Significance of the vascular renin-angiotensin pathway.

THE circulating renin-angiotensin system plays an important role in blood pressure regulation as well as in fluid and electrolyte balance. Its contribution to cardiovascular homeostasis has been well documented in studies that employ pharmacological or immunological inhibitors." Blockade of the renin-angiotensin system using peptide inhibitors or specific antibodies to renin, angiotensin converting enzyme (ACE) inhibitors, or angiotensin antagonists results in acute hypotensive responses in sodium-depleted animals or humans. In conditions associated with elevated plasma angiotensin II levels, such as experimental or clinical renovascular hypertension and congestive heart failure, these agents also bring about marked depressor responses. In all studies, the magnitude of acute depressor response can be predicted by the pretreatment plasma renin-angiotensin activity, indicating a causal relationship. In experimental as well as clinical studies, chronic administration of renin-angiotensin inhibitors has proven efficacious in lowering blood pressure in hypertension and in ameliorating edema formation in heart failure. As a result, specific inhibition of the renin-angiotensin system has become an important strategy in cardiovascular drug development. As drug development technology becomes more sophisticated, novel pharmacological agents with unique properties become available for experimental and clinical trials. A frequent outcome of these trials is an improved understanding of the biology and pharmacology of the particular system under study. For example, the development of pharmacological ligands has improved our understanding of the properties and roles of adrenergic, dopaminergic, serotoninergic, and histaminergic receptor subtypes." The development of various opioid agonists and antagonists has provided new insights into the biology of this peptidergic system. What have we learned from experiments of renin-angiotensin inhibition in the last decade? As stated earlier, studies of acute inhibition of this system have provided evidence that the renin-angiotensin system is important in acute blood pressure regulation during sodium depletion, anesthesia, and hemorrhage, as well as in the initiation of renovascular hypertension and in the development of the syndrome of congestive heart failure. These findings could have been predicted by the earlier observations that plasma renin activity (PRA) was elevated in the early phases of these conditions. However, during the chronic phase of these conditions, PRA was frequently normal and yet response to renin-angiotensin inhibition persisted, albeit attenuated. Therefore, invaluable and somewhat surprising lessons can be learned from the chronic administration of renin-angiotensin inhibitors. Although the acute blood pressure lowering effect of ACE inhibitors in humans correlates with the initial PRA, the