Kanako Kiyohara

High salt intake promotes a decline in renal function in hypertensive patients: a 10-year observational study

We investigated the influence of long-term salt load on renal function in hypertensive patients. The subjects were 133 hypertensive patients (80 women and 53 men, mean age 60±9 years) who underwent at least five successful 24 h home urine collections during the 10-year observation period. Blood pressure (BP) and 24-h urinary salt and creatinine excretion levels were measured. BP decreased from 143±12/85±8 to 129±14/68±11 mm Hg during the 10.5-year observation period, and this decrease was associated with patients taking an increased number of antihypertensive drugs (1.3±1.0 to 2.2±1.1). The estimated glomerular filtration rate (eGFR) also significantly decreased from 71.7±14.6 to 64.7±16.5 ml min−1 (P<0.01), and the change in eGFR was −0.68 ml min−1 per year on average. The average salt excretion was 8.6±2.2 g per day and showed a significant negative correlation with the change in eGFR (r=−0.21, P=0.02). Subjects with an average salt excretion<8 g per day showed a significantly slower decline in renal function than those with an average salt excretion ⩾8 g per day (the change in eGFR: −0.41±1.10 vs. −0.83±1.19 ml min−1 per year, P<0.05). In the multivariate analysis, the average salt excretion (partial r=−0.19, P=0.03) and baseline eGFR (partial r=−0.23, P=0.01) were significantly associated with the change in eGFR. This association was independent of BP change or an increased number of antihypertensive drugs. The results suggest that long-term salt load promotes a decline in renal function in hypertensive patients; thus, salt restriction is encouraged, to prevent renal damage.

Downregulation of Endothelial Transient Receptor Potential Vanilloid Type 4 Channel and Small-Conductance of Ca2+-Activated K+ Channels Underpins Impaired Endothelium-Dependent Hyperpolarization in Hypertension

Endothelium-dependent hyperpolarization (EDH)–mediated responses are impaired in hypertension, but the underlying mechanisms have not yet been determined. The activation of small- and intermediate-conductance of Ca2+-activated K+ channels (SKCa and IKCa) underpins EDH-mediated responses. It was recently reported that Ca2+ influx through endothelial transient receptor potential vanilloid type 4 channel (TRPV4) is a prerequisite for the activation of SKCa/IKCa in endothelial cells in specific beds. Here, we attempted to determine whether the impairment of EDH in hypertension is attributable to the dysfunction of TRPV4 and S/IKCa, using isolated superior mesenteric arteries of 20-week-old stroke-prone spontaneously hypertensive rats (SHRSP) and age-matched Wistar–Kyoto (WKY) rats. In the WKY arteries, EDH-mediated responses were reduced by a combination of SKCa/IKCa blockers (apamin plus TRAM-34; 1-[(2-chlorophenyl)diphenylmethl]-1H-pyrazole) and by the blockade of TRPV4 with the selective antagonist RN-1734 or HC-067047. In the SHRSP arteries, EDH-mediated hyperpolarization and relaxation were significantly impaired when compared with WKY. GSK1016790A, a selective TRPV4 activator, evoked robust hyperpolarization and relaxation in WKY arteries. In contrast, in SHRSP arteries, the GSK1016790A-evoked hyperpolarization was small and relaxation was absent. Hyperpolarization and relaxation to cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine, a selective SKCa activator, were marginally decreased in SHRSP arteries compared with WKY arteries. The expression of endothelial TRPV4 and SKCa protein was significantly decreased in the SHRSP mesenteric arteries compared with those of WKY, whereas function and expression of IKCa were preserved in SHRSP arteries. These findings suggest that EDH-mediated responses are impaired in superior mesenteric arteries of SHRSP because of a reduction in both TRPV4 and SKCa input to EDH.

Influence of salt intake on target organ damages in treated hypertensive patients.

