Physiologic & Pathologic Effects of Kinins

PHYSIOLOGIC & PATHOLOGIC EFFECTS OF KININS

Effects on the Cardiovascular System

Kinins produce marked arteriolar dilation in several vascular beds, including the heart, skeletal muscle, kidney, liver, and intestine. 

In this respect, kinins are approximately 10 times more potent on a molar basis than histamine. The vasodilation may result from a direct inhibitory effect of kinins on arteriolar smooth muscle or may be mediated by the release of nitric oxide or vasodilator pros-taglandins such as PGE₂ and PGI₂. In contrast, the predominant effect of kinins on veins is contraction; again, this may result from direct stimulation of venous smooth muscle or from the release of venoconstrictor prostaglandins such as PGF_2α. Kinins also pro-duce contraction of most visceral smooth muscle.

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 pro-duced 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 cate-cholamines 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 extra-cellular 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.

Effects on Endocrine & Exocrine Glands

As noted earlier, prekallikreins and kallikreins are present in sev-eral glands, including the pancreas, kidney, intestine, salivary glands, and sweat glands, and they can be released into the secre-tory 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 pan-creatic ducts, help regulate gastrointestinal motility, and act as local modulators of blood flow. Kinins also influence the tran-sepithelial 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 various prohormones, includ-ing proinsulin and prorenin.

Role in Inflammation & Pain

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 inflam-matory processes.

Kinins are potent pain-producing substances when applied to a blister base or injected intradermally. They elicit pain by stimu-lating nociceptive afferents in the skin and viscera.

Other Effects

There is evidence that bradykinin may play a beneficial, protective role in certain cardiovascular diseases and ischemic stroke-induced brain injury. On the other hand, it has been implicated in cancer and some central nervous system diseases.