1. Although angiotensin II (ANG II) has been identified as a key factor in the development of cardiac hypertrophy and remodelling, the role of its degradation fragment ANG II (3–8), angiotensin IV (ANG IV), is unknown. The presence of ANG IV in the blood circulation as well as the identification of ANG IV receptors in the heart and other organs indicates that ANG IV may act as a peptide hormone. 2. ANG IV receptors were characterized by binding of 125 I-ANG IV to membranes of cultured rabbit cardiac fibroblasts. Incorporation of [ 3 H]thymidine, [ 3 H]uridine and [ 3 H]Ieucine into DNA, RNA and proteins, respectively, was determined to analyse the growth effects of ANG IV, ANG II and the combination of both peptides. 3. ANG IV displaces 125 I-ANG IV bound to membranes of rabbit cardiac fibroblasts with high affinity, whereas ANG II receptor-specific ligands ([Sar 1 ,Ile 8 ]ANG II, losartan, CGP 42 112 A) do not. 125 I-ANG IV binds to a single class of binding site with a dissociation constant ( K d ) of 4.87 ± 0.11 nmol/l. The density of ANG IV receptors ( B max. ) is 371 ± 8.3 fmol/mg of protein. 125 I-ANG IV binding is not markedly affected in the presence of the non-hydrolysable GTP analogue GTPγS, whereas binding of 125 I-ANG II is reduced. 4. In quiescent cells, a 24 h exposure of ANG IV (100 nmol/l) increased rates of thymidine and uridine incorporation by 127% and 246%, respectively. A small but statistically insignificant increase in leucine incorporation was observed under these conditions. Similar effects have been observed after stimulation by ANG II (100 nmol/l, 24 h). The combination of ANG II and ANG IV has additive effects on uridine, but not on thymidine and leucine incorporation. 5. In conclusion, rabbit cardiac fibroblasts express a specific ANG IV receptor, distinct from the known ANG II receptors, which mediates the stimulation of cellular DNA and RNA synthesis.
1. To determine the influence of loss of atrioventricular synchrony on release of atrial natriuretic peptide (ANP), plasma ANP concentrations were measured by radioreceptor assay in 16 patients during sequential and ventricular cardiac pacing at normal heart rates. 2. Ventricular pacing induced an increase in plasma ANP concentrations (means ± SEM) from 44 ± 3 to 104 ± 4 pmol/l ( P < 0.01) in 11 patients in whom systemic blood pressure was maintained. 3. In contrast, when ventricular pacing was associated with a fall in blood pressure (five patients), ANP levels (means ± SEM) fell from 68 ± 6 to 14 ± 4 pmol/l ( n = 5, P < 0.05) within 5 min, despite an increase in atrial pressure. Plasma catecholamines also rose significantly in these latter patients. 4. We conclude that when loss of atrioventricular synchrony is well tolerated haemodynamically, cardiac release of ANP is increased in keeping with elevation in atrial pressure. However, the fall in plasma ANP concentration observed when ventricular pacing produces a fall in blood pressure suggests that in addition to atrial pressure, ANP release may be influenced by negative feedback mechanisms, possibly involving the baroreflex and autonomic nervous system.