OBJECTIVE: In heart failure, homologous downregulation of beta-adrenoceptors contributes to impaired adrenergic responsiveness of the myocardium. We evaluated alpha 1-adrenoceptors (alpha 1-AR) in a sparsely innervated and a densely innervated peripheral artery in an experimental model of left ventricular dysfunction post-myocardial infarction. METHODS: [3H]Prazosin binding was determined in arterial segments of Wistar-Kyoto rats (WKY), and of Wistar rats 5 weeks after myocardial infarction (MI) or sham operation (SHAM). RESULTS: In the thoracic aorta (TAO) of WKY, specific prazosin binding was: (i) prevented by the irreversible alpha 1B-AR and relatively selective alpha 1D-AR antagonist, chloroethylclonidine (CEC); (ii) displaced with low affinity (pKi 6.25) by the alpha 1A-AR selective ligand, (+)-niguldipine; and (iii) displaced with both high (pKi 10.4) and low (pKi 7.37) affinity by the alpha 1D-AR antagonist, BMY 7378. In mesenteric small arteries (MSA) of WKY, prazosin binding was: (i) reduced 50% by CEC; (ii) displaced in a biphasic fashion by (+)-niguldipine (pKi 8.60 and pKi 6.22); and (iii) displaced by BMY 7378 with low affinity only (pKi 6.86). Also in TAO of SHAM. prazosin binding was prevented by CEC, but neither 30 nM (+)-niguldipine nor 1 nM BMY 7378 affected it. In MSA of SHAM, prazosin binding was virtually abolished in the presence of 30 nM (+)-niguldipine and was not reduced by 1 nM BMY 7378. In TAO and MSA of MI, compared to SHAM, the density of binding sites tended to be increased rather than decreased and neither the affinity for the ligand nor the effects of alpha 1-AR subtype selective tools were significantly modified. CONCLUSIONS: These findings indicate that: (i) radioligand binding can be applied in intact arterial segments to quantify and characterize alpha 1-AR; (ii) although differences seem to exist between rat strains, alpha 1B-AR and alpha 1D-AR predominate in rat thoracic aorta and alpha 1A-AR and alpha 1B-AR in mesenteric small arteries; and (iii) alpha 1-AR density is not reduced in the poorly innervated aorta and the densely innervated mesenteric small arteries of rats with heart failure due to myocardial infarction.
OBJECTIVE: In heart failure, homologous downregulation of beta-adrenoceptors contributes to impaired adrenergic responsiveness of the myocardium. We evaluated alpha 1-adrenoceptors (alpha 1-AR) in a sparsely innervated and a densely innervated peripheral artery in an experimental model of left ventricular dysfunction post-myocardial infarction. METHODS: [3H]Prazosin binding was determined in arterial segments of Wistar-Kyoto rats (WKY), and of Wistar rats 5 weeks after myocardial infarction (MI) or sham operation (SHAM). RESULTS: In the thoracic aorta (TAO) of WKY, specific prazosin binding was: (i) prevented by the irreversible alpha 1B-AR and relatively selective alpha 1D-AR antagonist, chloroethylclonidine (CEC); (ii) displaced with low affinity (pKi 6.25) by the alpha 1A-AR selective ligand, (+)-niguldipine; and (iii) displaced with both high (pKi 10.4) and low (pKi 7.37) affinity by the alpha 1D-AR antagonist, BMY 7378. In mesenteric small arteries (MSA) of WKY, prazosin binding was: (i) reduced 50% by CEC; (ii) displaced in a biphasic fashion by (+)-niguldipine (pKi 8.60 and pKi 6.22); and (iii) displaced by BMY 7378 with low affinity only (pKi 6.86). Also in TAO of SHAM. prazosin binding was prevented by CEC, but neither 30 nM (+)-niguldipine nor 1 nM BMY 7378 affected it. In MSA of SHAM, prazosin binding was virtually abolished in the presence of 30 nM (+)-niguldipine and was not reduced by 1 nM BMY 7378. In TAO and MSA of MI, compared to SHAM, the density of binding sites tended to be increased rather than decreased and neither the affinity for the ligand nor the effects of alpha 1-AR subtype selective tools were significantly modified. CONCLUSIONS: These findings indicate that: (i) radioligand binding can be applied in intact arterial segments to quantify and characterize alpha 1-AR; (ii) although differences seem to exist between rat strains, alpha 1B-AR and alpha 1D-AR predominate in rat thoracic aorta and alpha 1A-AR and alpha 1B-AR in mesenteric small arteries; and (iii) alpha 1-AR density is not reduced in the poorly innervated aorta and the densely innervated mesenteric small arteries of rats with heart failure due to myocardial infarction.
Authors: Gizem Kaykı-Mutlu; Olga Papazisi; Meindert Palmen; A H Jan Danser; Martin C Michel; Ebru Arioglu-Inan Journal: Cells Date: 2020-11-04 Impact factor: 6.600