inflammatory response. These tools have also enabled elucidation of the pathways involved in mediating this effect and have highlighted a major role for chemokines, particularly CXCL5 and CCL2. Neutrophil recruitment is involved in the pathogenesis of renal disease and has very recently been implicated in the early stages of atherosclerosis. In this review we discuss the most recent evidence linking the B(1) receptor with the pathogenesis of these two inflammatory cardiovascular diseases and highlight the therapeutic potential of the kinin B(1) receptor in these disease states.

Topics: Animals; Anti-Inflammatory Agents; Atherosclerosis; Bradykinin; Bradykinin B1 Receptor Antagonists; Cardiovascular Diseases; Drug Delivery Systems; Humans; Inflammation; Inflammation Mediators; Kallidin; Kidney Diseases; Neutrophil Infiltration; Receptor, Bradykinin B1

Upregulation of vascular B(1) kinin receptor expression has been reported in human atheroma, but its role remains unclear. We examined vasomotor and fibrinolytic responses to selective B(1) and B(2) kinin receptor agonism in the human femoral circulation and correlated responses with femoral arterial plaque load. Femoral arterial cross-sectional area, blood flow and plaque volume were determined using intravascular ultrasound and Doppler during selective arterial infusion of Lys-des-Arg(9)-bradykinin (B(1) agonist), bradykinin (B(2) agonist) and sodium nitroprusside in eleven patients undergoing diagnostic coronary angiography. Net release of tissue plasminogen activator was determined across the femoral vascular bed. Mean femoral arterial plaque load was 8.1 (±0.9) mm(3)/mm of vessel. Bradykinin and sodium nitroprusside caused dose-dependent increases in femoral blood flow (p < 0.05 and p < 0.005, respectively). Bradykinin caused a dose-dependent increase in net tissue plasminogen activator release (p < 0.05), which was augmented by angiotensin-converting enzyme inhibition (p < 0.05). There were no correlations between plaque load and bradykinin-mediated vasodilation or tissue plasminogen activator release. Lys-des-Arg(9)-bradykinin had no effect on blood flow or tissue plasminogen activator release. The vasomotor and fibrinolytic actions of bradykinin in the femoral circulation are mediated solely by the B(2) kinin receptor, irrespective of the presence of atheroma. In keeping with previous data, bradykinin-mediated tissue plasminogen activator release was augmented in the presence of angiotensin-converting enzyme inhibition consistent with its putative vascular protective effect.

Topics: Adult; Aged; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Atherosclerosis; Blood Flow Velocity; Bradykinin; Dose-Response Relationship, Drug; Female; Femoral Artery; Fibrinolysis; Humans; Infusions, Intra-Arterial; Kallidin; Lower Extremity; Male; Middle Aged; Nitroprusside; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Regional Blood Flow; Scotland; Tissue Plasminogen Activator; Ultrasonography, Doppler; Ultrasonography, Interventional; Vasodilation; Vasodilator Agents; Vasomotor System