Effects of an orally effective endothelin-A receptor antagonist in dogs with pacing-induced heart failure.
Endothelin-1 (ET-1) is a potent vasoconstrictor that has been shown to be elevated in the plasma of humans and animals with heart failure (HF). The role of an increase in endothelin in the setting of chronic HF is not known.


METHODS
The present study was designed to determine the hemodynamic effects of a novel ET-A antagonist (PD-156,707) on the development of HF in dogs subjected to chronic ventricular tachycardia. Thirteen dogs were chronically instrumented to measure cardiac output (CO), left ventricular pressure (LVP), left atrial pressure (LAP), and arterial pressure (MAP). They were then paced at 210 bpm for 3 weeks and then at 245 bpm for 1 week (4th week). Two groups of dogs were studied, placebo group and a group of dogs administered the PD-156,707 compound (750 mg) orally three times per day beginning one day prior to the initiation of pacing. Hemodynamic measurements were made every three to four days during the four week pacing regimen. Arterial and venous blood samples were also taken to determine the plasma levels of endothelin-1 and PD-156-707.


RESULTS
Endothelin-1 in plasma increased in all dogs with pacing induced HF (placebo control 1.57 +/- 0.5 vs placebo HF 2.2 +/- 0.6 pg/ml and drug control 1.5 +/- 0.16 v.s. drug HF 14.6 +/- 3.8 pg/ml [p < 0.05]). Left ventricular end diastolic pressure (LVEDP) and LAP were equivalently and significantly elevated in both groups (p < 0.001) and LV dp/dt was significantly reduced (p < 0.001) in both groups 4 weeks after pacing. CO was slightly, but not significantly reduced after four weeks in both groups of dogs. However, administration of PD-157,707 significantly and profoundly reduced MAP at all times after 3 days of pacing (placebo HF[week 4]: 83.9 +/- 4.0 mmHg v.s. drug HF [week 4]: 72.4 +/- 2.3 mmHg [p < 0.05]) and total peripheral resistance (p < 0.05) at each time period following the induction of pacing.


CONCLUSIONS
These data indicate that ETA blockade reduces afterload early during the development of chronic HF implicating endothelin-1 as an early compensatory hormone in HF. These results also suggest that blocking the ET-A receptor may have a role as an afterload reducer in the setting of human congestive heart failure.
McConnell
P I
PI
Department of Physiology and Biophysics, University of Nebraska Medical School College of Medicine Omaha 68198, USA.
Wang
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W
Zucker
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IH
D000284:Administration, Oral; D000818:Animals; D002304:Cardiac Pacing, Artificial / Q000009:adverse effects; D004149:Dioxoles / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000097:blood; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male
D004149:Dioxoles; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; C093321:PD 156707