From salt sensitivity to hypertension – what do we know about endogenous cardiotonic steroids?**
Od sodowrażliwości do nadciśnienia tętniczego – co wiemy na temat endogennych steroidów kardiotonicznych?
Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia in Katowice
Head of Department: Professor Andrzej Więcek, MD, PhD
Dietary salt intake is an important factor implicated in the pathogenesis of hypertension. Both epidemiologic and observational studies have provided evidence that dietary sodium intake as well as urinary sodium excretion are closely associated with the prevalence of hypertension (1-3). There is also strong evidence that reduction in sodium intake can decrease blood pressure (4). In 1997, the Dietary Approaches to Stop Hypertension (DASH) trial has proven, that a low-sodium diet, rich in fruits and vegetables, can both prevent and treat hypertension (5). It has been demonstrated by Weinberger that increased salt loading causes an increase in blood pressure in all individuals (6). However, there is a substantial heterogeneity among-individuals in blood pressure responses to alterations in sodium and extracellular volume balance. The magnitude of this salt sensitivity is associated with a variety of demographic, physiological and genetic characteristics. It is possible to identify two main groups in the general population: salt-sensitive and salt-resistant. A variety of techniques and criteria have been proposed to assess the blood pressure response to changes in sodium and extracellular fluid balance, including specific maneuvers, such as intravenous infusion of saline, rapid sodium and volume depletion by diuretic administration or longer periods of dietary sodium manipulation. The largest epidemiological study conducted so far with 378 normotensive volunteers and 198 patients with essential hypertension, found 26% normotensive and 51% hypertensive subjects to be salt-sensitive (6).
The cardiovascular system and the kidneys play an indispensable role in the regulation of arterial blood pressure. The kidneys play a central role in both development and maintenance of arterial hypertension through a direct control of sodium and water homeostasis. Evidence from a variety of studies in humans suggests an abnormality in salt handling by the kidneys as an underlying factor causing salt-sensitive hypertension (7-10). These alterations in renal function, may contribute to the etiology of salt-sensitive hypertension and are mediated by both genetic and environmental factors (11). Experimental studies have clearly shown that the central nervous system, alongside kidneys, plays a critical role in many forms of salt-sensitive hypertension (12-16).
Molecular mechanisms linking salt intake and blood pressure elevation are complex, multifactorial and remain unresolved. Recent studies have demonstrated that endogenous cardiotonic steroids (CTS) are important regulators of renal sodium excretion as well as blood pressure and may play a key role in the pathogenesis of salt-induced hypertension (17-19).
The concept of circulating “humoral factor” hypothesized to induce salt-sensitive hypertension, came from the study performed by Dahl et al. in 1969 (20). In 1974, it was shown this pro-hypertensive “humoral factor” reduced activity of the sodium pump, the Na/K ATPase (21). A relationship between circulating Na/K ATPase inhibitors and blood pressure was first identified in humans in 1982. Moreover, there is a significant correlation between the level of these circulating inhibitors and mean arterial pressure in hypertensive patients (22). Based on numerous clinical studies and observations in volume expanded experimental animals, de Wardener and Clarkson suggested that a mysterious “humoral factor” implicated in pathogenesis of salt-sensitive hypertension is an endogenous natriuretic (23). Subsequent studies have shown that this presumptive “natriuretic hormone” has digitalis-like properties. Digitalis glycosides are specific ligands of Na/K ATPase and Na/K ATPase plays a major role in the renal tubular sodium transport. Therefore, a hypothesis was proposed that the essential role of endogenous digitalis is to promote natriuresis via inhibition of Na/K ATPase and sodium reabsorption in the renal proximal tubules (23). Moreover, endogenous digitalis-like factors could also contribute to vasoconstriction via inhibition of Na/K ATPase activity in vascular smooth muscle cells (24). In 1991 Hamlyn et al. suggested that their highly concentrated samples comprised a compound indistinguishable from plant-derived ouabain. Thus, endogenous ouabain (EO) was the first CTS to be identified in human plasma (25). Subsequent works by Bagrov et al. in patients after acute myocardial infarction have identified another widely studied member of the endogenous cardiotonic steroids, marinobufagenin (MBG) (26). Shortly thereafter, MBG has been detected in human plasma (27, 28).
Cardiotonic steroids were first found in plants, most notably digitalis in the foxglove plant, and then in the skin of toads like the Bufo marinus (29). They have been used in traditional ancient medicine to treat congestive heart failure (30). CTS, or digitalis-like substances, are divided into two distinct groups related by structure: cardenolides, represented by digoxin and ouabain, and bufadienolides, represented by marinobufagenin and telocinobufagin. Bufadienolides differ from cardenolides in having a double-unsaturated six-atom lactone ring. Considering that, the amphibian skin participates in water and electrolyte homeostasis and the concentration of bufadienolides in toad skin is regulated by the salt content and its environment, it was hypothesized that the sodium pump (Na/K ATPase) and bufadienolides work together as a regulatory system serving as a basic stimulus-response coupling mechanism to maintain water and electrolyte balance (31, 32). Extremely important contributions were made by several groups which indicated that human fluids contain material that cross-react with antibodies against one of the bufadienolides, bufalin (33, 34). In the 1990s, endogenous ouabain and marinobufagenin were purified from human plasma.
Na/K ATPase is an active transport mechanism moving sodium and potassium ions across the cell membrane. This process is responsible for maintaining both an electrical and chemical gradient that is essential for maintaining a number of vital cell functions, such as communication, excitation, muscle contraction, and many other cellular functions. Na/K ATPase is a membrane-spanning enzyme expressed in virtually all cells of higher organisms. It structurally consists of two subunits, a large catalytic subunit α and a smaller glycoprotein subunit β (35).
Endogenous cardiotonic steroids bind to a specific site within the α subunit of Na/K ATPase and inhibit its activity. There are four isoforms of the α-subunit that have been identified in various tissues (36). The α1 isoform is ubiquitous and it is the main isoenzyme expressed in the renotubular epithelium (35). The α2 isoform is predominant in heart, vascular smooth muscle, skeletal muscle, adipocytes and brain. The α3 isoform is mostly found in neurons and in the cardiac tissue. The α4 isoform is expressed in the testis (37). The renal α1 isoform of Na/K ATPase plays a key role in the sodium reabsorption along the nephron. The α1 and α2 isoforms are a major determinant of smooth muscle contraction and vasoconstriction.
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