Angiotensin IV has mixed effects on left ventricle systolic function and speeds relaxation.
OBJECTIVE
A novel angiotensin receptor has been described and named AT4. Ligands for this receptor include the angiotensin II (Ang II) metabolite Ang II (3-8), known as angiotensin IV (Ang IV). There is 10-fold more AT4 receptor than AT1 receptor in rabbit myocardium. The AT4 receptor has a high affinity for Ang IV (Ki in rabbit myocardium < 2 x 10(-9)) and similar ligands, but very low affinity for Ang II (Ki in rabbit myocardium > 10(-6)). Although several functions have been attributed to the novel Ang IV peptide/AT4 receptor system, the effect of this system on left ventricular (LV) function has not been studied. We hypothesized (1) that Ang IV would affect LV function and (2) that any effects would be opposite to those of Ang II.


METHODS
Using the buffer-perfused (30 degrees C) isolated rabbit heart, we studied the effect of the AT4 agonist Nle1-Ang IV on LV systolic function, quantified using both Frank-Starling and end-systolic pressure-volume relationships, and relaxation. We also studied the effect of the AT1/AT2 agonist, Sar1-Ang II on LV function. Finally, because the profile of effect of Nle1-Ang IV was similar to the reported effect of nitric oxide (NO), we also studied the effect of Nle1-Ang IV in the presence of the NO synthase inhibitor NG-monomethyl-L-arginine.


RESULTS
Nle1-Ang IV reduced LV pressure-generating capability at any volume but increased the sensitivity of pressure development to volume change. Nle1-Ang IV reduced LV ejection capability. Sar1-Ang II had the opposite effect-increasing both pressure generation and ejection capability. Finally, both Sar1-Ang II and Nle1-Ang IV speeded LV relaxation. Inhibition of NO synthase did not alter the effect of Nle1-Ang IV on LV systolic function or relaxation.


CONCLUSIONS
AT4 receptor agonism has mixed effects on LV systolic function, depressing pressure-generation and ejection capabilities, but enhancing the sensitivity of pressure development to volume change. It also speeds relaxation. The effect of Ang IV on systolic function is generally opposite to the effect of Ang II, whereas the Ang IV influence on relaxation is similar to the effect of Ang II.
Slinker
B K
BK
Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman 99164-6520, USA. slinker@vetmed.wsu.edu
Wu
Y
Y
Brennan
A J
AJ
Campbell
K B
KB
Harding
J W
JW
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000804:Angiotensin II / Q000819:agonists / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D016014:Linear Models; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010477:Perfusion; D011433:Propranolol / Q000494:pharmacology; D011817:Rabbits; D011897:Random Allocation; D011945:Receptors, Angiotensin / Q000032:analysis*; D013599:Systole; D016277:Ventricular Function, Left / Q000187:drug effects*; D019323:omega-N-Methylarginine / Q000494:pharmacology
C090830:AT4 receptor; D000319:Adrenergic beta-Antagonists; D011945:Receptors, Angiotensin; D000804:Angiotensin II; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; D019323:omega-N-Methylarginine; C074793:angiotensin II, Sar(1)-; D011433:Propranolol; D019001:Nitric Oxide Synthase