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Can a pill (Ca 2+ channel blockade) rescue the vascular endothelium from ageing?

2024; Wiley; Volume: 109; Issue: 5 Linguagem: Inglês

10.1113/ep091824

1469-445X

Seth W. Holwerda,

Cardiovascular and exercise physiology

Function of the vascular endothelium is impaired with ageing, which poses a challenge for a healthy and active lifestyle by restricting limb blood flow and increasing risk of cardiovascular disease. Leg blood flow is reduced by approximately 26% in older men compared with young men (Dinenno et al., 1999), but with habitual endurance exercise, leg blood flow can be preserved. In the current issue of Experimental Physiology, Iepsen and colleagues took a pharmacological approach and examined the extent to which low voltage T-type Ca2+ channel blockade improves function of the vascular endothelium in ageing men (Iepsen et al., 2024). Low voltage T-type Ca2+ channels play a significant role in vascular resistance and have increasingly become a therapeutic target for hypertension. However, controversy exists regarding the exact role that T-type Ca2+ channels play in the function of the vascular endothelium in humans. Studies in humans targeting the low voltage T-type Ca2+ channel for improving function of the endothelium have been scarce. Results from a randomized, double-blinded clinical trial (Oshima et al., 2005) showed significant improvement in endothelium-dependent dilatation in patients with essential hypertension following 12 weeks of T- and L-type Ca2+ channel blockade (efonidipine), but not after 12 weeks of L-type Ca2+ channel blockade alone (nifedipine). Thus, by deduction, the study paradigm isolates the influence of T-type Ca2+ channel blockade. The work by Iepsen and colleagues includes the same study approach but instead focuses on older men rather than patients with hypertension. Iepsen et al. report that endothelium-dependent dilatation was significantly increased in older men following 8 weeks of efonidipine, but not nifedipine. Endothelium-dependent dilatation has significant clinical value because it is inversely related to future risk of cardiovascular disease. Two principal elements of the study by Iepsen et al. should be mentioned. First, the study design includes randomization and double blinding, which remains the gold standard approach for demonstrating efficacy. A placebo condition was not included; however, nifedipine served as a necessary and sufficient comparator for efonidipine. Second, study participants did not have hypertension, nor did they demonstrate a statistically significant reduction in blood pressure (BP) following T-type Ca2+ channel blockade. This is significant because it suggests that T-type Ca2+ channel blockade does not require a major reduction in BP to elicit an improvement in endothelium-dependent dilatation. Endothelium-dependent dilatation declines after age 40, while systolic BP tends to increase thereafter. Hence, T-type Ca2+ channel blockade may have potential as a prophylactic for age-related reductions in function of the endothelium even before BP begins to increase if sufficient evidence bears out in future clinical studies. In ageing adults, it is critical to mitigate hypertension and its contributing factors (e.g., impaired endothelium-dependent dilatation) because hypertension is independently associated with damage to end organs, such as the brain, and contributes to risk of stroke and dementia. T-type Ca2+ channels are thought to make a larger contribution to vascular resistance in the smaller peripheral arteries compared with large peripheral arteries. Indeed, the relative expression of T- and L-type Ca2+ channels is inverse, where T-type Ca2+ channels are expressed more in the small arteries and L-type Ca2+ channels are expressed more in large arteries. T-type Ca2+ channels are also regulated by numerous G-protein-coupled receptors, which means that changes in the milieu (e.g., angiotensin II) may potentially alter T-type Ca2+ channel control of vascular function. A major obstacle to clinical research is the variation in the α1 subunit of the T-type Ca2+ channel (Cav.3.1, Cav.3.2 and Cav.3.3) because it creates difficulty in targeting the drug. However, development of knockout mice has made it possible to determine the functional role of T-type Ca2+ channel subtypes. Evidence suggests that Cav3.2 channels may affect vasodilatation through a vascular smooth muscle cell-related mechanism (Chen et al., 2003), whereas Cav.3.1 may affect vasodilatation through a nitric oxide mechanism (Svenningsen et al., 2014). Iepsen and colleagues provide evidence in humans that T-type Ca2+channel blockade improves function of the endothelium through a nitric oxide mechanism rather than a vascular smooth muscle cell-related mechanism because endothelium-dependent dilatation was significantly increased while dilatation in response to a nitric oxide donor was unchanged. While applauding the authors for performing a highly challenging study given the invasive nature of the assessments, we should also note the limitations and study outcomes that do not relieve controversy regarding the role of T-type Ca2+ channels in the function of the endothelium. First, despite higher endothelium-dependent dilatation following treatment, a parallel increase in plasma nitrite and nitrate (NOx) concentration was not observed. Nitric oxide production occurs primarily on the arterial side of the circulation, and increased concentration of NOx from arterial blood reflects higher endothelium-dependent dilatation. Thus, an increase in NOx was expected. Second, a comparison of biopsy from the vastus lateralus before and after treatment did not provide support for upregulation of endothelial nitric oxide synthase (eNOS). An alternative viewpoint is that eNOS is phosphorylated instead of upregulated following T-type Ca2+ channel blockade, indicating greater functional activity of eNOS rather than increased eNOS content. However, phosphorylated eNOS was not assessed by Iepsen et al., making this a notable limitation of the study. Advancements in the field often create more questions than answers, as does the study by Iepsen et al. For instance, it is unclear if an age threshold exists where T-type Ca2+ channel blockade does not improve function of the endothelium. Also, additional studies will be required to determine the extent to which T-type Ca2+ channel blockade improves age-related declines in function of the endothelium in women. No apparent sex differences were noted in a previous study that included adults with essential hypertension (Oshima et al., 2005), suggesting that T-type Ca2+ channel blockade could potentially be beneficial in ageing women. In summary, Iepsen et al. provide supporting evidence in humans that T-type Ca2+ channels contribute independently to function of the endothelium. It is quite notable that a +33% increase in endothelium-dependent dilatation was observed in the absence of a structured physical exercise regimen, which has been shown to increase endothelium-dependent dilatation in middle aged and older men by 30% (DeSouza et al., 2000). These data provide reason to be optimistic about larger clinical trials focused on nitric oxide bioavailability in the vascular endothelium following T-type Ca2+ channel blockade in middle-aged and older adults. Sole author. No conflicts of interest, financial or otherwise, are declared by the author.