title: Angiotensin receptors contribute to blood pressure homeostasis in salt-depleted SHR.
abstract: This study evaluated the contribution of angiotensin peptides acting at various receptor subtypes to the arterial pressure and heart rate of adult 9-wk-old male conscious salt-depleted spontaneously hypertensive rats (SHR). Plasma ANG II and ANG I in salt-depleted SHR were elevated sevenfold compared with peptide levels measured in sodium-replete SHR, whereas plasma ANG-(1-7) was twofold greater in salt-depleted SHR compared with salt-replete SHR. Losartan (32.5 micromol/kg), PD-123319 (0.12 micromol. kg(-1). min(-1)), [d-Ala(7)]ANG-(1-7) (10 and 100 pmol/min), and a polyclonal ANG II antibody (0.08 mg/min) were infused intravenously alone or in combination. Combined blockade of AT(2) and AT((1-7)) receptors significantly increased the blood pressure of losartan-treated SHR (+15 +/- 1 mmHg; P < 0.01); this change did not differ from the blood pressure elevation produced by the sole blockade of AT((1-7)) receptors (15 +/- 4 mmHg). On the other hand, sole blockade of AT(2) receptors in losartan-treated SHR increased mean arterial pressure by 8 +/- 1 mmHg (P < 0.05 vs. 5% dextrose in water as vehicle), and this increase was less than the pressor response produced by blockade of AT((1-7)) receptors alone or combined blockade of AT((1-7)) and AT(2) receptors. The ANG II antibody increased blood pressure to the greatest extent in salt-depleted SHR pretreated with only losartan (+11 +/- 2 mmHg) and to the least extent in salt-depleted SHR previously treated with the combination of losartan, PD-123319, and [d-Ala(7)]ANG-(1-7) (+7 +/- 1 mmHg; P < 0.01). Losartan significantly increased heart rate, whereas other combinations of receptor antagonists or the ANG II antibody did not alter heart rate. Our results demonstrate that ANG II and ANG-(1-7) act through non-AT(1) receptors to oppose the vasoconstrictor actions of ANG II in salt-depleted SHR. Combined blockade of AT(2) and AT((1-7)) receptors and ANG II neutralization by the ANG II antibody reversed as much as 67% of the blood pressure-lowering effect of losartan.
authors.affiliation: Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
authors.forename: Shigefumi
authors.initials: S
authors.lastname: Nakamura
authors.forename: David B
authors.initials: DB
authors.lastname: Averill
authors.forename: Mark C
authors.initials: MC
authors.lastname: Chappell
authors.forename: Debra I
authors.initials: DI
authors.lastname: Diz
authors.forename: K Bridget
authors.initials: KB
authors.lastname: Brosnihan
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Ferrario
mesh_terms: D000803:Angiotensin I / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000097:blood; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000097:blood / Q000276:immunology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D007106:Immune Sera / Q000276:immunology / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011945:Receptors, Angiotensin / Q000378:metabolism*; D012964:Sodium / Q000032:analysis* / Q000037:antagonists & inhibitors; D013997:Time Factors
chemical_list: D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D007106:Immune Sera; D011725:Pyridines; D011945:Receptors, Angiotensin; D000804:Angiotensin II; C073402:PD 123319; D000803:Angiotensin I; D012964:Sodium; D019808:Losartan