Ionic current changes underlying action potential repolarization responses to physiological pacing and adrenergic stimulation in adult rat ventricular myocytes.

This study aimed to simulate ventricular responses to elevations in myocyte pacing and adrenergic stimulation using a novel electrophysiological rat model and investigate ion channel responses underlying action potential (AP) modulations. Peak ion currents and AP repolarization to 50% and 90% of full repolarization (APD50-90 ) were recorded during simulations at 1-10 Hz pacing under control and adrenergic stimulation conditions. Further simulations were performed with incremental ion current block (L-type calcium current, ICa ; transient outward current, Ito ; slow delayed rectifier potassium current, IKs ; rapid delayed rectifier potassium current, IKr ; inward rectifier potassium current, IK1 ) to identify current influence on AP response to exercise. Simulated APD50-90 closely resembled experimental findings. Rate-dependent increases in IKs (6%-101%), IKr (141%-1339%), and ICa (0%-15%) and reductions in Ito (11%-57%) and IK1 (1%-9%) were observed. Meanwhile, adrenergic stimulation triggered moderate increases in all currents (23%-67%) except IK1 . Further analyses suggest AP plateau is most sensitive to modulations in Ito and ICa while late repolarization is most sensitive to IK1 , ICa , and IKs , with alterations in IKs predominantly stimulating the greatest magnitude of influence on late repolarization (35%-846% APD90 prolongation). The modified Leeds rat model (mLR) is capable of accurately modeling APs during physiological stress. This study highlights the importance of ICa , Ito , IK1, and IKs in controlling electrophysiological responses to exercise. This work will benefit the study of cardiac dysfunction, arrythmia, and disease, though future physiologically relevant experimental studies and model development are required.

Pharmacy and Exercise as Complimentary Partners for Successful Cardiovascular Ageing.

Diseases of the cardiovascular system have been the biggest cause of mortality for the majority of the last century, currently contributing to almost a third of deaths every year globally. Ageing associates with changes to the structure and function of the heart and vascular system that progressively increase the incidence of abnormalities, morbidity, and cardiovascular disease. The burden of ageing and its relationship to cardiovascular disease risk highlights the need for more research into the underlying mechanisms involved and how they may be treated and/or prevented. Factors influencing adrenergic dysfunction may explain a significant part of the age-related deterioration in health and responsiveness of the cardiovascular system. Increased sympathetic activity in old age overstimulates adrenergic receptors and causes detrimental changes within the associated signalling mechanisms, including a reduction in receptor number and downstream effector efficiency. Pharmacological agents, such as metformin, resveratrol, beta-blockers, and angiotensin converting enzyme (ACE) inhibitors, have been identified as potential anti-ageing therapies with cardiovascular effects, which may be beneficial in treating the decline in cardiovascular function with old age. Regular exercise has also shown promise in the prevention and treatment of harmful age-related effects on the cardiovascular system. This review will investigate age-associated vascular and cardiac remodelling, and the link between adrenergic dysfunction and vascular and cardiac control. This review will also consider whether pharmacological or non-pharmacological therapies are most effective, or indeed complimentary to potentially optimised ageing of the cardiovascular system and improved quality of life in the elderly.

Action potential responses to changes in stimulation frequency and isoproterenol in rat ventricular myocytes.

PURPOSE: Current understanding of ventricular action potential adaptation to physiological stress is generally based on protocols using non-physiological rates and conditions isolating rate effects from escalating adrenergic stimulation. To permit refined understanding, ventricular action potentials were assessed across physiological pacing frequencies in the presence and absence of adrenergic stimuli. Isolated and combined effects were analyzed to assess their ability to replicate in-vivo responses. METHODS: Steady-state action potentials from ventricular myocytes isolated from male Wistar rats (3 months; N = 8 animals) were recorded at 37°C with steady-state pacing at 1, 2, 4, 6, 8 and 10 Hz using whole-cell patch-clamp. Action potential repolarization to 25, 50, 75, 90 and 100% of full repolarization (APD25-100 ) was compared before and after 5 nM, 100 nM and 1 µM isoproterenol doses. RESULTS: A Repeated measures ANOVA found APD50-90  shortened with 5 nM isoproterenol infusion by 6-25% (but comparable across doses) (p ≤ 0.03). Pacing frequencies emulating a normal rat heart rate (6 Hz) prolonged APD50 23% compared with 1 Hz pacing. Frequencies emulating exercise or stress (10 Hz) shortened APD90 (29%). CONCLUSION: These results demonstrate modest action potential shortening in response to adrenergic stimulation and elevations in pacing beyond physiological resting rates. Our findings indicate changes in action potential plateau and late repolarization predominantly underlie simulated exercise responses in the rat heart. This work provides novel action potential reference data and will help model cardiac responses to physiological stimuli in the rat heart via computational techniques.

Reduced cardiac response to the adrenergic system is a key limiting factor for physical capacity in old age.

Ageing is associated with a progressive reduction in physical capacity reducing quality of life. One key physiological limitation of physical capacity that deteriorates in a progressive age-dependent manner is cardiac reserve. Peak cardiac output falls progressively with advancing age such that in extreme old age there is limited ability to enhance cardiac output beyond basal function as is required to support the increased metabolic needs of physical activity. This loss of dynamic range in cardiac output associates with a progressive reduction in the heart's response to adrenergic stimulation. A combination of decreases in the expression and functioning of beta1 adrenergic receptors partially underlies this change. Changes in end effector proteins also have a role to play in this decline. Alterations in the efficiency of excitation-contraction coupling contribute to the reduced chronotropic, inotropic and lusitropic responses of the aged heart. Moderate to vigorous endurance exercise training however has some potential to counter elements of these changes. Further studies are required to fully elucidate the key pivotal mechanisms involved in the age-related loss of response to adrenergic signalling to allow targeted therapeutic strategies to be developed with the aim of preserving physical capacity in advanced old age.

The effect of varying intensities of lower limb eccentric muscle contractions on left ventricular function.

PURPOSE: The effect of eccentric (ECC) resistance exercise (RE) on myocardial mechanics is currently unknown. METHOD: This study investigated ECC RE at varying intensities on left ventricular (LV) function using LV strain (ε), wall stress and haemodynamic parameters. Twenty-four healthy male volunteers completed ECC leg extensions at 20%, 50% and 80% of their ECC maximal voluntary contraction (MVC), whilst receiving echocardiograms. Global longitudinal ɛ, strain rate (SR), longitudinal tissue velocity, heart rate (HR), blood pressure (BP), mean arterial pressure (MAP), LV wall stress and rate pressure product (RPP) were assessed at baseline and during exercise. RESULTS: Left ventricular global ɛ, systolic SR and wall stress remained unchanged throughout. Systolic blood pressure (sBP), MAP and RPP increased at 80% and 50% intensities compared to rest (P < 0.01). Eccentric RE increased HR and peak late diastolic SR at all intensities compared to rest (P < 0.02). CONCLUSION: The findings suggest acute ECC RE may not alter main parameters of LV function, supporting future potential for wider clinical use. However, future studies must investigate the impact of multiple repetitions and training on LV function.