The synthesis of kinins can be inhibited with the kallikrein inhibitor aprotinin. Kinin synthesis can also be inhibited by two preparations of human plasma C1-INH, cinryze and berinert, and these are used for the intravenous prophylaxis or treatment of hereditary angioedema. Ecallantide, a more recently developed recombinant plasma kallikrein inhibitor, is also effective. It is more potent and selective than C1-INH and can be administered by subcutaneous injection.
Actions of kinins mediated by prostaglandin generation can be blocked nonspecifically with inhibitors of prostaglandin synthesis such as aspirin. Conversely, the actions of kinins can be enhanced with ACE inhibitors, which block the degradation of the peptides. Indeed, as noted above, inhibition of bradykinin metabolism by ACE inhibitors contributes significantly to their antihypertensive action.
Selective B2 agonists are under study and have been shown to be effective in some animal models of human cardiovascular disease. These drugs have potential for the treatment of hypertension, myocardial hypertrophy, and other diseases.
Vasopressin (arginine vasopressin, AVP; antidiuretic hormone, ADH) plays an important role in the long-term control of blood pressure through its action on the kidney to increase water reabsorption. This and other aspects of the physiology of AVP are discussed in Chapters 15 and 37 and will not be reviewed here.
AVP also plays an important role in the regulation of arterial pressure by its vasoconstrictor action. Mutant mice lacking the gene for the V1a receptor (see below) show significantly lower blood pressure compared with control mice. AVP increases total peripheral resistance when infused in doses less than those required to produce maximum urine concentration. Such doses do not normally increase arterial pressure because the vasopressor activity of the peptide is buffered by a reflex decrease in cardiac output. When the influence of this reflex is removed, eg, in shock, pressor sensitivity to AVP is greatly increased. Pressor sensitivity to AVP is also enhanced in patients with idiopathic orthostatic hypotension. Higher doses of AVP increase blood pressure even when baroreceptor reflexes are intact.
VASOPRESSIN RECEPTORS, AGONISTS, & ANTAGONISTS
Three subtypes of AVP receptors have been identified; all are G protein-coupled. V1a receptors mediate the vasoconstrictor action of AVP; V1b receptors mediate release of ACTH by pituitary corticotropes; and V2 receptors mediate the antidiuretic action. V1a effects are mediated by Gq activation of phospholipase C, formation of inositol trisphosphate, and increased intracellular calcium concentration. V2 effects are mediated by Gs activation of adenylyl cyclase.
AVP analogs selective for vasoconstrictor or antidiuretic activity have been synthesized. The first specific V1 vasoconstrictor agonist to be synthesized was [Phe2, Ile3, Orn8]vasotocin. [Phe2, Ile8, Hgn4, Orn(i-Pr)8]vasopressin, or selepressin, is a newer short-acting selective V1a receptor agonist. Selective V2 antidiuretic analogs include 1-deamino[D-Arg8]arginine vasopressin (dDAVP) and 1-deamino[Val4, D-Arg8]arginine vasopressin (dVDAVP).