Hedner T, Sun X, Junggren I L, Pettersson A, Edvinsson L
Department of Pharmacology, University of Göteborg, Sweden.
J Hypertens Suppl. 1992 Dec;10(7):S121-32.
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.
评估开发新型药理药物用于治疗高血压和心血管疾病的潜力。
药理降压的基础：自近100年前蒂格斯特德发现肾素-血管紧张素系统以来，已发现大量血管活性肽。通过与内分泌、血管周围或内皮来源的此类肽相互作用，血压可能会得到调节。肾素-血管紧张素系统的阻断：血管紧张素转换酶（ACE）抑制剂在高血压和充血性心力衰竭治疗中的成功通常归因于血管紧张素II生成减少。最近开发的特异性且高效的血管紧张素II 1型亚型受体拮抗剂，如氯沙坦（DuP753、MK954），为抑制肾素-血管紧张素系统提供了新机会，目前正在高血压患者中进行探索。此外，阻断肾素-血管紧张素系统的首个限速反应，即抑制肾素活性，也是抗高血压药物开发的一个靶点。然而，目前这一开发受到活性肾素代偿性增加的阻碍，这种增加在临床上抵消了肾素抑制剂的降压作用。药理学诱导心房利钠肽（ANP）增加：通过NEP-24.11抑制剂药物抑制其代谢清除，可增加循环或组织中ANP的可用性。这些药物在动物模型中可降低血压并产生利尿作用，可能成为治疗高血压和充血性心力衰竭患者的一类新型药物。高血压管理中的其他潜在药理学靶点：有几个潜在的药理学靶点可能会在未来促成新型抗高血压药物的开发。这些包括血管升压肽的相互作用或阻断。开发途径包括神经肽Y1受体拮抗剂，其可阻断神经肽Y的节后血管升压作用，或内皮素拮抗剂，其可在内皮素A受体位点阻断内皮素的升压作用。功能性神经肽Y抑制剂α-三肌醇（PP 56）的心血管作用为降低高血压患者血压提供了一种潜在的新机制。此外,最近发现的对内皮素A受体亚型具有高效力和特异性的小分子药物，在特定血管疾病状态下可能也有价值。
未来的发展可能会为我们提供基于与血管活性肽相互作用的新型药物，这可能会改善对特定心血管疾病状态的管理。
