Differential effects of natriuretic peptides and NO on LV function in heart failure and normal dogs.
beta-Adrenergic hyporesponsiveness in congestive heart failure (CHF) is mediated, in part, by nitric oxide (NO). NO and brain natriuretic peptide (BNP) share cGMP as a second messenger. Left ventricular (LV) function and inotropic response to intravenous dobutamine (Dob) were assessed during sequential intracoronary infusion of saline, HS-142-1 (a BNP receptor antagonist), and HS-142-1 + N(G)-monomethyl-L-arginine (L-NMMA) in anesthetized dogs with CHF due to rapid pacing and in normal dogs during intracoronary infusion of saline, exogenous BNP, and sodium nitroprusside (SNP). In CHF dogs, intracoronary HS-142-1 did not alter the inotropic response to Dob [percent change in first derivative of LV pressure (% Delta dP/dt) 47 +/- 4% saline vs. 54 +/- 7% HS-142-1, P = not significant]. Addition of intracoronary L-NMMA to HS-142-1 enhanced the response to Dob (% Delta dP/dt 73 +/- 8% L-NMMA + HS-142-1, P < 0.05 vs. H142-1). In normal dogs, intracoronary SNP blunted the inotropic response to Dob (% Delta dP/dt 93 +/- 6% saline vs. 71 +/- 5% SNP, P < 0.05), whereas intracoronary BNP had no effect. In CHF dogs, the time constant of LV pressure decay during isovolumic relaxation increased with intracoronary HS-142-1 (48 +/- 4 ms saline vs. 58 +/- 5 ms HS-142-1, P < 0.05) and further increased with intracoronary L-NMMA (56 +/- 6 ms HS-142-1 vs. 66 +/- 7 ms L-NMMA + HS-142-1, P < 0.05). Endogenous BNP and NO preserve diastolic function in CHF, whereas NO but not BNP inhibits beta-adrenergic responsiveness.
Hart
C Y
CY
Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
Hahn
E L
EL
Meyer
D M
DM
Burnett
J C
JC
Redfield
M M
MM
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D006152:Cyclic GMP / Q000502:physiology; D003971:Diastole; D004280:Dobutamine / Q000494:pharmacology; D004285:Dogs; D004357:Drug Synergism; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006333:Heart Failure / Q000503:physiopathology*; D006439:Hemodynamics; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D020097:Natriuretic Peptide, Brain / Q000494:pharmacology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D012016:Reference Values; D015290:Second Messenger Systems / Q000502:physiology; D013599:Systole; D016277:Ventricular Function, Left / Q000187:drug effects*
D000318:Adrenergic beta-Agonists; D020097:Natriuretic Peptide, Brain; D009569:Nitric Oxide; D004280:Dobutamine; D006152:Cyclic GMP