Non-dipping in diabetic patients: insights from the siesta.

Non-dipping, ie failure to lower blood pressure during sleep, has been found to be more prevalent in diabetic than in non-diabetic subjects. However, the reasons remain to be clarified. Diabetic patients may wake up more frequently during the night (for instance, due to nocturia). This may result in inclusion of awake blood pressure measurements in the night-time average and thus erroneously raise this average, causing misclassification of patients as non-dippers. However, non-dipping in diabetes may be due to blunted effect of sleep itself on blood pressure secondary to autonomic neuropathy. We undertook this study in order to further clarify this question. We studied 23 diabetic patients, and 23 matched controls who underwent 24-h ambulatory blood pressure monitoring, and reported taking an afternoon nap. Afternoon nap, by virtue of its short duration, is devoid of interruptions, and thus can be used as a model for tiled, non-interrupted sleep. We found that, both in diabetic patients and controls, blood pressure declined during the afternoon nap in a similar magnitude to the night-time decline. However, this decline was significantly blunted in the diabetic patients (13.9 +/- 2.2% decline in diastolic blood pressure during naptime in the diabetic patients, as compared with 24 +/- 2.3% decline in diastolic blood pressure during the siesta in the control group, P < 0.02). The blunted decline of blood pressure during the nap in diabetic patients demonstrates that non-dipping is due to the blunted effect of sleep itself. This can be another facet of autonomic dysfunction seen in diabetes mellitus.

The effect of the fast of Ramadan on ambulatory blood pressure in treated hypertensives.

Every year, millions of Moslems throughout the world fast from sunrise till sunset daily during the month of Ramadan, that is, experience repeated cycles of fasting-refeeding. Studies in animal models have shown that repeated cycles of fasting-refeeding may cause or exacerbate hypertension. Changes in sleeping patterns as well as changes in medication timing may also influence ambulatory blood pressure. We undertook this study in order to examine the effect of the Ramadan fast on treated hypertensive subjects. Seventeen hypertensive subjects were examined, and 24-h blood pressure monitoring was carried out twice, before and during the last week of the Ramadan. All continued their medications, which were all once-daily preparations. Twenty-four hour mean blood pressure as well as average awake and average asleep blood pressure were compared. There was no difference between mean blood pressure before and during the Ramadan (138.5 +/- 18.5/77.2 +/- 8.1 mm Hg vs 136.4 +/- 20.4/75.7 +/- 5.9 mm Hg, P-nonsignificant). Blood pressure load also did not differ before and during Ramadan (systolic load 49% vs. 44%, diastolic load 21% vs. 18%, P-nonsignificant). Weight was reduced by 1.4 +/- 1.6 kg (P < 0.002). We conclude, that according to our findings, treated, hypertensive patients may be assured that, with continuation of previous medications, traditional fasting during the month of Ramadan can be safely undertaken.

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.

Abnormal regulation of cytosolic calcium and pH in platelets of Sabra rats in early phases of salt hypertension development.

Platelet cytosolic free calcium concentration ([Ca2+]i) and pH (pHi) have been reported to be altered in both human essential and rat spontaneous hypertension. The aim of our study was not only to search for the occurrence of such alterations in platelets of rats with salt-induced hypertension but also to investigate whether these changes might precede blood pressure rise in this form of experimental hypertension. Using fluorescent probes fura-2 and BCECF, basal values and thrombin-induced changes of [Ca2+]i and pHi were determined in platelets of young hypertension-prone (SBH) and hypertension-resistant (SBN) Sabra rats fed either low-salt (0.3% NaCl) or high-salt (4% NaCl) diets. Under the conditions of low salt intake, basal [Ca2+]i values were similar in SBH and SBN rats, whereas pHi was significantly lower in SBH than in SBN animals. Thrombin induced smaller [Ca2+]i elevation but greater pHi rise in SBH rats compared with SBN animals. The initial rate of thrombin-induced Mn2+ entry, which reflects the opening of a particular subclass of thrombin-operated Ca2+ channels, was similar in both strains. The moderate hypertension elicited in SBH rats by high salt intake was not associated with major alterations of basal [Ca2+]i or pHi values. High salt diet feeding did not influence [Ca2+]i and pHi responses to thrombin in either strain. In contrast, high salt intake reduced thrombin-induced Mn2+ entry in SBN but not in SBH rats. Basal platelet [Ca2+]i values correlated positively with systolic but not with diastolic blood pressure. This could be ascribed to a very close relationship of basal [Ca2+]i values with pulse pressure. The abnormalities of [Ca2+]i and pHi handling in platelets of Sabra rats with salt-dependent genetic hypertension differ from those described in essential hypertensive patients or rat strains with spontaneous forms of genetic hypertension. Our study also indicated that alterations of platelet [Ca2+]i do not precede blood pressure elevation in salt hypertension.

Development, genotype and phenotype of a new colony of the Sabra hypertension prone (SBH/y) and resistant (SBN/y) rat model of slat sensitivity and resistance.