This study investigates the influence of salt intake on renin–angiotensin–aldosterone system and clarifies their role to the target organ damage in the treated hypertensive patients. Subjects were 188 treated hypertensive outpatients (96 females and 92 males, mean age 67 ± 11 y). Patients underwent 24-hour home urine collection to measure urinary salt excretion and proteinuria. Clinical blood pressure (BP) and blood chemistry including plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were determined. Left ventricular mass index (LVMI) was also determined by echocardiography. Average BP was 129 ± 16/68 ± 10 mm Hg with the use of 2.0 antihypertensive drugs on average. Urinary salt excretion, PRA, and PAC were 8.1 ± 3.2 g/day, 2.2 ± 2.8 ng/mL/h, and 112 ± 54 pg/mL, respectively. Even in the patients taking angiotensin receptor blocker or angiotensin-converting enzyme inhibitors (n = 146), 15.1% showed low PRA (<0.5 ng/mL/h) levels and salt excretion in these patients with low PRA (9.1 ± 4.2 g/day) did not differ from those with higher PRA levels (8.2 ± 2.6 g/day, NS). There was no correlation between salt excretion and PRA (r = 0.03, NS), while salt excretion showed a significant negative correlation to PAC (r = −0.17, P < .05). Urinary salt excretion was also correlated with proteinuria (r = 0.25, P < .01) and LVMI (r = 0.16, P < .05). In the multivariate analysis, salt excretion contributed to proteinuria (P < .05) or LVMI (P = .11) independent of age, sex, serum creatinine, and BP levels. Results indicate that PRA levels were relatively low and unaffected by salt intake in Japanese patients treated with antihypertensive drugs. Since high salt intake was possibly associated with target organ damages, strict salt reduction should be encouraged.

Consequence of Masked Hypertension in Treated Hypertensive Outpatients: 1-Year Follow-Up Study

Abstract Since masked hypertension (MHT) is high risk for cardiovascular disease, the importance of home blood pressure (HBP) control is emphasized. The aim of this study was to investigate the prevalence of MHT in the treated hypertensives and the consequence of their BP control status after a 1-year follow up period. Subjects are 262 treated hypertensive outpatients. We assessed BP control status, background characteristics, and antihypertensive drugs in both 2008 and 2009. Clinic BP (CBP) and morning HBP in 2008 were 133 ± 12/73 ± 9 mmHg and 132 ± 11/77 ± 8 mmHg, which significantly decreased to 129 ± 11/70 ± 10 mmHg and 130 ± 10/76 ± 8 mmHg in 2009, respectively (p < 0.01). The patients with sustained hypertension (SHT) decreased from 17.9% in 2008 to 6.9% in 2009. Thirty-four percent of SHT patients in 2008 turned out to be MHT and another 34.0% belonged to normotension (NT) in 2009. Among 79 MHT patients in 2008, 62.0% remained as MHT, while 32.9% turned out to be NT in 2009. The sustained MHT patients were more male and showed a higher prevalence of habitual alcohol intake. Nighttime dosing of antihypertensive drugs and the addition of diuretics were major causes of improving morning HBP. Results suggest that one-third of MHT patients showed the improvement of HBP after the 1-year follow-up period. Not only intensive antihypertensive treatment with the appropriate use of diuretics, but also the encouragement of lifestyle modification including alcohol restriction, seems to be important to the management of MHT.

Trend of Blood Pressure Control Status in Hypertensive Outpatients: With Special Reference to Elderly Hypertensives

Blood pressure (BP) control in hypertensives has improved; however, it still remains to be insufficient. We have investigated the trend in BP control status of the hypertensive patients followed for 10 years in hypertension clinic. Subjects included 133 patients who have been followed from the first visit during 1998–2000 to the last visit during 2008–2010. During the mean follow-up period of 10.5 years, average BP and body weight significantly (P < .01) decreased from 143 ± 12/85 ± 8 mm Hg to 129 ± 14/68 ± 11 mm Hg, and from 59.8 ± 9.9 kg to 58.7 ± 10.6 kg, respectively. The achievement rate of good BP control defined as <140/90 mm Hg and the number of antihypertensive drugs also increased significantly during this period (39.1%–77.5% and 1.3 ± 1.0–2.2 ± 1.1, respectively, P < .01). Blood pressure control improved and the number of antihypertensive drugs also increased in 45 patients who were older than 65 years at the last visit. The use of Ca channel blockers (CCBs), angiotensin II receptor antagonists, and diuretics increased significantly during this period. Results suggest that lifestyle modification including body weight reduction as well as intensive antihypertensive treatment contributed to the improved BP control in hypertensive patients including the elderly.

