Losartan decreases vasopressin-mediated cAMP accumulation in the thick ascending limb of the loop of Henle in rats with congestive heart failure.
BACKGROUND
Vasopressin (AVP) stimulates sodium reabsorption and Na,K,2Cl-cotransporter (NKCC2) protein level in the thick ascending limb (TAL) of Henle's loop in rats. Rats with congestive heart failure (CHF) have increased protein level of NKCC2, which can be normalized by angiotensin II receptor type-1 (AT(1)) blockade with losartan.


OBJECTIVE
In this study, we investigated whether CHF rats displayed changes in AVP stimulated cAMP formation in the TAL and examined the role of AT(1) receptor blockade on this system.


METHODS
CHF was induced by ligation of the left anterior descending coronary artery (LAD). SHAM-operated rats were used as controls. Half of the rats were treated with losartan (10 mg kg day(-1) i.p.).


RESULTS
CHF rats were characterized by increased left ventricular end diastolic pressure. Measurement of cAMP in isolated outer medullary TAL showed that both basal and AVP (10(-6) m) stimulated cAMP levels were significantly increased in CHF rats (25.52 +/- 4.49 pmol cAMP microg(-1) protein, P < 0.05) compared to Sham rats (8.13 +/- 1.14 pmol cAMP microg(-1) protein), P < 0.05). Losartan significantly reduced the basal level of cAMP in CHF rats (CHF: 12.56 +/- 1.93 fmol microg(-1) protein vs. Los-CHF: 7.49 +/- 1.08, P < 0.05), but not in Sham rats (SHAM: 4.66 +/- 0.59 vs. Los-SHAM: 4.75 +/- 0.71). AVP-mediated cAMP accumulation was absent in both groups treated with losartan (Los-SHAM: 4.75 +/- 0.71 and Los-CHF: 7.49 +/- 1.08).


CONCLUSIONS
The results indicate that the increased NKCC2 protein level in the mTAL from CHF rats is associated with increased cAMP accumulation in this segment. Furthermore, the finding that AT(1) receptor blockade prevents AVP-mediated cAMP accumulation in both SHAM and CHF rats suggests an interaction between angiotensin II and AVP in regulation of mTAL Na reabsorption.
Torp
M
M
Department of Pharmacology, University of Copenhagen, Copenhagen N, Denmark.
Brønd
L
L
Hadrup
N
N
Nielsen
J B
JB
Praetorius
J
J
Nielsen
S
S
Christensen
S
S
Jonassen
T E N
TE
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006333:Heart Failure / Q000378:metabolism*; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism; D008138:Loop of Henle / Q000187:drug effects / Q000378:metabolism*; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D064466:Solute Carrier Family 12, Member 1; D014667:Vasopressins / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D010726:Phosphodiesterase Inhibitors; C578716:Slc12a1 protein, rat; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D014667:Vasopressins; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D000254:Sodium-Potassium-Exchanging ATPase; D019808:Losartan; D015056:1-Methyl-3-isobutylxanthine