Salt-sensitive hypertension: A new therapeutic approach

Alpha-1 adrenergic receptor blockers reduce the activity of the renal sodium re-absorption process, which increases salt excretion and thus lowers blood pressure.

Alpha-1 adrenergic receptor blockers reduce certain kidney activities

People with salt-sensitive hypertension do not respond to conventional anti-hypertensive drugs. The Boston University School of Medicine (USA) has made new discoveries about the complex interaction between the sympathetic nervous system and the kidneys. Alpha-1 adrenergic receptor blockers reduce the activity of the renal sodium re-absorption process, which increases salt excretion and thus lowers blood pressure.

From the age of 60 onward, up to one in two people have arterial hypertension values and thus a significantly increased risk of life-threatening cardiovascular and vascular diseases (especially vascular calcification/atherosclerosis). Particularly dreaded secondary diseases include heart attacks and strokes, but kidney failure and blindness are also possible.

The consumption of excessive amounts of table salt (sodium chloride) promotes the development of hypertension. Salt binds water in the body, the volume of fluid in the bloodstream increases, and with it, the pressure in the blood vessels. The consumption of salt causes high blood pressure in many people. This is due to a specific genetic predisposition (salt sensitivity), but diabetes mellitus, kidney disease or disorders of the autonomic nervous system can also contribute to the development of high blood pressure.

In salt-sensitive hypertension, activity of the sympathetic nervous system is increased

Patients with salt-sensitive hypertension typically have increased activity of the sympathetic nervous system and their kidneys retain too much salt instead of excreting it with urine (renal sodium retention). The neurotransmitter norepinephrine activates the alpha receptors of the blood vessels, which narrow (vasoconstriction) and blood pressure rises. Norepinephrine also stimulates the renal sodium-chloride symporter (NCC) in the cell membranes of the renal tubules, which is why more sodium is transported from the urine back into the blood. However, the exact mechanism of renal sodium retention by norepinephrine has not been clarified. Studies investigating the adrenaline- or norepinephrine-controlled signalling pathways of the sympathetic nervous system that regulate NCC activity have not yet shown consistent results.

Alpha-blockers have a vasodilating effect by relaxing the vascular smooth muscles (vascular dilatation). The researchers in Boston showed that alpha-1 adrenergic receptor blockers also reduce the activity of the sodium reuptake process, thereby lowering blood pressure. Selective alpha-1 receptor blockers were used to detect norepinephrine-dependent NCC activation in a salt-sensitive rat strain via an alpha-1 receptor-dependent signalling pathway.

Tests in mice are promising

The animals' salt intake was increased via diet, which resulted in a significant increase in NCC activity and expression, and development of hypertension. Treatment with alpha-1 receptor blockers resulted in a reduction in blood pressure - mediated by a decrease in NCC activity and expression (i.e. lower NCC levels on cell membranes), which prevented renal salt retention. The alpha-1 receptor blockers were effective both when administered before high salt intake started and in previously developed salt-sensitive hypertension. Detailed molecular analyses revealed that in salt sensitive hypertension (as opposed to rat strains with salt resistant normotension) there is a disruption of the enzyme "WNK kinase 1/4" or a malfunction of the "WNK/SPAK/OxSR1" kinase signalling pathway that regulates NCC activity.

Selective alpha-1 receptor blockers appear to inhibit salt-sensitive hypertension

"These research results show how complex the pathomechanisms and connections between the sympathetic nervous system and the kidneys are in the development of hypertension," commented Prof. Dr. med. Ulrich Wenzel from the University Medical Center Hamburg-Eppendorf (Germany). "Even though the exact pathomechanisms are not yet known, selective alpha-1-receptor blockers seem to be able to specifically prevent salt-sensitive hypertension.

If these animal experimental findings are confirmed in clinical trials, this would be of great practical relevance, as these drugs could break the vicious circle and lead to normal blood pressure values in many people in whom conventional antihypertensive drugs do not work (patients with so-called therapy-refractory hypertension).

“So far we have only been able to recommend that these patients keep their salt intake to a minimum, but this is far from easy to implement, partly because of 'hidden salt' levels in many foods. A targeted therapy for salt-sensitive hypertension would help to bring many more patients with their blood pressure values into the target range and suffer fewer secondary diseases", addded Prof. Dr. Wenzel.

Franco Puleo, Kiyoung Kim, Alissa A. Frame, Kathryn R. Walsh, Mohammed Z. Ferdaus, Jesse D. Moreira, Erica Comsti, Elizabeth Faudoa, Kayla M. Nist, Eric Abkin, Richard D. Wainford. “Sympathetic Regulation of the NCC (Sodium Chloride Cotransporter) in Dahl Salt–Sensitive Hypertension.” Hypertension. 2020;76:1461–1469. Originally published28 Sep 2020