Impact of serum uric acid on incident hypertension in a worksite population of Japanese men

Objective: Higher levels of serum uric acid are associated with an increased risk of cardiovascular diseases, which may be confounded by comorbidities. We investigated the effects of serum uric acid on the risk of hypertension in Japanese men at a worksite. Methods: We evaluated a total of 2335 Japanese male workers without hypertension who ranged in age from 18 to 64 years at a worksite in 2009. These men were followed for 6 years from 2009 to 2015. Results: During the follow-up period, 380 individuals developed hypertension. The odds ratio for the incident hypertension was estimated according to quartiles of serum uric acid levels of 5.1 or less, 5.2–5.8, 5.9–6.6, and at least 6.7 mg/dl. The multivariable-adjusted risk of incident hypertension was significantly higher in the highest serum uric acid quartile than in the lowest: odds ratio 1.00 (reference) for the lowest quartile, 1.34 (0.91–1.97) for the second quartile, 1.42 (0.97–2.06) for the third quartile, and 1.65 (1.14–2.40) for the highest quartile. In stratified analyses, the association between serum uric acid and incident hypertension was significant in the patients of aged below 45 years and without comorbidities, namely diabetes and low levels of high-density lipoprotein-cholesterol. Conclusions: Serum uric acid levels were associated with the future incidence of hypertension, and the association was observed in the younger individuals, those without diabetes, and those with preserved high-density lipoprotein cholesterol levels in a worksite population of Japanese men.

ISH NIA PS 01-06 Downregulation of endothelial TRPV4 channel contributes to the reduced endothelium-dependent hyperpolarization in genetically hypertensive rats

Objective: Endothelium-dependent hyperpolarization (EDH)-mediated responses are decreased in hypertension. However, the underlying mechanisms have not yet been determined. Several recent studies have suggested that Ca2+ influx through endothelial transient receptor potential vanilloid 4 channel (TRPV4) plays a role in EDH-mediated hyperpolarization via the downstream activation of small- and intermediate-conductance of Ca2+-activated K+ channels (SKCa and IKCa). The present study was designed to elucidate whether the impairment of EDH-mediated responses in hypertension is attributable to the dysfunction of TRPV4 and/or KCa. Design and Method: Conventional electrophysiological and molecular biology techniques were used in isolated superior mesenteric arteries of 20-week-old stroke-prone spontaneously hypertensive rats (SHRSP) and age-matched Wistar-Kyoto (WKY) rats. Results: In the WKY mesenteric arteries, acetylcholine (ACh)-induced, EDH-mediated relaxations were reduced by a combination of KCa blockers (apamin plus TRAM-34), and by the blockade of TRPV4 with the selective antagonist RN-1734 or HC-067047. In the SHRSP mesenteric arteries, the ACh-induced, EDH-mediated hyperpolarization and relaxation were significantly smaller compared with those of WKY. GSK1016790A, a selective TRPV4 activator, evoked robust hyperpolarization and relaxation in WKY arteries. In contrast, in SHRSP arteries, the GSK1016790A-evoked hyperpolarization was small and relaxation was absent. Hyperpolarization and relaxation in response to CyPPA, a selective SKCa activator, were marginally decreased in SHRSP arteries compared with those of WKY. On the other hand, hyperpolarization and relaxation in response to 1-EBIO, a selective IKCa activator, and to levcromakalim, an ATP-sensitive K+ channel opener, were comparable between groups. The expression of endothelial TRPV4 and SKCa protein were significantly decreased in the SHRSP mesenteric arteries compared to those of WKY. Conclusions: These findings suggest that downregulation of endothelial TRPV4 predominantly underpins the reduced ACh-induced, EDH-mediated responses in mesenteric arteries of SHRSP.

Perioperative Blood Pressure Variability in the Treated Hypertensive Patients

Perioperative blood pressure (BP) management is important to prevent cardiovascular complication, especially for hypertensive patients. In the present study, we investigated perioperative BP variability and contributing factors in hypertensive patients. Subjects were 28 treated hypertensive patients who underwent total or subtotal gastrectomy. Ambulatory BP monitoring was carried out before and after (16 days in average) the surgery. Angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and diuretics were withdrawn on the previous day, while other drugs were administered until the day of surgery. BP, body weight, blood chemistry, as well as the use of intravenous vasopressor or vasodepressor agents during the perioperative period were investigated. The 24-hour BP before surgery was 124 ± 19/70 ± 12 mm Hg, and the number of antihypertensive drugs was 1.8. In 22 patients, intravenous vasopressor agents were used during surgery, while another patient received intravenous vasodepressor agents after surgery. The 24-hour BP significantly decreased after surgery (−8.2 ± 14.7/−2.6 ± 7.3 mm Hg). Body weight, serum Na, and hematocrit also decreased. There were nine patients whose 24-hour systolic BP decreased by more than 10 mm Hg and for two patients more than 20 mm Hg. The decrease in BP correlated with the change in serum Na. Forty-three percent of the patients who took ACE inhibitors/ARBs showed BP reduction greater than 10 mm Hg, while 25% of the patients without these drugs showed such BP reduction. Our findings suggest that 24-hour BP decreases after gastrectomy. Patients taking ACE inhibitors or ARBs may need careful monitoring to prevent excessive BP fall.