OBJECTIVES: Variations in the blood pressure response to salt-loading, the lack of quality control measures, and the need to prepare the strains for genetic studies led to renewed secondary inbreeding of the original colony of Sabra hypertension prone (SBH) and resistant (SBN) rats in order to regain genotypic and phenotypic homogeneity of the substrains. METHODS: Animals from the original breeding colony were selectively inbred for basal normotension and for susceptibility or resistance to the development of hypertension following salt-loading with deoxycorticosterone acetate (DOCA)-salt. Efficacy of inbreeding was tested by genome screening with 416 microsatellite primer sets. Phenotyping was based on measurements of systolic blood pressure by the tail-cuff methodology in awake, undisturbed animals maintained on standard diet and after salt-loading with DOCA-salt. Telemetric measurements of blood pressure were performed in a small number of animals to validate tail-cuff measurements. RESULTS: Animals from the new colony were designated SBH/y and SBN/y to differentiate from the original colony. Fourteen generations have been inbred over the past 4 years. Of the 402 microsatellites that amplified, 183 (45.5%) were polymorphic between the two substrains, and not a single locus was found to be heterozygous in either substrain. Phenotypic characteristics are provided for SBH/ y and SBN/y rats with respect to tail-cuff systolic blood pressure. The values obtained, which were validated by telemetry, demonstrate classical features of salt sensitivity or resistance, respectively. CONCLUSIONS: The genetic homogeneity found in SBH/y and SBN/y, the phenotype demonstrating salt-sensitivity or salt-resistance in terms of development of hypertension, and the relatively high frequency of informative genetic markers identify this Sabra rat model as highly suited for studies concerning the molecular genetics of gene-environment interactions affecting blood pressure regulation.

Disparate expression of the AVP gene in Sabra hypertension-prone and hypertension-resistant rats.

We recently re-inbred the original colony of SBH-SBN rats, a model of salt-induced hypertension. In the course of phenotyping the new colony, SBH/y were found to excrete a lower urine flow with a higher urine osmolality than SBN/y. Thus disparate water handling between the substrains, a phenotype characteristic of the original colony, was retained throughout the selection procedure and transmitted down the generations to the new colony. As water handling is directly linked to arginine vasopressin (AVP) and in view of potential linkage of this phenotype to salt sensitivity or resistance in terms of the development of hypertension, the AVP axis was further investigated in the new substrains. Basal plasma AVP levels were higher in SBH/y (2.86 +/- 0.22 pg/ml; n = 10) than in SBN/y (1.98 +/- 0.11 pg/ml; n = 10, P < 0.05). Water deprivation for 48 h increased plasma AVP levels severalfold in both substrains to similar levels. Niravoline, a kappa receptor agonist that inhibits central release of AVP, produced at 0.6 and 0.9 mg/kg a more profound diuretic effect in SBN/y than in SBH/y, suggesting greater pituitary release of AVP into the circulation of SBH/y. AVP mRNA contents were compared in SBH/y and SBN/y rats in whole hypothalamic extracts and in the supraoptic (SON) and paraventricular (PVN) nuclei by RNA protection assay. Under basal conditions, AVP mRNA content (in ng) in the hypothalamus of SBH/y was 4.48 +/- 0.52 (n = 29) and of SBN/y was 3.13 +/- 0.35 (n = 30), P < 0.05; in the SON of SBH/y, AVP mRNA content was 3.62 +/- 0.44 (n = 11) and of SBN/y was 2.21 +/- 0.54 (n = 10), P < 0.05; in the PVN of SBH/y, AVP mRNA content was 0.78 +/- 0.16 (n = 9) and of SBN/y was 0.77 +/- 0.13 (n = 11, not significant). Thus the differences in hypothalamic AVP mRNA were primarily in the SON. Water deprivation as well as salt loading (8% NaCl) induced a significant elevation in AVP mRNA content in SBN/y but a blunted response in SBH/y. These data suggest that there is genetically transmitted enhanced hypothalamic expression of the AVP gene in SBH/y compared with SBN/y which results, under basal conditions, in greater pituitary release of AVP, in higher plasma AVP levels, and in increased renal concentrating activity. As AVP has been implicated in various forms of hypertension, these findings render AVP a candidate gene for salt sensitivity or resistance in the Sabra rat model of hypertension.

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.

The siesta and ambulatory blood pressure: is waking up the same in the morning and afternoon?

