Drori Ben-Ishay

Predictors of All-Cause Mortality in Clinical Ambulatory Monitoring: Unique Aspects of Blood Pressure During Sleep

The prognostic value of sleep blood pressure reported by recent studies is variable. Our aim was to examine the relationship of sleep blood pressure, measured by 24-hour ambulatory blood pressure monitoring, with all-cause mortality. We studied a cohort of 3957 patients aged 55±16 (58% treated) referred for ambulatory monitoring (1991–2005). Sleep, including daytime sleep, was recorded by diary. Linkage with the national population register identified 303 deaths during 27 750 person-years of follow-up. Hazard ratios (HRs) for mortality in Cox proportional hazards models that included age, sex, hypertension, and diabetes treatment were 1.32 (95% CI: 0.99 to 1.76) for awake hypertension (≥135/85 mm Hg), and 1.67 (95% CI: 1.25 to 2.23) for sleep hypertension (≥120/70 mm Hg). By quintile analysis, the upper fifths of systolic and diastolic dipping during sleep were associated with adjusted HRs of 0.58 (95% CI: 0.41 to 0.82) and 0.68 (95% CI: 0.48 to 0.96), respectively. In a model controlling for awake systolic blood pressure, hazards associated with reduced systolic dipping increased from dippers (>10%; HR: 1.0), through nondippers (0% to 9.9%; HR: 1.30; 95% CI: 1.00 to 1.69) to risers (<0%; HR: 1.96; 95% CI: 1.43 to 2.96). Thus, in practice, ambulatory blood pressure predicts mortality significantly better than clinic blood pressure. The availability of blood pressure measures during sleep and, in particular, the pattern of dipping add clinically predictive information and provide further justification for the use of ambulatory monitoring in patient management.

Nitric Oxide and the Regulation of Blood Pressure in the Hypertension-Prone and Hypertension-Resistant Sabra Rat

We examined the role of nitric oxide (NO) in the inherited resistance or susceptibility to hypertension in the Sabra hypertension-prone (SBH) and hypertension-resistant (SBN) rat. Basal mean arterial blood pressure was significantly greater in SBH than in SBN rats. Phenylephrine elevated blood pressure to a similar extent in both substrains, whereas the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) had a greater pressor effect in SBN rats. The vasoconstrictor potency of phenylephrine was significantly higher in endothelium-intact aortic rings from the SBH rat, whereas the vasoconstrictor potency of L-NMMA was higher in those from the SBN substrain. Acetylcholine-induced endothelium-dependent relaxation was greater in aortic rings from SBN rats. The vasodilator potency of glyceryl trinitrate was significantly higher in aortic rings from SBH rats and was enhanced after endothelium removal. Both the activity of calcium-dependent NO synthase from aortic endothelial cells and the basal concentration of nitrite/nitrate in plasma were significantly greater in SBN than in SBH rats. In normotensive Wistar rats, basal mean arterial blood pressure, the pressor effect of L-NMMA, endothelial NO synthase activity, and plasma nitrite/ nitrate concentrations were all between the values in SBH and SBN rats. These results indicate that a decrease in NO generation plays a role in the susceptibility of SBH rats to hypertension. Furthermore, the resistance to hypertension in the SBN strain may be related to increased NO generation.

Increased erythrocytes sodium efflux in genetic hypertensive rats of the Hebrew University strain

Nous avons étudié le flux du sodium (Na22) dans des hématies provenant de 2 souches de rats obtenues par croisement consanguin et possédant une susceptibilité

Calcium channel blockers in the management of hypertension in the elderly

Calcium channel blockers seem to be particularly suitable for elderly hypertensive patients since these agents do not cause salt and fluid retention, postural hypotension, sedation, depression, or biochemical abnormalities. Moreover, their use is compatible with several common diseases of old age, such as diabetes, obstructive lung disease, and peripheral vascular disease. We recently conducted a study in 21 patients (average age, 79 +/- 2 years) who completed an eight-week trial with 20-mg nifedipine tablets taken twice daily. Mean blood pressure decreased from 191 +/- 2/96 +/- 2 mm Hg to 151 +/- 4/80 +/- 3 mm Hg. In 15 patients (71 percent), blood pressure decreased to less than or equal to 160/90 mm Hg; in four additional patients (19 percent), diastolic blood pressure decreased by 15 to 25 percent. Thus, there was a sustained lowering of blood pressure in 90 percent of the participants receiving nifedipine monotherapy. A review of recent studies in elderly hypertensive patients revealed similarly favorable results with calcium channel blockers given alone or in combination with other agents. The accumulating data suggest that these compounds may offer a useful new approach to the treatment of hypertension in old age. However, in these studies, the number of patients and the duration of follow-up need to be extended to confirm the favorable impression obtained thus far.

