Masae Tanaka

Chloride-Dominant Salt Sensitivity in the Stroke-Prone Spontaneously Hypertensive Rat

We tested the hypothesis that in the stroke-prone spontaneously hypertensive rat (SHRSP), the Cl− component of dietary NaCl dominantly determines its pressor effect (salt-sensitivity). We telemetrically measured systolic aortic blood pressure (SBP) in SHRSP loaded with: nothing (CTL); NaCl alone (NaCl) (44 mmol/100 grams chow); KCl (KCl) alone (44 mmol); NaCl (44 mmol) combined with KHCO3 (77 mmol) (NaCl/KBC) or with KCl (77 mmol) (NaCl/KCl). Across all groups, from age 10 to 15 or 16 weeks, SBP increased linearly (mm Hg/week) (dp/dt, change in SBP as a function of time): CTL, 5.6; NaCl, 9.5; KCl, 8.8; NaCl/KBC, 9.1; and NaCl/KCl, 14.6. Thus, the value of dp/dt in KCl matched that in NaCl. The value of dp/dt in NaCl/KCl exceeded that in NaCl in direct proportion to the greater Cl− load. Across all groups, only Cl− load bore a direct, highly linear relationship with dp/dt. Strokes occurred only, but always with SBP >250 mm Hg, a value observed almost exclusively in NaCl/KCl. Thus, Cl− dominantly determined the pressor effect induced with dietary NaCl, both with NaCl loaded alone and combined with either KCl or KHCO3, and thereby likely determined the occurrence of stroke with NaCl loading. Over the initial 3-day period of NaCl loading and exacerbating hypertension, external balance of Na+ increased similarly among all groups. However, within 24 hours of initiating NaCl loading, urinary creatinine excretion decreased in direct proportion to dp/dt and urinary Cl− excretion. We conclude that in the SHRSP, the Cl− component of a dietary NaCl dominantly determines salt sensitivity and thereby phenotypic expression. We suggest that Cl− might do so by inducing renal vasoconstriction.

NaCl-Induced Renal Vasoconstriction in Salt-Sensitive African Americans Antipressor and Hemodynamic Effects of Potassium Bicarbonate

In 16 African Americans (blacks, 14 men, 2 women) with average admission mean arterial pressure (MAP, mm Hg) 99.9+/-3.5 (mean+/-SEM), we investigated whether NaCl-induced renal vasoconstriction attends salt sensitivity and, if so, whether supplemental KHCO3 ameliorates both conditions. Throughout a 3-week period under controlled metabolic conditions, all subjects ate diets containing 15 mmol NaCl and 30 mmol potassium (K+) (per 70 kg body wt [BW] per day). Throughout weeks 2 and 3, NaCl was loaded to 250 mmol/d; throughout week 3, dietary K+ was supplemented to 170 mmol/d (KHCO3). On the last day of each study week, we measured renal blood flow (RBF) and glomerular filtration rate (GFR) using renal clearances of PAH and inulin. Ten subjects were salt sensitive (SS) (DeltaMAP >+5%) and 6 salt resistant (SR). In NaCl-loaded SS but not SR subjects, RBF (mL/min/1.73 m2) decreased from 920+/-75 to 828+/-46 (P<0.05); filtration fraction (FF, %) increased from 19. 4+/- to 21.4 (P<0.001); and renal vascular resistance (RVR) (10(3)xmm Hg/[mL/min]) increased from 101+/-8 to 131+/-10 (P<0.001). In all subjects combined, DeltaMAP varied inversely with DeltaRBF (r =-0.57, P=0.02) and directly with DeltaRVR (r = 0.65, P=0.006) and DeltaFF (r = 0.59, P=0.03), but not with MAP before NaCl loading. When supplemental KHCO3 abolished the pressor effect of NaCl in SS subjects, RBF was unaffected but GFR and FF decreased. The results show that in marginally K+-deficient blacks (1) NaCl-induced renal vasoconstrictive dysfunction attends salt sensitivity; (2) the dysfunction varies in extent directly with the NaCl-induced increase in blood pressure (BP); and (3) is complexly affected by supplemented KHCO3, GFR and FF decreasing but RBF not changing. In blacks, NaCl-induced renal vasoconstriction may be a pathogenetic event in salt sensitivity.

Vasodysfunction That Involves Renal Vasodysfunction, Not Abnormally Increased Renal Retention of Sodium, Accounts for the Initiation of Salt-Induced Hypertension.

It has long been recognized that in some people substantially increasing dietary intake of salt (NaCl) increases blood pressure, whereas in others, “salt loading” has little or no effect on blood pressure.1 Blood pressure so affected by salt has been called salt sensitive and salt resistant, respectively. Although the blood pressure response to salt is a continuous variable and the trait of salt sensitivity, like that of hypertension, is arbitrarily defined,2 it has been estimated that 30% to 50% of hypertensive humans are salt sensitive and ≈25% of normotensive humans are salt sensitive.3,4 Salt sensitivity confers an increased risk for the occurrence of hypertension and cardiovascular disease.5–7 Furthermore, pathophysiological mechanisms mediating salt sensitivity may contribute to the risk for cardiovascular disease beyond their effects on blood pressure.5 Accordingly, the mechanisms of salt sensitivity continue to be studied intensively with the hope that better understanding of those mechanisms could lead to improved approaches to the prevention and treatment of salt-induced increases in blood pressure and cardiovascular disease. Response by Hall on p 893 Prevailing theory holds that an abnormally large increase in renal retention of salt8–16 is an early pathophysiological event in the causation of salt sensitivity and salt-induced hypertension. In accord with this theory, it is held that a substantial increase in dietary salt does not induce a pressor effect in salt-resistant subjects because they excrete a salt load more rapidly and retain less sodium than salt-sensitive individuals.12,17 In the present analysis, we challenge this conventional view of salt sensitivity/salt resistance and make the case for a “vasodysfunction” theory for the initiation of salt-induced hypertension: An abnormal vascular resistance response to increases in salt intake, in the absence of an abnormally large increase in renal …

