Autocrine, paracrine, endocrine, and neuroendocrine hormonal systems help regulate cardio-vascular and renal function. Any change in the balance among these systems may result in
hypertension and target organ damage, whether the cause is genetic, environmental or a combination of the two. Endocrine and neuroendocrine vasopressor
hormones such as the renin-angiotensin system (RAS),
aldosterone, and
catecholamines are important for regulation of blood pressure and pathogenesis of
hypertension and target organ damage. While the role of vasodepressor
autacoids such as
kinins is not as well defined, there is increasing evidence that they are not only critical to blood pressure and renal function but may also oppose remodeling of the cardiovascular system. Here we will primarily be concerned with
kinins, which are
oligopeptides containing the aminoacid sequence of
bradykinin. They are generated from precursors known as
kininogens by
enzymes such as tissue (glandular) 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).
Kinins help protect against cardiac
ischemia and play an important part in preconditioning as well as the cardiovascular and renal protective effects of
angiotensin-converting enzyme (ACE) and
angiotensin type 1 receptor blockers (ARB). But the role of
kinins in the pathogenesis of
hypertension remains controversial. 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. Moreover, researchers have identified a restriction fragment length polymorphism (RFLP) that distinguishes the
kallikrein gene family found in one strain of spontaneously hypertensive rats (SHR) from a homologous gene in normotensive Brown Norway rats, and in recombinant inbred substrains derived from these SHR and Brown Norway rats this RFLP cosegregated with an increase in blood pressure. However, humans, rats and mice with a deficiency in one or more components of the kallikrein-kinin-system (KKS) or chronic KKS blockade do not have
hypertension. In the kidney,
kinins are essential for proper 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 are involved in the acute
antihypertensive effects of
ACE inhibitors but not their chronic effects (save for
mineralocorticoid-
salt-induced
hypertension).
Kinins appear to play a role in the pathogenesis of inflammatory diseases such as
arthritis and skin
inflammation; they act on innate immunity as
mediators of inflammation by promoting maturation of dendritic cells, which activate the body's adaptive immune system and thereby stimulate mechanisms that promote
inflammation. On the other hand,
kinins acting via NO contribute to the vascular protective effect of
ACE inhibitors during
neointima formation. In
myocardial infarction produced by
ischemia/reperfusion,
kinins help reduce
infarct size following preconditioning or treatment with
ACE inhibitors. In
heart failure secondary to
infarction, the
therapeutic effects of
ACE inhibitors are partially mediated by
kinins via release of NO, while drugs that activate the
angiotensin type 2 receptor act in part via
kinins and NO. Thus
kinins play an important role in regulation of cardiovascular and renal function as well as many of the beneficial effects of
ACE inhibitors and ARBs on target organ damage in
hypertension.