1052 TRENDS IN SALT INTAKE AND THE ACHIEVEMENT OF SALT REDUCTION IN HYPERTENSIVE PATIENTS

Objectives: We examined chronological changes in salt intake in Japanese hypertensive patients. Methods: Subjects were 1,671 hypertensive patients (mean age 57.6 years; 761 males, 910 females) who visited the division of Hypertension, National Kyushu Medical Center, Fukuoka, Japan from 1998 to 2011. The 24-h urine was collected at home using a proportional urine-sampling device. Subjects collected 24-h urine 3.7 times in average and 6,137 urine samples in total were used for analysis. Results: Mean 24-h salt excretion, blood pressure and proteinuria in 1998 were 9.8 ± 4.0 g/day, 143 ± 11/87 ± 7 mmHg, and 0.6 ± 0.9 g/day, respectively. In 2011, salt excretion decreased to 8.6 ± 3.3 g/day, blood pressure to 129 ± 12/70 ± 12 mmHg, and proteinuria to 0.2 ± 0.7 g/day (p < 0.01). Achievement rate of salt reduction (<6 g/day) in 1998 was 12.6%, which increased to 20.8% in 2011. Salt excretion showed a weak negative correlation with age, and a positive correlation with body weight (r = 0.33, p<0.01). Males (N = 2,759) showed higher salt excretion (10.0 ± 4.0 g/day) than females (8.2 ± 3.2 g/day, N = 3,378). Among 738 patients who collected urine at least twice, subjects who successfully reduced salt excretion to less than 6 g/day at the final measurement (N = 165) showed significant reductions in systolic blood pressure (-13.0 ± 19.4 mmHg vs -9.1 ± 18.2 mmHg, p<0.05) and proteinuria (-0.21 ± 1.06 g/day vs -0.03 ± 0.76 g/day, p<0.05), as compared with those whose salt excretion were consistently higher than 6 g/day (N = 500). Conclusions: Although repeated measurements of 24-h salt excretion are effective to reduce salt intake and blood pressure control in hypertensive patients, further efforts are required to improve the achievement rate of salt reduction.

857 PERIOPERATIVE BLOOD PRESSURE VARIABILITY IN THE TREATED HYPERTENSIVE PATIENTS

Backgrounds: Perioperative blood pressure (BP) management is important to prevent cardiovascular complication, especially for hypertensive patients. In the present study, we investigated perioperative BP variability and contributing factors in hypertensive patients. Methods: Subjects were 25 treated hypertensive patients who underwent total or subtotal gastrectomy. Ambulatory BP monitoring was carried out before and after (16 days in average) the surgery. ACE inhibitors, ARB and diuretics were withdrawn on the previous day, while other drugs were administered until the day of surgery. BP, body weight, blood chemistry as well as the use of intravenous vasopressor or vasodepressor agents during the perioperative period were investigated. Results: The 24-h BP before surgery was 124 ± 19/70 ± 12 mmHg, and the number of antihypertensive drugs was 1.7. In 22 patients, intravenous vasopressor agents were used during surgery while another patient received intravenous vasodepressor agents after surgery. The 24-h BP significantly decreased after surgery (-8.2 ± 14.7/-2.6 ± 7.3mmHg). Body weight, serum Na and hematocrit also decreased. There were 9 patients whose 24-h systolic BP (SBP) decreased more than 10 mmHg and 2 patients more than 20 mmHg. The decrease in BP correlated with the change in serum Na. The 47 % of the patients who took ACE inhibitors/ARB showed BP reduction greater than 10 mmHg, while 20 % of patients without these drugs showed such BP reduction. Conclusions: Our findings suggest that 24-h BP decreases after gastrectomy. Patients taking ACE inhibitors or ARB tended to show greater BP reduction and thus need careful monitoring to prevent excessive BP fall.