Zinc offers a potential new pathway for therapies to treat hypertension


High blood pressure, or hypertension, is the leading modifiable risk factor for cardiovascular diseases and premature death worldwide. And key to treating patients with conditions ranging from chest pain to stroke is understanding the intricacies of how the cells around arteries and other blood vessels work to control blood pressure.

While the importance of metals like potassium and calcium in this process are known, a new discovery about a critical and underappreciated role of another metal – zinc – offers a potential new pathway for therapies to treat hypertension.

All the body’s functions depend on arteries channeling oxygen-rich blood – energy – to where it’s needed, and smooth muscle cells within these vessels direct how fast or slow the blood gets to each destination. As smooth muscles contract, they narrow the artery and increase the blood pressure, and as the muscle relaxes, the artery expands and blood pressure falls.

If the blood pressure is too low the blood flow will not be enough to sustain a person’s body with oxygen and nutrients. If the blood pressure is too high, the blood vessels risk being damaged or even ruptured.

“Fundamental discoveries going back more than 60 years have established that the levels of the calcium and potassium in the muscle surrounding blood vessels control how they expand and contract,” say lead author Ashenafi Betrie, Ph.D., and senior authors Scott Ayton, Ph.D., and Christine Wright, Ph.D., of the Florey Institute of Neuroscience and Mental Health and The University of Melbourne in Australia.

Specifically, the researchers explain, potassium regulates calcium in the muscle, and calcium is known to be responsible for causing the narrowing of the arteries and veins that elevate blood pressure and restrict blood flow. Other cells that surround the blood vessel, including endothelial cells and sensory nerves, also regulate the calcium and potassium within the muscle of the artery, and are themselves regulated by the levels of these metals contained within them.

“Our discovery that zinc is also important was serendipitous because we’d been researching the brain, not blood pressure,” says Betrie. “We were investigating the impact of zinc-based drugs on brain function in Alzheimer’s disease when we noticed a pronounced and unexpected decrease in blood pressure in mouse models treated with the drugs.”

In collaboration with researchers at the University of Vermont’s Larner College of Medicine in the United States and TEDA International Cardiovascular Hospital in China, the investigators learned that coordinated action by zinc within sensory nerves, endothelial cells and the muscle of arteries triggers lower calcium levels in the muscle of the blood vessel.

This makes the vessel relax, decreasing blood pressure and increasing blood flow. The scientists found that blood vessels in the brain and the heart were more sensitive to zinc than blood vessels in other areas of the body – an observation that warrants further research.

“Essentially, zinc has the opposite effect to calcium on blood flow and pressure,” says Ayton. “Zinc is an important metal ion in biology and, given that calcium and potassium are famous for controlling blood flow and pressure, it’s surprising that the role of zinc hasn’t previously been appreciated.”

Another surprising fact is that genes that control zinc levels within cells are known to be associated with cardiovascular diseases including hypertension, and hypertension is also a known side effect of zinc deficiency. This new research provides explanations for these previously known associations.

“While there are a range of existing drugs that are available to lower blood pressure, many people develop resistance to them,” says Wright, who added that a number of cardiovascular diseases, including pulmonary hypertension, are poorly treated by currently available therapies.

“New zinc-based blood pressure drugs would be a huge outcome for an accidental discovery, reminding us that in research, it isn’t just about looking for something specific, but also about just looking.”

Zn2+ deficiency (ZnD) is a common comorbidity with numerous chronic diseases (3, 18), including type 2 diabetes and chronic kidney disease. In these patients, the incidence of hypertension is high (9, 11). In support of the idea that ZnD contributes to blood pressure (BP) dysregulation, it has been reported that populations with low dietary Zn2+ intake have a high prevalence of hypertension (7, 13). These and other epidemiological studies suggest a possible inverse correlation between Zn2+ levels and BP (1, 7, 13).

Experimental studies also suggest that Zn2+ may contribute to BP regulation (2, 4, 20, 24). Epigenetic studies demonstrate that in utero ZnD predisposes rat offspring to hypertension (14, 24). Specifically, ZnD in prenatal and postnatal rats induces BP derangements that are accompanied by cardiovascular and renal morphological and functional changes.

These studies demonstrate the importance of prenatal and postnatal Zn2+ in programming hypertension in adulthood. Hypertensive models have also implicated ZnD in BP dysregulation. Notably, plasma Zn2+ levels are reduced in salt-sensitive hypertensive rats (20). Additionally, in spontaneous hypertension-prone rats, dietary Zn2+ restriction exacerbates systolic BP (20), whereas Zn2+ supplementation attenuates these BP responses (2).

Although these studies highlight the potential effects of Zn2+ on BP regulation, confounding factors associated with pregnancy and hypertension cannot be ignored. Therefore, Zn2+ effects on BP in normotensive, adult populations should be investigated and are the focus of this study.

Renal modulation of urinary Na+ excretion is the cornerstone of BP control. The renal Na+-Cl− cotransporter (NCC) is an important Na+ reabsorptive pathway that plays a critical role in BP regulation (26, 27). Notably, NCC dysregulation is implicated in several genetic disorders of hypotension and hypertension (26).

This thiazide-sensitive NCC is specifically expressed in the distal convoluted tubule (DCT), where it plays a major role in Na+ handling and subsequent BP regulation. Zn2+ is an essential cofactor that influences the expression and activity of numerous enzymes, transcription factors, and regulatory proteins.

Recently, it was suggested that a Zn2+-dependent metalloprotease may regulate with-no-lysine kinase (WNK) kinases, powerful regulators of NCC (16). However, a direct link between NCC and ZnD-induced BP dysregulation has not been investigated.

Using in vivo and in vitro models of ZnD, we explored the role of Zn2+ bioavailability in BP regulation. Our novel findings demonstrate that 1) Zn2+ contributes to BP regulation via modulation of renal Na+ transport, 2) renal NCC mediates ZnD-induced hypertension, and 3) NCC is a Zn2+-regulated transporter that is upregulated by ZnD.

Importantly, this study directly demonstrates that Zn2+ plays a critical role in BP regulation and identifies NCC as an important mechanism involved in ZnD-induced renal Na+ retention and subsequent BP increases.

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483028/

More information: Ashenafi H. Betrie et al, Zinc drives vasorelaxation by acting in sensory nerves, endothelium and smooth muscle, Nature Communications (2021). DOI: 10.1038/s41467-021-23198-6


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