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Opiate receptor inhibition improves the blunted baroreflex function in conscious dogs with right-sided congestive
1Department of Medicine, University of Rochester Medical Center, New York 14642.
Abstract:
The endogenous opiate system is activated in congestive heart failure. because endogenous opioids are known to depress the baroreflex function, we conducted studies to determine whether the increased endogenous opioids play a role in causing the reduced baroreflex function that occurs in heart failure. Right-sided congestive heart failure was produced in 16 dogs by tricuspid avulsion and progressive pulmonary artery constriction. Seven sham-operated dogs were included for comparison. Baroreflex function was measured in the conscious dogs after pretreatment with either normal saline or an opiate-receptor antagonist by bolus administration of phenylephrine. The slope of the regression line relating systolic blood pressure to cardiac cycle (R-R) interval was taken as an index of baroreflex sensitivity. Plasma beta-endorphin was elevated in the dogs with heart failure (15.3 +/- 2.5 pmol/l) compared with the sham-operated dogs (4.2 +/- 0.4 pmol/l, p less than 0.001). The dogs with heart failure also exhibited a reduced baroreflex sensitivity (3.84 +/- 0.19 msec/mm Hg) after saline pretreatment when compared with the sham-operated dogs (10.86 +/- 1.20 msec/mm Hg, p less than 0.001). Administration of naloxone hydrochloride increased the baroreflex sensitivity of dogs with heart failure to 5.16 +/- 0.26 msec/mm Hg (p less than 0.01) but produced no significant effects in sham-operated dogs (11.36 +/- 1.42 msec/mm Hg). To further study the site of action for the effect of naloxone, we measured baroreflex sensitivity in the dogs with heart failure after pretreatment with naloxonazine, a selective mu-receptor antagonist, with ICI 154,129, a selective delta-receptor antagonist, or with naloxone methobromide, a quaternary analogue of naloxone that does not penetrate the blood-brain barrier.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Increased endogenous opioids contribute to reduced baroreflex sensitivity in heart failure. Blocking these opioid receptors with naloxone improved baroreflex function in dogs with heart failure.
Area of Science:
- Cardiovascular Physiology
- Neuroendocrinology
Background:
- Congestive heart failure (CHF) is associated with activation of the endogenous opiate system.
- Endogenous opioids are known to impair baroreflex function.
Purpose of the Study:
- To investigate the role of increased endogenous opioids in reduced baroreflex sensitivity in CHF.
- To determine if blocking opioid receptors can restore baroreflex function in CHF.
Main Methods:
- Congestive heart failure was induced in dogs via tricuspid avulsion and pulmonary artery constriction.
- Baroreflex sensitivity was assessed by measuring the change in R-R interval in response to phenylephrine-induced blood pressure changes.
- The effects of saline, naloxone hydrochloride, and selective opioid receptor antagonists (naloxonazine, ICI 154,129, naloxone methobromide) were evaluated.
Main Results:
- Dogs with CHF exhibited elevated plasma beta-endorphin levels and significantly reduced baroreflex sensitivity compared to sham-operated controls.
- Administration of naloxone hydrochloride significantly increased baroreflex sensitivity in dogs with CHF.
- Selective mu-receptor and delta-receptor antagonists, as well as a blood-brain barrier-impermeable naloxone analogue, were used to further investigate the site of action.
Conclusions:
- Increased endogenous opioids play a significant role in the diminished baroreflex sensitivity observed in congestive heart failure.
- Opioid receptor antagonism, particularly involving central pathways, may offer a therapeutic target for improving autonomic dysfunction in CHF.