Peptides as targets for antihypertensive drug development

Abstract

To assess the potential for development of new classes of pharmacological drugs in the treatment of hypertension and cardiovascular disease. Basis of pharmacological blood pressure reduction: Since the discovery of the renin-angiotensin system by Tigerstedt almost 100 years ago, a large number of vasoactive peptides have been discovered. By interaction with such peptides of endocrine, perivascular or endothelial origin, blood pressure may be modulated. BLOCKADE OF THE RENIN-ANGIOTENSIN SYSTEM: The success of the angiotensin converting enzyme (ACE) inhibitors in hypertension and congestive heart failure is generally attributed to reduced generation of angiotensin II. The recent development of specific and highly potent Ang II type 1 subtype receptor antagonists such as losartan (DuP753, MK954) have provided a new opportunity to inhibit the renin-angiotensin system, and this is currently being explored in hypertensive patients. In addition, blockade of the first and rate-limiting reaction of the renin-angiotensin system, inhibition of renin activity, is also a target for the development of antihypertensive drugs. However, this development is hampered at present by a compensatory increase in active renin that clinically offsets the antihypertensive action of renin inhibitors. PHARMACOLOGICALLY INDUCED INCREASE IN ATRIAL NATRIURETIC PEPTIDE (ANP): The availability of circulating or tissue ANP may be increased by inhibiting its metabolic clearance by NEP-24.11 inhibitor drugs. These agents induce a reduction in blood pressure and diuretic effects in animal models, and may become a new class of drugs for the clinical management of patients with hypertension and congestive heart failure. OTHER POTENTIAL PHARMACOLOGICAL TARGETS IN THE MANAGEMENT OF HYPERTENSION: There are several potential pharmacological targets that may lead to the development of novel antihypertensive agents in the future. These include the interaction or blockade of vasopressor peptides. Routes of development include neuropeptide Y1 receptor antagonists, which block the postjunctional vasopressor effect of neuropeptide Y, or endothelin antagonists, which block endothelin pressor actions at the endothelin A receptor site. The cardiovascular actions of the functional neuropeptide Y inhibitor alpha-trinositol (PP 56) provide a potential new mechanism for reducing blood pressure in hypertension. In addition, the recent discovery of small molecular agents with high potency and specificity for the endothelin A receptor subtype may also be of value in specific vascular disease states. Future development is likely to provide us with novel drugs based on interactions with vasoactive peptides that may improve the management of specific cardiovascular disease states.