Disparate effects of exercise training on glucose tolerance and insulin levels and on ambulatory blood pressure in hypertensive patients

Objective: To assess the relationship of insulin levels and glucose tolerance to blood pressure in hypertension. Design: An open, prospective trial of exercise training with ambulatory blood pressure monitoring and intravenous glucose tolerance testing before and after a 14-week training programme. Patients: Twenty sedentary, untreated, non-obese, normoglycaemic individuals of both sexes with uncomplicated essential hypertension, of whom 16 completed the study. Intervention: Fourteen weeks of supervised, low-intensity, group exercise of three 1-h sessions per week. Main outcome measures: Ambulatory and clinic blood pressure, and glucose and insulin responses to an intravenous glucose tolerance test. Results: Maximal work capacity on a bicycle ergometer increased by 20% (P < 0.001); 24-h ambulatory blood pressure was 143 ± 12/87 ± 5 mmHg before and 142 ± 13/87 ± 7 mmHg after training. Clinic blood pressure decreased from 166 ± 14/103 ± 5 mmHg to 157 ± 12/99 ± 6 mmHg (P < 0.03). Two-way analysis of variance indicated significant decreases in both glucose (P < 0.04) and insulin (P < 0.03), fasting and throughout the intravenous glucose tolerance test. Conclusions: Although mild exercise reduced clinic blood pressure significantly, it did not affect ambulatory blood pressure despite a marked reduction in glucose and insulin levels. This finding argues against a determinant role of insulin in the 24-h maintenance of blood pressure in hypertensive patients under the conditions of the study.

Water handling by the sabra hypertension prone (SBH) and resistant (SBN) rats

The renal handling of water by SBH and SBN rats was evaluated under basal conditions and following various intervention procedures. During 17 weeks of unrestricted water intake, SBH rats drank less water and excreted less urine with a higher osmolality than SBN. The differences in urine volume and osmolality persisted during 2 weeks of paired water intake. Acute water loading elicited comparable dilution of the urine in the two strains. Water deprivation for 48 h resulted in a marked rise in urine osmolality, which tended to be higher in SBN. Administration of exogenous vasopressin in water loaded animals caused a similar rise in urine osmolality. Papillary solute and urea content was higher in SBH than in SBN, but comparable in water loaded animals. The results show that although SBH differ from SBN rats in the handling of water under basal conditions, their renal diluting and concentrating capacity is comparable at extreme conditions. GFR and RBF were equal in both strains. The data suggest that SBH rats have increased renal water reabsorption as compared to SBN, which may be mediated by ADH, PG or other mechanisms. This characteristic may be related to their propensity to develop hypertension.

Experimental hypertension and catecholamine distribution in the rat brain

Hypertension was induced in rats (Hebrew University strain) by three different procedures: (1) deoxycorticosterone acetate (DOCA)--salt treatment; (2) unilateral renal artery clip or (3) chronic salt-loading. Noradrenaline (NA) and dopamine (DA) distribution in different brain areas was assayed following induction of hypertension. NA content increased significantly in various areas: the increase of NA in the pons-medulla was common to all procedures inducing hypertension. NA content increased also in the mesencephalon, the hypothalamus and the rest of the forebrain (DOCA--salt hypertension), in the mesencephalon, the hypothalamus and the cortex (in renal clip hypertension). No significant changes in DA content were observed in any region of the brain following induction of hypertension by the three different methods. In two substrains, selected from the Hebrew University strain, for their respective sensitivity (H) or immunity (N) to hypertension induced by DOCA--salt treatment, there were no significant increases in NA or DA in any part of the brain following DOCA--salt treatment. Comparison of NA concentrations in these strains showed that NA was significantly higher in the pons-medulla of the untreated N strain rats than in the medulla of untreated H strain or in untreated rats of the original strain (Hebrew University). A model is presented suggesting that central NA-containing neurons plays a major role in controlling hypertension.

Sodium chloride preference in hypertensive (H) and normotensive (N) rats.

