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Relationship between beta-adrenoceptors and calcium channels in human ventricular myocardium
Insights
This study investigated the relationship between beta-adrenoceptors and calcium channels in human heart muscle. A significant correlation was found in hypertrophic obstructive cardiomyopathy patients, suggesting co-regulation of these receptors and channels.
Area of Science:
- Cardiology
- Pharmacology
- Molecular Biology
Background:
- Adrenoceptors and calcium channels play crucial roles in cardiac function.
- Understanding their interplay is vital for treating cardiovascular diseases.
Purpose of the Study:
- To investigate the stoichiometric relationship between adrenoceptors and 1,4-dihydropyridine binding sites in calcium channels.
- To examine potential co-regulation of beta-adrenoceptors and calcium channels in human ventricular myocardium.
Main Methods:
- Utilized radioligand binding assays with specific labels ([3H]-prazosin, [125I]-HEAT, [3H]-rauwolscine, [3H]-(-)-dihydroalprenolol, [125I]-(-)-iodocyanopindolol, [3H]-nimodipine, [3H]-(+)-PN 200-110, [125I]-iodipine).
- Analyzed membrane particles from human ventricular myocardium of patients with hypertrophic obstructive cardiomyopathy (HOCM) and mitral valve disease.
- Quantified adrenoceptor densities (alpha 1, alpha 2, beta) and calcium channel densities, along with their equilibrium dissociation constants (KD).
Main Results:
- Marginal alpha 1-adrenoceptor density and no detectable alpha 2-adrenoceptors were observed.
- Beta-adrenoceptor densities were similar in HOCM and mitral valve disease groups.
- Calcium channel densities varied between HOCM and mitral valve disease groups, with higher density in HOCM patients when labeled with [3H]-(+)-PN 200-110 and [125I]-iodipine.
- A significant positive correlation was found between beta-adrenoceptor density and calcium channel density in HOCM patients, but not in the mitral valve disease group.
Conclusions:
- The study suggests a potential co-regulation of beta-adrenoceptors and calcium channels in human ventricular myocardium, particularly in the context of HOCM.
- While not proving causality, the observed correlation aligns with the known functional link between beta-adrenergic stimulation and calcium channel activity.
- Further research is warranted to elucidate the mechanisms underlying this potential co-regulation and its clinical implications.
Abstract:
The stoichiometric relationship between adrenoceptors and saturable binding sites for 1,4-dihydropyridines in calcium channels was investigated in human ventricular myocardium. Membrane particles were prepared from heart specimens of patients undergoing open heart surgery. The patients suffered from hypertrophic obstructive cardiomyopathy (HOCM) or mitral valve disease. Using [3H]-prazosin and [125I]-2-beta-hydroxy-3-iodiphenyl-ethyl-aminoethyl tetralone ([125I]-HEAT) as labels we detected only a marginal density of alpha 1-adrenoceptors, regardless of disease. No alpha 2-adrenoceptors were detected with [3H]-rauwolscine. In HOCM patients we estimated 72 +/- 10 fmol mg-1 (n = 12) beta-adrenoceptors labelled with [3H]-(-)-dihydroalprenolol and 74 +/- 5 fmol mg-1 (n = 2) beta-adrenoceptors labelled with [125I]-(-)-iodocyanopindolol; the equilibrium dissociation constants KD, were 1.2 +/- 0.2 nmol l-1 for [3H]-(-)-dihydroalprenolol and 7 +/- 1 pmol l-1 for [125I]-(-)-iodocyanopindolol. In patients with mitral valve disease we estimated 84 +/- 11 fmol mg-1 (n = 3) labelled with [3H]-(-)-dihydroalprenolol and 66 +/- 13 fmol mg-1 (n = 2) labelled with [125I]-(-)-iodocyanopindolol. The KD values were 1.8 +/- 0.6 nmol l-1 for [3H]-(-)-dihydroalprenolol and 8 +/- 2 pmol l-1 for [125I]-(-)-iodocyanopindolol. In 14 HOCM patients we estimated 107 +/- 12 fmol mg-1 calcium channel sites labelled with [3H]-nimodipine with a KD of 280 +/- 4 pmol l-1. In 5 patients with mitral valve disease the density of calcium channel sites labelled with [3H]-nimodipine was 78 +/- 5 fmol mg-1 with a KD of 290 +/- 20 pmol l-1, In HOCM patients the density of calcium channel sites labelled with the benzoxadiazol 1,4-dihydropyridine ([3H]-(+)-PN 200-110) was 1.6 fold of that labelled with [3H]-nimodipine with a KD of 84 +/- 11 pmol l-1. In a group of 4 HOCM patients in which calcium channels were labelled with [125I]-iodipine, the density of sites was 1.37 +/- 0.07 fold the density of sites labelled by [3H]-(+)-PN 200-11-. The KD value of [125I]-iodipine was 246 +/- 16 pmol-1. (+)-PN 200-110 was approximately 100 fold more potent than (-)-PN 200-110 as a competitor of [125I]-iodipine binding. For the HOCM group a significant correlation was found between beta-adrenoceptor density and calcium channel density, whereas in the mitral valve group no such correlation was found. This does not prove that there is causal interaction leading to a relationship between the density of beta-adrenoceptors and calcium channels. However, because positive inotropic effects of catecholamines mediated by beta-adrenoceptors are associated with opening of calcium channels, this suggests that the density of both beta-adrenoceptors and calcium channels could be co-regulated.