Kinins and Cardiovascular Disease

Autocrine, endocrine, and neuroendocrine hormonal systems are important factors that regulate cardiovascular and renal function. Alteration of the balance among these systems may result in hypertension and target organ damage. Changes in this balance could be due to (a) genetic factors and/or (b) environmental factors. Endocrine and neuroendocrine vasopressor hormonal systems, such as the renin angiotensin system, aldosterone, and catecholamines, play a well-established and important role in the regulation of blood pressure and the pathogenesis of some forms of hypertension and target organ damage. The role of vasodepressor autacoids such as kinins is less well established. However, there is increasing evidence that vasodepressor hormones not only play an important role in the regulation of blood pressure and renal function but may also oppose remodeling of the cardiovascular system. Here we will primarily review the role of kinins, which are oligopeptides containing the sequence of bradykinin. They are generated from precursors known as kininogens by enzymes such as glandular (tissue) and plasma kallikrein. Some of the effects of kinins are mediated via autacoids such as eicosanoids, nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF), and/or tissue plasminogen activator (tPA). Acting via these mediators, kinins play an important role in the regulation of cardiovascular and renal function as well as some of the cardiovascular and renal effects of angiotensin-converting enzyme (ACE) and angiotensin type 1 receptor antagonists (ARB). A study of Utah families revealed that a dominant kallikrein gene expressed as high urinary kallikrein excretion was associated with a decreased risk of essential hypertension. Also, a restriction fragment length polymorphism (RFLP) that distinguishes the kallikrein gene family in one strain of spontaneously hypertensive rats (SHR) from normotensive Brown Norway rats has been identified; in recombinant inbred substrains derived from these SHR and Brown Norway strains, the RFLP marking the kallikrein gene family of the SHR cosegregated with an increase in blood pressure. However, humans, rats, and mice with a deficiency of one component of the kallikrein-kinin system or chronic blockade of the kallikrein-kinin system do not have hypertension. In the kidney, kinins participate in the regulation of papillary blood flow and water and sodium excretion. B2-KO mice appear to be more sensitive to the hypertensinogenic effect of salt. Kinins participate in the acute antihypertensive effect of ACE inhibitors; however, in general, they are not involved in the chronic antihypertensive effects of ACE inhibitors except for the acute phase of mineralocorticoid-salt-induced hypertension. Kinins acting via nitric oxide (NO) participate in the vascular protective effect of ACE inhibitors during neointima formation. In myocardial infarction produced by ischemia/reperfusion, kinins play an important role in the reduction of infarct size induced by preconditioning or ACE inhibitors. In heart failure secondary to infarction, the therapeutic effects of ACE inhibitors are partially mediated by kinins via the release of NO. The therapeutic effect of ARB in heart failure is partly due to activation of angiotensin type 2 receptors via kinins and NO. Thus kinins could play an important role in the regulation of cardiovascular and renal function as well as in many of the beneficial effects of ACE inhibitors and ARB.