Figure 1. Interaction of the Modern Western Diet and the Kidneys in the Pathogenesis of Primary Hypertension. The modern Western diet interacts with the kidneys to generate excess sodium and cause a deficit of potassium in the body; these changes increase peripheral vascular resistance and establish hypertension. An initial increase in the volume of extracellular fluid is countered by pressure natriuresis.
Figure 2. Molecular Mechanisms Implicated in the Retention of Sodium and Loss of Potassium by the Kidneys in Primary Hypertension. Solid arrows indicate an increase or stimulation, and the broken arrow indicates inhibition. Numbers on the left denote the approximate percentage of reabsorption of filtered sodium in each nephronal segment during normal conditions. Several influences acting on the luminal sodium transporters and the basolateral sodium pump stimulate sodium retention and potassium loss. Promotion of sodium reabsorption by the activated epithelial sodium channel (ENaC) generates a more negative luminal membrane voltage (Vm) in the collecting duct that enhances potassium secretion through the luminal potassium channel and promotes kaliuresis. NHE-3 denotes sodium–hydrogen exchanger type 3, ACE angiotensin-converting enzyme, NKCC2 sodium–potassium2 chloride cotransporter, and NCC sodium–chloride cotransporter. PST 2238 (rostafuroxin) antagonizes the effect of digitalis-like factor on the sodium pump.
Figure 3. Molecular Pathways Implicated in the Generation of Increased Arterial and Arteriolar Smooth-Muscle Tone by an Excess of Sodium and a Deficit of Potassium in Primary Hypertension. Solid arrows indicate an increase or stimulation, and broken arrows indicate a decrease or inhibition. The inhibition of the sodium pump and the resulting stimulation of the sodium–calcium exchanger type 1 (NCX1) increase the intracellular concentration of calcium that in turn triggers actin–myosin interaction and stimulation of vascular contraction. Na+ i denotes intracellular sodium concentration, K+ i intracellular potassium concentration, Ca2+ i intracellular calcium concentration, Vm membrane potential, and RyR ryanodine-receptor calcium channel. PST 2238 (rostafuroxin) antagonizes the effect of digitalis-like factor on the sodium pump. SEA-0400 is a specific inhibitor of the bidirectional NCX1 preferentially blocking the calcium influx pathway.
Figure 4. Molecular Pathways Implicated in Potassium-Induced, Endothelium-Dependent Vasodilatation. Solid arrows indicate an increase or stimulation, and broken arrows indicate a decrease or inhibition. The stimulation of the sodium pump and the opening of the potassium channels hyperpolarize the endothelial cell (with membrane potential [Vm] shifting to more negative values). Endothelial-cell hyperpolarization is transmitted to the vascular smooth-muscle cell by means of myoendothelial gap junctions and also by increasing the intracellular calcium concentration (Ca2+ i). The latter change activates potassium channels of small (SK3) and intermediate (IK1) conductance localized to the cell membrane, causing the potassium to exit the cells and to accumulate in the myoendothelial intercellular space. This accumulation of potassium adds to vascular smooth-muscle hyperpolarization by activating membrane potassium channels and stimulating the sodium pump. Vascular smooth-muscle hyperpolarization lowers Ca2+ i, resulting in vascular relaxation.
K+ channels and vascular tone. Schematic of a vascular smooth muscle cell (top) and cross sections through an arteriole (bottom) that shows that opening K+ channels leads to diffusion of K+ ions out of the cell, membrane hyperpolarization, closure of voltage-gated Ca2+ channels, decreased intracellular Ca2+, etc (see text), which leads to vasodilatation. Closure of K+ channels has the opposite effect. Modified from Jackson.8
Fig 2 Effect of increased potassium intake on resting systolic blood pressure in adults: by hypertension status and total
Fig 3 Effect of increased potassium intake on resting diastolic blood pressure in adults: by hypertension status and total
Fig 6 Effect of increased potassium intake on resting systolic blood pressure in children. Sinaiko 1993 reported results for boys and girls separately, and Wilson 1996 reported results for two groups separately on basis of their change in blood pressure between waking and sleeping hours during pilot phase of study
The Cardiovascular Health Study (CHS) is a population-based, longitudinal study of coronary heart disease and stroke in adults aged 65 years and older. The main objective of the study is to identify factors related to the onset and course of coronary heart disease and stroke. CHS is designed to determine the importance of conventional cardiovascular disease (CVD) risk factors in older adults, and to identify new risk factors in this age group, especially those that may be protective and modifiable. The study design called for enrollment of 1250 men and women in each of four communities: Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Pittsburgh, Pennsylvania. Eligible participants were sampled from Medicare eligibility lists in each area. Extensive physical and laboratory evaluations were performed at baseline to identify the presence and severity of CVD risk factors such as hypertension, hypercholesterolemia and glucose intolerance; subclinical disease such as carotid artery atherosclerosis, left ventricular enlargement, and transient ischemia; and clinically overt CVD. These examinations in CHS permit evaluation of CVD risk factors in older adults, particularly in groups previously under-represented in epidemiologic studies, such as women and the very old. The first of two examination cycles began in June 1989. A second comprehensive examination will be repeated three years later. Periodic interim contacts are scheduled to ascertain and verify the incidence of CVD events, the frequency of recurrent events, and the sequellae of CVD.
Methods: The study comprised 5,600 men and women older than 65 years who were free of stroke at enrollment. Baseline data included serum potassium level, dietary potassium intake, and diuretic use. Participants were followed for 4 to 8 years, and the incidence and types of strokes were recorded. Low serum potassium was defined as less than 4.1 mEq/L, and low potassium intake as less than 2.4 g/d. Results: Among diuretic users, there was an increased risk for stroke associated with lower serum potassium (relative risk [RR]: 2.5, p 0.0001). Among individuals not taking diuretics, there was an increased risk for stroke associated with low dietary potassium intake (RR: 1.5, p 0.005). The small number of diuretic users with lower serum potassium and atrial fibrillation had a 10-fold greater risk for stroke compared with those with higher serum potassium and normal sinus rhythm. Conclusions: A lower serum potassium level in diuretic users, and low potassium intake in those not taking diuretics were associated with increased stroke incidence among older individuals.
Lower serum potassium was associated with a particularly high risk for stroke in the small number of diuretic users with atrial fibrillation. Further study is required to determine if modification of these factors would prevent strokes.
Table 2 Baseline Characteristics of the Participants According to Study Group.
Figure 1 Kaplan–Meier Estimates of the Incidence of Outcome Events in the Total Study Population. Panel A shows the incidence of the primary end point (a composite of acute myocardial infarction, stroke, and death from cardiovascular causes), and Panel B shows total mortality. Hazard ratios were stratified according to center (Cox model with robust variance estimators). CI denotes confidence interval, EVOO extra-virgin olive oil, and Med Mediterranean.
Table 3 Outcomes According to Study Group.
Fig 4 Association between higher potassium intake and risk of incident cardiovascular disease, stroke, and coronary heart disease in adults
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