AVP, often in combination with norepinephrine, has proved beneficial in the treatment of septic and other vasodilatory shock states, at least in part by virtue of its V1a agonist activity. Terlipressin (triglycyl lysine vasopressin), a synthetic vasopressin analog that is converted to lysine vasopressin in the body, is also effective. However, AVP and terlipressin also stimulate renal V2 receptors, and this may have undesirable effects. Therefore, interest has focused on the use of selepressin in septic shock. Two phase 2 trials are in progress, and preliminary results are positive.
Antagonists of the vasoconstrictor action of AVP are also available. The peptide antagonist d(CH2)5[Tyr(Me)2]AVP also has antioxytocic activity but does not antagonize the antidiuretic action of AVP. A related antagonist d(CH2)5[Tyr(Me)2 Dab5]AVP lacks oxytocin antagonism but has less anti-V1 activity. Nonpeptide, orally active V1a-receptor antagonists have been developed, examples being relcovaptan and SRX251.
The V1a antagonists have been particularly useful in revealing the important role that AVP plays in blood pressure regulation in situations such as dehydration and hemorrhage. They have potential as therapeutic agents for the treatment of such diverse conditions as Raynaud’s disease, hypertension, heart failure, brain edema, motion sickness, cancer, preterm labor, and anger management. To date, most studies have focused on heart failure; promising results have been obtained with V2 antagonists such as tolvaptan, which is, however, currently approved only for use in hyponatremia. V1a antagonists also have potential, and conivaptan (YM087), a drug with both V1a and V2 antagonist activity, has also been approved for treatment of hyponatremia (see Chapter 15).
The atria and other tissues of mammals contain a family of peptides with natriuretic, diuretic, vasorelaxant, and other properties. The family includes atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). The peptides share a common 17-amino-acid disulfide ring with variable Cand N-terminals. A fourth peptide, urodilatin, has the same structure as ANP with an extension of four amino acids at the N-terminal. The renal effects of these peptides are discussed in Chapter 15.
ANP is derived from the carboxyl terminal end of a common precursor termed preproANP. ANP is synthesized primarily in cardiac atrial cells, but it is also synthesized in ventricular myocardium, by neurons in the central and peripheral nervous systems, and in the lungs.
The most important stimulus to the release of ANP from the heart is atrial stretch via mechanosensitive ion channels. ANP release is also increased by volume expansion, changing from the standing to the supine position, and exercise. ANP release can also be increased by sympathetic stimulation via α1A adrenoceptors, endothelins via the ETA-receptor subtype (see below), glucocorticoids, and AVP. Plasma ANP concentration increases in several pathologic states, including heart failure, primary aldosteronism, chronic renal failure, and inappropriate ADH secretion syndrome.
Administration of ANP increases sodium excretion and urine flow. The ANP-induced natriuresis is due both to an increase in glomerular filtration rate and a decrease in proximal tubular sodium reabsorption. ANP also inhibits the release of renin, aldosterone, and AVP; these changes may also increase sodium and water excretion. Finally, ANP causes vasodilation and decreases arterial blood pressure. Suppression of ANP production or blockade of its action impairs the natriuretic response to volume expansion, and increases blood pressure.