Cardiac hypertrophy diminished the effects of isoproterenol on delayed rectifier potassium current in rat heart
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Published on: October 3, 2019
Tomohiko Sakatani1, Takeshi Shirayama, Taku Yamamoto
1Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan. sakatani@koto.kpu-m.ac.jp
Insights
In hypertrophic rat hearts, reduced potassium current (I(K)) prolongs action potential duration. Isoproterenol fails to stimulate I(K) due to increased phosphodiesterase activity, worsening heart dysfunction.
Area of Science:
- Cardiology
- Electrophysiology
- Molecular Cardiology
Background:
- Left ventricular hypertrophy (LVH) alters cardiac electrophysiology.
- Sympathetic nerve activity influences ion channel function in the heart.
Purpose of the Study:
- To investigate the relationship between sympathetic stimulation and potassium current (I(K)) in a rat model of cardiac hypertrophy.
- To elucidate the mechanisms behind altered action potential duration (APD) in hypertrophic hearts.
Main Methods:
- Induction of LVH via suprarenal aortic constriction in rats.
- Whole-cell patch clamp technique to measure ion currents (I(K), I(Ca)) and APD.
- Pharmacological stimulation with isoproterenol, forskolin, and IBMX.
Main Results:
- Hypertrophic hearts showed a 28.2% decrease in I(K), leading to prolonged APD(90).
- Isoproterenol failed to stimulate I(K) in hypertrophic hearts, unlike in sham controls.
- Isoproterenol increased L-type calcium current (I(Ca)) similarly in both groups, further prolonging APD in hypertrophic hearts.
- Forskolin did not enhance I(K) in hypertrophy, but IBMX did, suggesting a role for phosphodiesterase.
Conclusions:
- Enhanced phosphodiesterase activity in hypertrophic hearts impairs isoproterenol-mediated I(K) stimulation.
- This impairment contributes to excessive action potential duration prolongation and cardiac dysfunction in hypertrophy.
Abstract:
We investigated the association between sympathetic nerve activity and delayed rectifier potassium current (I(K)) in hypertrophic rat hearts. Left ventricular hypertrophy was induced by a 50% constriction of suprarenal abdominal aorta for 6 weeks. The effects of isoproterenol on action potential duration (APD), I(K), and L-type calcium current (I(Ca)) were investigated using the whole-cell patch clamp technique. In hypertrophic rats, I(K) was decreased by 28.2%, resulting in significant APD(90) (90% repolarization) prolongation (sham: 55 +/- 3.9, hypertrophy: 98 +/- 11 ms, P = 0.01). Isoproterenol (100 nM)-stimulated I(K) was increased by 54.9% +/- 0.10% in sham-operated rats, but not in hypertrophic rats. On the other hand, isoproterenol increased I(Ca) in both sham-operated (77.7% +/- 7.6%) and hypertrophic rats (69.6% +/- 9.7%). Consequently, isoproterenol prolonged further APD in hypertrophic rats (98 +/- 11 vs. 145 +/- 8.6 ms, P < 0.01), but not in sham-operated rats (55 +/- 3.9 vs. 61 +/- 5.6 ms, n.s.). Forskolin (1 microM, an adenylyl cyclase stimulator) did not enhance I(K) in hypertrophic rats, but IBMX (100 microM, a nonselective phosphodiesterase inhibitor) enhanced the current (30.2 +/- 0.05%), as much as in sham-operated rats. We concluded that in hypertrophic hearts, I(K) was not increased by isoproterenol because of the enhanced activity of phosphodiesterase, which leads to excessive APD prolongation.
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