Smooth muscle relaxing, acute and long-term blood pressure lowering effects of atriopeptins. Structure-activity relationship

The relationship between the arterial relaxing, acute and long-term blood pressure lowering effects of atriopeptins were analyzed. We therefore evaluated effects of atriopeptin (103-126), i.e., atriopeptin III, and compared them to those of selected analogs. Atriopeptin (103-126) relaxed isolated aortas (1-30 nM) and lowered systolic blood pressure in conscious spontaneously hypertensive rats when high doses (4-400 nmol/kg i.v.) were administered acutely or low doses (0.4-4.0 nmol/kg/hr i.v.) were administered chronically. The relaxing effect was not affected by amino-terminal extension with up to four amino acids and by carboxy-terminal deletion of one amino acid. Further deletions lowered the relaxing potency. The observed maximal amplitude of the acute blood pressure lowering was reduced drastically by carboxy-terminal deletion of even one amino acid. This was prevented by substitution of the carboxy-terminal acid by an amide. Although not affecting the amplitude, amino-terminal extension with Arg or Arg-Arg prolonged markedly the duration of action of the acute effect. Chronic administration of atriopeptin (103-126), (103-125) and (103-123) affected blood pressure similarly. These findings illustrate different structure-activity relationships for the smooth muscle relaxing, acute and long-term antihypertensive activities of atriopeptins. From this it is suggested that the carboxy-terminal amino acids modulate differently the biological activities of atriopeptins, that amino-terminal amino acids modulate the duration of action of the acute in vivo effects and that the long-term antihypertensive effects of atriopeptins are not related directly to their arterial smooth muscle relaxing and acute blood pressure lowering effects.