Chronic interval exercise training prevents BKCa channel-mediated coronary vascular dysfunction in aortic-banded miniswine

Abstract

Conventional treatments have failed to improve the prognosis of heart failure with preserved ejection fraction (HFpEF) patients. Thus, the purpose of this study was to determine the therapeutic efficacy of chronic interval exercise training (IT) on large-conductance Ca²⁺-activated K⁺ (BK_Ca) channel-mediated coronary vascular function in heart failure. We hypothesized that chronic interval exercise training would attenuate pressure overload-induced impairments to coronary BK_Ca channel-mediated function. A translational large-animal model with cardiac features of HFpEF was used to test this hypothesis. Specifically, male Yucatan miniswine were divided into three groups ( n = 7/group): control (CON), aortic banded (AB)-heart failure (HF), and AB-interval trained (HF-IT). Coronary blood flow, vascular conductance, and vasodilatory capacity were measured after administration of the BK_Ca channel agonist NS-1619 both in vivo and in vitro in the left anterior descending coronary artery and isolated coronary arterioles, respectively. Skeletal muscle citrate synthase activity was decreased and left ventricular brain natriuretic peptide levels increased in HF vs. CON and HF-IT animals. A parallel decrease in NS-1619-dependent coronary vasodilatory reserve in vivo and isolated coronary arteriole vasodilatory responsiveness in vitro were observed in HF animals compared with CON, which was prevented in the HF-IT group. Although exercise training prevented BK_Ca channel-mediated coronary vascular dysfunction, it did not change BK_Ca channel α-subunit mRNA, protein, or cellular location (i.e., membrane vs. cytoplasm). In conclusion, these results demonstrate the viability of chronic interval exercise training as a therapy for central and peripheral adaptations of experimental heart failure, including BK_Ca channel-mediated coronary vascular dysfunction. NEW & NOTEWORTHY Conventional treatments have failed to improve the prognosis of heart failure with preserved ejection fraction (HFpEF) patients. Our findings show that chronic interval exercise training can prevent BK_Ca channel-mediated coronary vascular dysfunction in a translational swine model of chronic pressure overload-induced heart failure with relevance to human HFpEF.

Keywords: BKCa; coronary vascular function; exercise; heart failure; pressure-volume analysis.

Fig. 1.

Skeletal muscle citrate synthase activity, left ventricle (LV) brain natriuretic peptide (BNP) mRNA levels, body weight, and cardiac remodeling in nonsham sedentary control (CON), aortic-banded heart failure sedentary (HF), and aortic-banded heart failure interval exercise-trained (HF-IT) animals. A: exercise training prevents decreased skeletal muscle citrate synthase activity observed in HF animals (1-way ANOVA, P < 0.05). B: exercise training attenuates increased BNP mRNA levels in the LV of the HF group (1-way ANOVA, P < 0.05). C: aortic banding generates cardiac hypertrophy evident by increased postmortem LV + septum (LV+S), right ventricle (RV), and left + right atria (ATRIA) weight that is not inhibited by exercise training (1-way ANOVA, P < 0.05). Body weight was the same in all groups. *Post hoc vs. CON (P < 0.05); †post hoc vs. HF-IT (P < 0.05); #post hoc vs. CON (P < 0.10). n = 7, 7, and 7 for CON, HF, and HF-IT, respectively.

Fig. 2.

Representative pressure-volume (P-V) loops at Baseline from individual nonsham sedentary control (CON; A), aortic-banded heart failure sedentary (HF; B), and aortic-banded heart failure interval exercise-trained (HF-IT; C) animals. ESPVR, end-systolic P-V relationship; EDPVR, end-diastolic P-V relationship.

Fig. 3.

In vivo normalized coronary blood flow (CBF) and vascular conductance responses to large-conductance Ca²⁺-activated K⁺ (BK_Ca) channel α-subunit activation in nonsham sedentary control (CON), aortic-banded heart failure sedentary (HF), and aortic-banded heart failure interval exercise-trained (HF-IT) animals. A: CBF response [relative to left ventricle (LV) weight] following BK_Ca channel α-subunit activation by NS-1619 is dependent on group (repeated-measures ANOVA, P < 0.05). B: exercise training prevents decreased BK_Ca channel-mediated increases in CBF observed in HF animals, measured as the difference (∆) in CBF following infusion of NS-1619 minus Baseline (1-way ANOVA, P < 0.05). C: NS-1619-induced increases in CBF are attenuated by pretreatment with penitrem A (Pen A) [P = not significant (NS)]. D: increased coronary vascular conductance (CVC; relative to LV weight) following BK_Ca channel α-subunit activation by NS-1619 is dependent on group (repeated-measures ANOVA, P < 0.05). E: again, exercise training prevents decreased BK_Ca channel-mediated vasodilatory capacity observed in HF animals, measured as the difference in CVC following infusion of NS-1619 minus Baseline (1-way ANOVA, P < 0.05). F: NS-1619-induced increases in CVC are attenuated by pretreatment with Pen A (P = NS). §Interaction effect: Group × Dose (P < 0.05); *post hoc vs. CON (P < 0.05), †post hoc vs. HF-IT (P < 0.05); #post hoc vs. CON (P < 0.10); ‡post hoc HF vs. HF-IT (P < 0.10). n = 5, 6, and 6 for CON, HF, and HF-IT, respectively.

Fig. 4.

In vitro coronary arteriole functional responses to large-conductance Ca²⁺-activated K⁺ (BK_Ca) channel α-subunit activation in nonsham sedentary control (CON), aortic-banded heart failure sedentary (HF), and aortic-banded heart failure interval exercise-trained (HF-IT) animals. A: exercise training prevents the decreased vasodilation in isolated coronary arterioles observed in HF animals after activation of the BK_Ca channel α-subunit by NS-1619 (repeated-measures ANOVA, P < 0.05). B and C: biochemical analysis of isolated coronary arterioles show no differences in BK_Ca channel α-subunit mRNA levels (B) or protein (C). D: representative Western blots of BK_Ca channel α-subunit and β-actin (loading control) arteriole protein levels. + CON, positive control – rat brain. A separate group of animals not included in the analysis of the present report were run on the original gel. Since these samples are not relevant to the present study, they have been removed from the gel as indicated by white dividing lines. E: biotinylation analysis reveals no differences in the cellular distribution of the BK_Ca channel α-subunit in denuded right coronary artery samples. F: representative Western blot of membrane (mem) and cytosolic (cyt) BK_Ca channel α-subunit protein levels in the right coronary artery. + CON, positive control – CON arteriole sample from D. §Interaction effect: Group × Dose (P < 0.05); *post hoc vs. CON (P < 0.05); †post hoc vs. HF-IT (P < 0.05); #post hoc vs. CON (P < 0.10); ‡post hoc vs. HF-IT (P < 0.10). n = 6, 5, and 6 for CON, HF, and HF-IT, respectively, for A; n = 6, 6, and 7 for CON, HF, and HF-IT, respectively, for B–F.