Vasodilators bradykinin

The kallikrein-kinin system is an enzymatic pathway giving rise to two predominant vasoactive peptides, kallidin and bradykinin. Kallikrein, the enzyme responsible for the formation of these peptides, exists in plasma and tissues. However, circulating levels of the end products, kalhdin and bradykinin, are quite low because the kalhkrein enzymes are present largely in inactive forms. In addition, the short half-life of these peptides (15 seconds) also contributes to low plasma levels. In general, the kinins produce relaxation of vascular smooth muscle and vasodilation. Bradykinin causes... 

Peptides are used by most tissues for cell-to-cell communication. As noted in Chapters 6 and 21, they play important roles in the autonomic and central nervous systems. Several peptides exert important direct effects on vascular and other smooth muscles. These peptides include vasoconstrictors (angiotensin II, vasopressin, endothelins, neuropeptide Y, and urotensin) and vasodilators (bradykinin and related kinins, natriuretic peptides, vasoactive intestinal peptide, substance P, neurotensin, calcitonin gene-related peptide, and adrenomedullin). This chapter focuses on the smooth muscle actions of the peptides. 

Omission of the C-terminal Arg residue from the vasodilator bradykinin... 

Angiotensin converting enzyme (ACE) inhibitor. ACE is a dipep-tidylaminopeptidase (EC 3.4.15.1) which cleaves dipeptides from the C-terminus of peptides. It converts angiotensin I to the potent vasoconstrictor, angiotensin II, and inactivates the vasodilator, bradykinin. The dodecapep-tide, H.Phe.Phe.Val.Ala.Pro.Phe.Pro.Glu.Val.Phe.Gly.Lys, i.e. a i-CN f23-34, from tryptic hydrolysates of casein inhibits ACE. The C-terminal sequence of aji-casein, H.Thr.Thr.Met.Pro.Leu.Tyr, a j-CN fl94-199, also has ACE inhibitory activity. Peptides from the sequence 39-52 of human )8-casein, especially H.Ser.Phe.Gln.Pro.Gln.Pro.Leu.Ile.Tyr.Pro (j8-CN f43-52), also have ACE inhibitory activity. 

ACE-inhibitor [42 5], Clinical and biochemical observations showed that by this means, the vasodilator bradykinin is activated. A severe blood pressure drop followed in those hemodialysis patients who had been treated with such a membrane. Clinical consequences in terms of blood pressure drop and duration were dependent on ACEi dose (Fig. 13.8, [46]). The effect is currently mentioned in leaflets that accompany medicinal drugs and alert for contraindications. They could, however prevented by changing the pH of the buffer solution (Eig. 13.9, [47,48]). This observation should be kept in mind, when other negatively charged polymers are used in clinical application, such as, for instance, for adsorber particles made from dextran sulfate or acrylic acid. 

Vasodilating molecule(s) liberated from vascular endothelial cells in response to chemical substances (i.e., Acetylcholine, bradykinin, substance P, etc.) or mechanical stimuli (i.e., shear stress, transmural pressure, etc.). The EDRF includes NO, prostaglandin J2 (prostacyclin), and endothelium-derived hypeipolarizing factor (EDHF). 

XIa and also releases bradykinin (a nonapeptide with potent vasodilator action) from HMW kininogen. 

Chin et al. (1992) have su ested that oxidized LDL and high-density lipoprotein (HDL) inactivate endothelial cell-derived NO. NO inactivation was due to the oxidized lipids within the lipoprotein particles and was thought to be explained by a chemical reaction between the lipoproteins and NO. Other investigators have shown that relaxation of vascular smooth muscle by acetylcholine or bradykinin (endothelium-dependent vasodilators) is inhibited by LDL (Andrews etal., 1987). The role of NO in the modification of LDL is discussed in full detail in Chapter 2. 

Nerve receptors, or nociceptors, may release substance P, a peptide that causes vasodilation when released.20 This dilation occurs mainly through substance P-induced production of the vasodilator nitric oxide. Substance P also generates the release of histamine, leading to bradykinin release and activation of an inflammatory process. Capsaicin relieves pain by stimulating the release of substance P from sensory nerve fibers, which ultimately depletes stores of substance P. 

A deficiency in the local synthesis of vasodilating substances in the vascular endothelium, such as prostacyclin, bradykinin, and nitric oxide, or an increase in production of vasoconstricting substances such as angiotensin II and endothelin I ... 

I to angiotensin II, a potent vasoconstrictor and stimulator of aldosterone secretion. ACE inhibitors also block the degradation of bradykinin and stimulate the synthesis of other vasodilating substances including prostaglandin E2 and prostacyclin. The fact that ACE inhibitors lower BP in patients with normal plasma renin activity suggests that bradykinin and perhaps tissue production of ACE are important in hypertension. 

Bradykinin is a small peptide that is released from a precursor, kininogen, by the action of the proteolytic enzyme kallikrein, which itself is formed from a precursor, prekallikrein, by the action of the blood clotting factor, Xlla (Figure 17.4). Bradykinin is responsible for the pain, vasodilation and increased permeability of the blood vessels by stimulating formation and release of prostaglandins and prostacyclins from the endothelial cells (see Chapter 11). 

Figure 22.16 Regulation of vasoconstriction/vasodilation by angiotensin-II and bradykinin. The mechanism by which angiotensin-II stimulates vasoconstriction is shown in Figure 22.15. Angiotensin-converting enzyme is also responsible for bradykinin inactivation. Bradykinin stimulates endothelial cells to produce and secrete nitric oxide and prostacyclin, both of which are vasodilators. Consequently the effect of an ACE inhibitor is to decrease the concentration of angiotensin-II, which lowers blood pressure, and to increase the concentration of bradykinin, which also lowers blood pressure.

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