SummarySalt consumption was compared in two strains of rats, selected for their disparate proneness (strain “H”) or resistance (strain “N”) to Doca-salt hypertension.NaCl intake was similar in “H” and “N” rats prior to an following administration of Doca, while their respective blood pressures at the end of this experiment was 178±5 mm Hgvs. 134±3 mm Hg. Thus, disparate responses of the blood pressure to Doca in the two strains cannot be ascribed to differences in salt intake.In another study, salt preference was tested in “H” and “N” rats by two-bottle self-selecting technique. Before Doca, saline preference in “H” rats averaged 60.3±5.8% of total daily fluid consumption,vs 18±4.2% in “N” rats. Following Doca treatment for 3 weeks the respective values were 96±1.7%vs. 67±6.6%. Thus Doca treatment enhanced salt appetite in both strains, but salt preference remained significantly higher in the “H” rats.The increased susceptibility to hypertension and the enhanced salt appetite in the “H” rat, corroborates similar reports in the Okamoto “SH” rat. In the Brookhaven “S” rat, however, susceptibility to hypertension is associated with salt avoidance. The conflicting data do not support a unified concept of a genetically determined link between salt appetite and proneness to hypertension.

Effect of Acute N-Nitro-l-Arginine Methyl Ester (L-NAME) Hypertension on Glucose Tolerance, Insulin Levels, and [3H]-Deoxyglucose Muscle Uptake

This study was conducted to test the hypothesis that acute, widespread N-nitro-L-arginine methyl ester (L-NAME) induced vasoconstriction and hypertension may affect glucose tolerance and insulin sensitivity in normal rats. Comparisons were made of blood pressure, intravenous glucose tolerance, and insulin response and [3H]-deoxyglucose tissue uptake between L-NAME and control treated rats. Chronically instrumented, awake rats were administered L-NAME (30 mg/kg) (n = 8) or saline (0.3 mL) (n = 8) intravenously. After blood pressure stabilized, a bolus injection containing glucose (300 mg/kg) and trace [3H]-deoxyglucose was administered. Arterial blood was sampled for evaluation of glucose tolerance, insulin response, and [3H]-deoxyglucose muscle uptake. L-NAME treated rats had a persistent 54 +/- 4 mm Hg blood pressure rise while fasting, and postload plasma glucose and insulin responses did not differ, nor did heart and striated muscle [3H]-deoxyglucose uptake differ. In conclusion, acute L-NAME induced hypertension does not result in glucose intolerance, hyperinsulinemia, or decreased [3H]-deoxyglucose muscle uptake.

Chronic exogenous hyperinsulinaemia without sugar supplementation: acute salt-sensitive hypertension without changes in resting blood pressure.

Objective: To study the effects of chronic insulin administration without sugar supplementation on blood pressure and response to acute saline loading in normal rats. Design: Design: Comparison of blood pressure, insulin and glucose levels in 24 insulin-treated and 12 control rats on regular rat chow (not supplemented with sugar). Methods: Sustained-release insulin implants (or sham implantation for the control rats) were administered subcutaneously. The sustained-release insulin implant size was gradually increased. Tail-cuff systolic blood pressure, insulin and glucose were measured twice a week for 8 weeks, after which intra-arterial blood pressure was recorded under resting conditions and 2 h after saline loading in seven insulin-treated and seven control rats. Results: Insulin-treated rats had a 1.2- to twofold increase in insulin without hypoglycaemia, a small but significant increase in glucose levels being found at weeks 6 and 8. When the rats were killed (week 8) triglyceride and fructosamine levels were increased in the insulin-treated rats in comparison with controls. Neither tail-cuff systolic blood pressure nor resting intra-arterial blood pressure differed between the two groups. However, acute saline loading resulted in significantly higher blood pressure in the insulin-treated rats, without altering renal Na+ excretion. Conclusions: Insulin-treated rats had a 1.2- to twofold increase in insulin without hypoglycaemia, a small but significant increase in glucose levels being found at weeks 6 and 8. When the rats were killed (week 8) triglyceride and fructosamine levels were increased in the insulin-treated rats in comparison with controls. Neither tail-cuff systolic blood pressure nor resting intra-arterial blood pressure differed between the two groups. However, acute saline loading resulted in significantly higher blood pressure in the insulin-treated rats, without altering renal Na+ excretion.