When injected intravenously, kinins produce a rapid but brief fall in blood pressure that is due to their arteriolar vasodilator action. Intravenous infusions of the peptide fail to produce a sustained decrease in blood pressure; prolonged hypotension can only be produced by progressively increasing the rate of infusion. The rapid reversibility of the hypotensive response to kinins is due primarily to reflex increases in heart rate, myocardial contractility, and cardiac output. In some species, bradykinin produces a biphasic change in blood pressure—an initial hypotensive response followed by an increase above the preinjection level. The increase in blood pressure may be due to a reflex activation of the sympathetic nervous system, but under some conditions, bradykinin can directly release catecholamines from the adrenal medulla and stimulate sympathetic ganglia. Bradykinin also increases blood pressure when injected into the central nervous system, but the physiologic significance of this effect is not clear, since it is unlikely that kinins cross the blood-brain barrier. (Note, however, that bradykinin can increase the permeability of the blood-brain barrier to some other substances.) Kinins have no consistent effect on sympathetic or parasympathetic nerve endings.
The arteriolar dilation produced by kinins causes an increase in pressure and flow in the capillary bed, thus favoring efflux of fluid from blood to tissues. This effect may be facilitated by increased capillary permeability resulting from contraction of endothelial cells and widening of intercellular junctions, and by increased venous pressure secondary to constriction of veins. As a result of these changes, water and solutes pass from the blood to the extracellular fluid, lymph flow increases, and edema may result.
The role that endogenous kinins play in the regulation of blood pressure is not clear. They do not appear to participate in the control of blood pressure under resting conditions but may play a role in postexercise hypotension.
As noted earlier, prekallikreins and kallikreins are present in several glands, including the pancreas, kidney, intestine, salivary glands, and sweat glands, and they can be released into the secretory fluids of these glands. The function of the enzymes in these tissues is not known. Since kinins have such marked effects on smooth muscle, they may modulate the tone of salivary and pancreatic ducts, help regulate gastrointestinal motility, and act as local modulators of blood flow. Kinins also influence the transepithelial transport of water, electrolytes, glucose, and amino acids, and may regulate the transport of these substances in the gastrointestinal tract and kidney. Finally, kallikreins may play a role in the physiologic activation of certain prohormones, including proinsulin and prorenin.
Bradykinin has long been known to produce the four classic symptoms of inflammation—redness, local heat, swelling, and pain. Kinins are rapidly generated after tissue injury and play a pivotal role in the development and maintenance of these inflammatory processes.
Kinins are potent pain-producing substances when applied to a blister base or injected intradermally. They elicit pain by stimulating nociceptive afferents in the skin and viscera.
Hereditary angioedema is a rare autosomal dominant disorder that results from deficiency or dysfunction of the C1 esterase inhibitor (C1-INH), a major inhibitor of proteases of the complement, coagulation, and kallikrein-kinin systems. C1-INH deficiency results in activation of kallikrein and increased formation of bradykinin, which by increasing vascular permeability and other actions, causes recurrent episodes of angioedema of the airways, gastrointestinal tract, extremities, and genitalia. Hereditary angioedema can be treated with drugs that inhibit the formation or actions of bradykinin (see below).