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Alpha-adrenoceptors and alpha-adrenoceptor-mediated positive inotropic effects in failing human myocardium
1Medizinische Klinik I der Universität München, Klinikum Grosshadern, Munich, F.R.G.
Insights
Cardiac alpha-adrenoceptors remain unchanged in heart failure, unlike beta-adrenoceptors which decrease in severe cases. This suggests alpha-adrenoceptors do not downregulate or compensate in failing human hearts.
Area of Science:
- Cardiology
- Pharmacology
- Molecular Biology
Background:
- Heart failure is associated with altered adrenergic receptor function.
- Cardiac alpha-adrenoceptors play a role in myocardial contractility.
- Understanding receptor changes in heart failure is crucial for therapeutic development.
Purpose of the Study:
- To characterize cardiac alpha-adrenoceptors and their mediated effects in human heart failure.
- To compare alpha-adrenoceptor and beta-adrenoceptor levels and function in moderate versus severe heart failure.
- To investigate potential compensatory changes in alpha-adrenoceptors during heart failure progression.
Main Methods:
- Human myocardial tissue from NYHA class II-III and IV heart failure patients was used.
- Radioligand binding assays (3H-prazosin, 3H-CGP 12177) quantified alpha- and beta-adrenoceptor density.
- Pharmacological assessment of alpha- and beta-adrenoceptor-mediated positive inotropic effects.
Main Results:
- Alpha-adrenoceptor density was similar in moderate (NYHA II-III) and severe (NYHA IV) heart failure.
- Alpha-adrenoceptor-mediated positive inotropic effects were not significantly different between groups.
- Beta-adrenoceptor density and isoprenaline-induced inotropic effects were significantly reduced in severe heart failure (NYHA IV).
Conclusions:
- Severe heart failure is characterized by reduced beta-adrenoceptors and their associated positive inotropic effects.
- Cardiac alpha-adrenoceptors and their positive inotropic effects remain unchanged across heart failure severity.
- Downregulation or compensatory upregulation of cardiac alpha-adrenoceptors does not occur in human heart failure.
Abstract:
Experiments were designed to characterize cardiac alpha-adrenoceptors and the alpha-adrenoceptor-mediated positive inotropic effects in human myocardial tissue from patients with moderate New York Heart Association (NYHA) class II-III and severe (NYHA class IV) heart failure. The number of cardiac alpha-adrenoceptors was low but similar in moderate and severe heart failure (NYHA class II-III: 6.7 +/- 0.8 fmol/mg protein 3H-prazosin bound, n = 12; NYHA class IV: 7.4 +/- 0.9 fmol/mg protein 3H-prazosin bound, n = 9; NS). Correspondingly, the alpha-adrenoceptor-mediated positive inotropic effect (phenylephrine in the presence of propranolol) did not significantly differ in both groups. In the same hearts, the number of beta-adrenoceptors was measured. The number of beta-adrenoceptors was significantly reduced in severe heart failure (NYHA class II-III: 22.0 +/- 1.5 fmol/mg protein 3H-CGP 12177 bound, n = 12; NYHA class IV: 11.9 +/- 0.8 fmol/mg protein 3H-CGP 12177 bound, n = 9; p less than 0.05). The positive inotropic effect of isoprenaline was significantly reduced in NYHA class IV. The positive inotropic effect of Ca2+ was similar in both groups. In conclusion, cardiac beta-adrenoceptors and the beta-adrenoceptor-mediated positive inotropic effects were reduced in severely failing myocardium. Cardiac alpha-adrenoceptors and the positive inotropic effect resulting from their stimulation is unchanged. Therefore, down regulation in response to increased sympathetic stimulation or a compensatory increase of alpha-adrenoceptors does obviously not occur in the human heart.(ABSTRACT TRUNCATED AT 250 WORDS)