The Role of Epithelial Sodium Channel and Sympathetic Nervous Potentiation in the Development of Salt Sensitive Hypertension among Nigerians in Lagos
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Date
2012-08
Authors
Elias, S.O
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Abstract
The mechanisms by which salt causes hypertension are not conclusive. Increased sympathetic activity and systemic vascular dysfunction have both been implicated as well as mutations of the epithelial sodium channel (ENaC) that resulted in increased reabsorption of salt from the distal nephron. However, although an adrenergic overdrive has been observed in some hypertensive patients, it is not clear whether this adrenergic overdrive is the hallmark of hypertension. It has equally been a subject of debate whether exaggerated vascular reactivity is a cause or consequence of hypertension. Also, whereas ENaC mutations especially the β-T594M variant has been related to salt sensitive hypertension among Black individuals living in London, similar associations have not been recorded in African-Americans. On the other hand, among South Africans of black ancestry, some studies have shown no incidence of β-T594M ENaC mutation while a different type of ENaC mutation has been recorded in one study.
The present study was therefore designed to determine the role of salt sensitivity, autonomic potentiation and the epithelial sodium channel activity in the development of hypertension among Nigerians. Fifty-three otherwise healthy hypertensive (HT) adults and forty-seven age-matched normotensive (NT) subjects were studied. After baseline parameters had been obtained, the subjects were salt-loaded with 200 mmol/day of Na+ as sodium chloride for 5 days. Thereafter salt sensitivity was determined in all the subjects as ΔMABP ≥ +5mmHg following the salt-loading. As a test of mechanism for salt-sensitivity, plasma Na+, urine Na+ excretion (UNaV), salt sensitivity index (SSI) and sodium clearance were determined. To assess the effect of the sympathetic nervous system on the cardiovascular system of the subjects, vascular reactivity and forearm vascular resistance (FVR) were determined before and after exposing the subjects to the cold pressor test for one minute. To assess the relationship between ENaC markers and salt sensitivity, the subjects were again salt-loaded with 200mmol/day of Na+ with which 5mg Amiloride was co-administerd for the duration. Blood pressure, plasma K+, plasma renin activity (PRA) and serum aldosterone were determined thereafter. Blood was then collected for DNA isolation, amplification and sequencing.
Significant pressor responses to salt-loading alone were recorded in the NT (p <0.01) and HT (p < 0.001) subjects. Salt sensitivity was significantly higher (p<0.01) among HT subjects when compared with NT subjects. At baseline and after salt-loading, plasma Na+ concentration was similar among the NT and HT subjects though higher among the HT subjects. Urine Na+ excretion was significantly lower (p < 0.05) in HT subjects compared with NT subjects. Salt sensitivity index (SSI) was higher (p < 0.01) among the HT subjects compared with in the NT subjects. Peak systolic and diastolic blood pressures were significantly higher (p < 0.001) among the two groups of subject compared to basal blood pressures before and after salt-loading; this was moreso in the hypertensive subjects. Hypertensive subjects showed higher systolic and diastolic vascular hyperreactivity compared to the NT subjects (p < 0.05) at baseline. However, following salt-loading, systolic vascular hyperreactivity increased significantly (p < 0.05) among the NT subjects and becoming higher than that recorded among the HT subjects at baseline. Systolic salt hyperreactivity was significantly higher (p < 0.05) among the NT subjects compared with the HT subjects. Similarly, diastolic salt hyperreactivity was higher in the NT subjects compared with HT subjects. Before salt-loading in NT subjects, there was a significant and positive correlation between salt sensitivity and systolic vascular reactivity (p < 0.05) while salt sensitivity showed a significant and negative correlation with diastolic vascular reactivity (p < 0.05). After salt-loading in NT subjects, there was a significant and negative correlation between salt sensitivity and systolic vascular reactivity (p < 0.05). Forearm vascular resistance (FVR) was significantly lower (p < 0.05) among the NT subjects compared with the HT subjects at baseline. Sympathetic nervous stimulation by means of the cold pressor test before and after salt-loading led to significant increases (p < 0.001) in FVR which were similar in both NT and HT groups. Co-administration of salt and amiloride led to significant decreases in systolic and diastolic blood pressure compared with baseline in NT (p < 0.05) and HT (p < 0.001) subjects. Plasma K+ was significantly lower (p < 0.05) among the HT subjects at baseline compared with the NT subjects. Following salt-loading, there was significant fall in plasma K+ in the NT (p < 0.05) but not in the HT subjects. On co-administration of salt and amiloride however, plasma K+ increased significantly (p < 0.001) in the HT subjects but not in the NT subjects. Plasma renin activity (PRA) was lower in the HT subjects (p < 0.05) compared with NT subjects before and after salt-loading. There were significant increases (p < 0.05) in PRA in both the NT and HT subjects after the salt load. The β-T594M mutation of the epithelial sodium channel was recorded among 5 percent of the study population while four previously undocumented non-synonymous mutations: β-E636V, β-E632V, β-D638Y and β-L628Q were observed in another 4 percent of the subjects.
The results of this study show that HT subjects were more salt sensitive than NT subjects and inabilty of the HT subjects to excrete a salt-load is contributory to this. Although the effect of sympathetic stimulation on FVR was similar in both the NT and HT subjects, NT subjects displayed enhanced vascular hyperreactivity after salt-loading, higher than that observed in hypertensive subjects at baseline. This is an indication that vascular hyperreactivity, a reflection of sympathetic potentiation is important in the development of hypertension among the subjects. Also there was significant correlation between systolic hyperreactivity and salt sensitivity among the NT subjects which is a strong indicator of development of hypertension in the future. Furthermore, amiloride studies indicated that enhanced epithelial sodium channel activity is important in the development of hypertension among Nigerians. The β-T594M mutation of the epithelial sodium channel was recorded among 5 percent of the study population confirming the presence of this mutation in Nigerian subjects. Also four new mutations of the epithelial sodium channel with the potential to affect blood pressure were recorded in 4 percent of the subjects.
Description
A Thesis Submitted to the School of Postgraduate Studies, University of Lagos
Keywords
Hypertension , Systemic vascular dysfunction , Adrenergic overdrive , Hypertensive patients , Research Subject Categories::MEDICINE::Physiology and pharmacology::Physiology
Citation
Elias, S.O (2012). The Role of Epithelial Sodium Channel and Sympathetic Nervous Potentiation in the Development of Salt Sensitive Hypertension among Nigerians in Lagos. A Thesis Submitted to University of Lagos School of Postgraduate Studies Phd Thesis and Dissertation, 268pp.