Kininogens—the substrates for kallikreins and precursors of kinins—are present in plasma, lymph, and interstitial fluid. Two kininogens are present in plasma: a low-molecular-weight form (LMW kininogen) and a high-molecular-weight form (HMW kininogen). The two forms result from differential splicing of the kininogen gene to generate proteins that differ at the C-terminus. About 15–20% of the total plasma kininogen is in the HMW form. It is thought that LMW kininogen crosses capillary walls and serves as the substrate for tissue kallikreins, whereas HMW kininogen is confined to the bloodstream and serves as the substrate for plasma kallikrein.
The pathway for the formation and metabolism of kinins is shown in Figure 17–4. The two major kinins in humans are bradykinin and Lys-bradykinin or kallidin. Bradykinin is released from HMW kininogen by plasma kallikrein, whereas kallidin is released from LMW kininogen by tissue kallikrein. Kallidin can be converted to bradykinin by an arginine aminopeptidase. The two kinins are present in plasma and urine. Bradykinin is the predominant kinin in plasma, whereas Lys-bradykinin is the major urinary form.
Kinins are metabolized rapidly (half-life < 15 seconds) by nonspecific exopeptidases or endopeptidases, commonly referred to as kininases. Two plasma kininases have been characterized. Kininase I, apparently synthesized in the liver, is a carboxypeptidase that releases the carboxyl terminal arginine residue. Kininase II is present in plasma and vascular endothelial cells throughout the body. It is identical to angiotensin-converting enzyme (ACE, peptidyl dipeptidase), discussed above. Kininase II inactivates kinins by cleaving the carboxyl terminal dipeptide phenylalanyl-arginine. Like angiotensin I, bradykinin is almost completely hydrolyzed during a single passage through the pulmonary vascular bed.
FIGURE 17–4 The kallikrein-kinin system. Kininase II is identical to converting enzyme peptidyl dipeptidase (ACE).
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 prostaglandins 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 PGF2α. Kinins also produce contraction of most visceral smooth muscle.