An alternative hypothesis to the widely held view that renal excretion of sodium accounts for resistance to salt-induced hypertension

It is widely held that in response to high salt diets, normal individuals are acutely and chronically resistant to salt-induced hypertension because they rapidly excrete salt and retain little of it so that their blood volume, and therefore blood pressure, does not increase. Conversely, it is also widely held that salt-sensitive individuals develop salt-induced hypertension because of an impaired renal capacity to excrete salt that causes greater salt retention and blood volume expansion than that which occurs in normal salt-resistant individuals. Here we review results of both acute and chronic salt-loading studies that have compared salt-induced changes in sodium retention and blood volume between normal subjects (salt-resistant normotensive control subjects) and salt-sensitive subjects. The results of properly controlled studies strongly support an alternative view: during acute or chronic increases in salt intake, normal salt-resistant subjects undergo substantial salt retention and do not excrete salt more rapidly, retain less sodium, or undergo lesser blood volume expansion than do salt-sensitive subjects. These observations: (i) directly conflict with the widely held view that renal excretion of sodium accounts for resistance to salt-induced hypertension, and (ii) have implications for contemporary understanding of how various genetic, immunologic, and other factors determine acute and chronic blood pressure responses to high salt diets.

Radial Arterial Spasm in Uremic Patients Undergoing Construction of Arteriovenous Hemodialγsis Fistulas: Diagnosis and Prophylaxis with Intravenous Nicardipine

Radial arterial spasm in uremic patients undergoing construction of internal arteriovenous (AV) dialysis fistulas was investigated transcutaneously using ultrasonic Doppler flowmetry. In 5 of 15 patients, radial arterial blood flow was significantly decreased 5 min after anastomosing the radial cephalic vein with the radial artery (14.3 +/- 4.5%, mean +/- SE, of the initial value; p < 0.001 vs. the initial blood flow), indicating vasospasm. Vasospasm disappeared 20 min after anastomosing. In 10 patients who were continuously given nicardipine intravenously (1 microgram/kg/min) during surgery, vasospasm did not occur. Arterial blood flow was significantly increased in patients who received nicardipine as compared with patients who did not receive nicardipine and did not have vasospasm, both at 10 min (171.2 +/- 16.2 vs. 124.3 +/- 11.9%, p < 0.05) and at 20 min (176.5 +/- 17.6 vs. 130.2 +/- 11.2%, p < 0.05) after anastomosing. Mean blood pressure was significantly reduced without causing hypotensive symptoms in patients who received nicardipine as compared with patients who did not receive nicardipine and did not have vasospasm. Our study suggests that ultrasonic Doppler flowmetry is useful for diagnosing vasospasm in patients undergoing the creation of AV fistulas and that nicardipine may be effective in preventing vasospasm safely.

Selective chloride loading is pressor in the stroke-prone spontaneously hypertensive rat despite hydrochlorothiazide-induced natriuresis.

Objective To test the hypothesis that in the stroke-prone spontaneously hypertensive rat (SHRSP), the pressor effect of selective dietary chloride loading depends on a positive external sodium balance. Methods In 43 male SHRSP fed a Japanese style diet containing a low normal amount of NaCl (0.4%), we compared the effects on telemetrically measured SBP of hydrochlorothiazide, 25 mg/kg per day, alone (‘TZ’, n = 11); hydrochlorothiazide combined with either KCl (‘KCLTZ’, 2%K+, n = 10) or KHCO3 (‘KBCTZ’, 2%K+, n = 11) and no hydrochlorothiazide (‘CTL’, n = 11) over a 10-week period starting at 10 weeks of age. Results With either TZ or KBCTZ, SBP did not increase above baseline values. However, KCLTZ induced a sustained increase in SBP of 17 mmHg (P < 0.0001), an increase almost half of that occurring without hydrochlorothiazide (CTL), 38 mmHg (P < 0.0001). Such divergence of blood pressures with KCLTZ and KBCTZ began over the first 3 days of their administration, even while they induced similarly negative external sodium balances, a positive one occurring only in CTL. Body weight increased more without, than with, hydrochlorothiazide, but did not differ between KCLTZ and KBCTZ. Changes in SBP occurring on day 2 after treatment assignment predicted final changes. Conclusion These results demonstrate that in the SHRSP, dietary KCl loading can induce a pressor effect despite concomitant hydrochlorothiazide-induced natriuresis that elicits a negative external sodium balance. The results provide evidence that in the SHRSP the pressor effect of selective chloride loading does not depend on a positive external sodium balance, but rather on a mechanism actuated by chloride per se.