Catecholamines and heart function in heart transplant patients: effects of beta1- versus nonselective beta-blockade.
OBJECTIVE
To evaluate cardiac responses to norepinephrine and epinephrine in heart transplant patients compared with patients with mild essential hypertension and to evaluate the contribution of beta2-receptors versus beta1-receptors to the cardiac responses by assessing the effects of the 2 agonists after treatment with placebo compared with the beta1-selective blocker atenolol and the nonselective blocker nadolol.


METHODS
A double-blind, randomized crossover design was used to study patients after administration of placebo, atenolol, or nadolol for 2 weeks. Infusion of norepinephrine was performed at incremental rates of 12.5, 25, 50, and 100 ng/kg/min and of epinephrine at rates of 20, 40, 80, and 120 ng/kg/min. Blood pressure, heart rate, left ventricular function (by echocardiogram), and venous plasma concentrations were assessed at rest and at the end of each infusion rate.


RESULTS
Infusion of epinephrine and norepinephrine was associated with 3-fold and 2-fold higher increases, respectively, in plasma concentrations in the transplant patients versus patients with hypertension. Enhanced blood pressure responses to either agonist were found in the transplant patients, but not when venous plasma concentrations were considered. Norepinephrine decreased heart rate and cardiac index in patients with hypertension receiving placebo and more markedly when receiving atenolol and nadolol. In contrast, heart transplant patients showed increases in heart rate, ejection fraction, and cardiac index, which largely were blocked (but not reversed into decreases) by atenolol and nadolol. In patients with hypertension receiving placebo, epinephrine increased heart rate, ejection fraction, and cardiac index. These responses were enhanced in transplant patients, also relative to plasma concentrations. Atenolol had only minor effects on these cardiac responses. On nadolol epinephrine decreased heart rate, stroke volume, and cardiac index in the patients with hypertension, whereas the transplant patients receiving nadolol showed no longer increases in cardiac function by epinephrine.


CONCLUSIONS
Both absence of parasympathetic buffering and diminished systemic clearance contributed to the enhanced cardiac responses to infusion of norepinephrine and epinephrine in heart transplant patients compared with patients with essential hypertension. Cardiac beta2-receptors mediate most of the chronotropic and inotropic responses to epinephrine in both patients with hypertension and heart transplant patients.
Leenen
F H
FH
Division of Cardiology, University of Ottawa Heart Institute, Ontario, Canada. fleenen@ohi-net.heartinst.on.ca
Davies
R A
RA
Fourney
A
A
D058671:Adrenergic beta-1 Receptor Antagonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000328:Adult; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001262:Atenolol / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D015986:Confounding Factors, Epidemiologic; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004837:Epinephrine / Q000097:blood / Q000494:pharmacology*; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology*; D006334:Heart Function Tests; D006339:Heart Rate / Q000187:drug effects; D016027:Heart Transplantation / Q000009:adverse effects*; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009248:Nadolol / Q000627:therapeutic use*; D009638:Norepinephrine / Q000097:blood / Q000494:pharmacology; D013318:Stroke Volume / Q000187:drug effects
D058671:Adrenergic beta-1 Receptor Antagonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D009248:Nadolol; D001262:Atenolol; D009638:Norepinephrine; D004837:Epinephrine