We have shown previously that blood pressure (BP) reduction after the siesta is similar to that after night sleep. As cardiovascular events cluster around morning waking hours, when there is a sharp rise of BP and heart rate (HR), the double-product of which is a major determinant of cardiac oxygen consumption, we also investigated changes after the siesta. Twenty-four-hour ambulatory BP monitorings of 156 consecutive patients referred for evaluation of hypertension who reported the siesta (afternoon nap) were analysed. The mean daytime awake BP and HR were 145 +/- 18/80 +/- 10 mm Hg and 71 +/- 11 beats per minute (bpm). During night sleep and the siesta BP decreased significantly (P < 0.00001) to 126 +/- 20/67 +/- 10 and 125 +/- 17/65 +/- 10 mm Hg, respectively. HR decreased during the siesta (69 +/- 11 bpm; P < 0.00001) but even more so (P < 0.00001) during the night (62 +/- 8 bpm; P < 0.00001). When normotensive subjects (n = 38), untreated (n = 33) and treated hypertensives (n = 85) were evaluated separately, they all had similar trends. However, when percentage rise over the sleeping baseline was considered, there were no significant differences in the rise of BP after the siesta and night sleep. The rise in HR for the normotensives and treated hypertensives was 16% and 8%, respectively, higher in the morning than after the siesta (P < 0.0004 and P < 0.001, respectively). The double-product increased significantly more in the morning than after the siesta (both P < 0.0001) in the normotensives (by 20%) and treated hypertensives (by 10%). In untreated hypertensives the rise in HR and double-product was no different between the time periods. In conclusion, there is a higher rise of HR and double-product in the morning. The relatively lower rise after the siesta may indicate a lesser increase in cardiac oxygen consumption and, therefore, lesser potential for acute ischemia.

Chronic exogenous hyperinsulinaemia accelerates the development of hypertension in spontaneously hypertensive rats.

1. An association between hyperinsulinaemia, insulin resistance and hypertension was previously described in spontaneously hypertensive rats (SHR). We therefore tested whether chronic exogenous hyperinsulinaemia, which did not affect blood pressure of normotensive rats, may aggravate hypertension in young SHR. 2. Insulin was administered for 4 weeks by a graded increase of a sustained release insulin implant, without carbohydrate supplementation. 3. Initial bodyweight of seven SHR and five sham-implanted control SHR, aged 6-8 weeks, was not different between the groups or by week 4. 4. Glucose levels decreased in the treated rats [2-way ANOVA F(1:10) = 18.7. P < 0.005] and were 7.3 +/- 0.1 mmol/L in the controls and 4.4 +/- 0.7 mmol/L in the treated SHR, respectively. Insulin levels were comparable at baseline and increased to 1002 +/- 978 pmol/L in treated rats at week 4 while remaining 270 +/- 78 pmol/L in the controls [F(1:10) = 6.1, P < 0.05]. The systolic blood pressure (tail-cuff) was significantly increased in insulin treated SHR in weeks 1-3[F(1:10) = 5.1, P < 0.05] though it was comparable at baseline and week 4. 5. In the presence of a hypertensive predisposition, chronic exogenous hyperinsulinaemia accelerates the time course of the development of hypertension without affecting its severity.

Insulin-induced renal dysfunction in regular Sabra rats.

1. We tested the effects of chronic hyperinsulinaemia on renal function. Hyperinsulinaemia, in the range of 1.5-4 times the control levels, was achieved using a sustained-release insulin implant. Sham-treated rats served as controls. 2. Experiment 1. Acute saline loading: seven sham and seven hyperinsulinaemic rats received an acute saline load (4 mL/100 g). Two h post-load urea and creatinine excretion rats were (mu mol/min) 15 +/- 5 and 9 +/- 4, and 0.17 +/- 0.05 and 0.10 +/- 0.04, respectively; P < 0.05 for both. 3. Experiment 2. Chronic saline loading: 12 sham- and 24 insulin-treated rats drank saline for 8 weeks plus 4% NaCl in the food for 2 more weeks. By week 10 plasma creatinine (mu mol/L) was 62 +/- 12 and 78 +/- 13, and creatinine clearance (mL/min) was 1.9 +/- 0.5 and 1.5 +/- 0.4, respectively; P < 0.05 for both. 4. Experiment 3. Regular diet: 10 sham- and 14 insulin-treated rats had, by week 8, plasma creatinine (mu mol/L) of 75 +/- 34 and 96 +/- 37 and creatinine clearance (mL/min) of 1.260 +/- 0.025 and 0.97 +/- 0.22, respectively; P < 0.02 for both. Bodyweight, resting blood pressure and urinary Na+ and K+ excretion were comparable in sham- and insulin-treated rats. 5. In three experimental settings long-term hyperinsulinaemia was associated with a subtle but significant renal dysfunction. This finding may be related to the aetiology of renal complications of hypertension and diabetes mellitus, both of which are insulin-resistant and hyperinsulinaemic states.

Nitrendipine improves glucose tolerance and deoxyglucose uptake in hypertensive rats.

We assessed the effect of the vasodilating calcium channel blocker nitrendipine on glucose tolerance in young spontaneously hypertensive rats (SHR) (n = 15). The nitrendipine group received 1 g/kg chow for 3 weeks. Untreated SHR (n = 14) served as controls. At 3 weeks body weight was comparable, whereas systolic blood pressure was 157 +/- 9 mm Hg in nitrendipine-treated rats versus 191 +/- 10 mm Hg in controls (mean +/- SD, P < .00001). Fasting glucose was 6.8 +/- 2.7 mmol/L in nitrendipine-treated versus 8.9 +/- 1.5 mmol/L in control rats (P < .03). An intravenous glucose tolerance test (300 mg/kg) showed plasma glucose levels at 2, 5, 15, and 30 minutes to be significantly lower in the nitrendipine-treated group versus controls (two-way ANOVA, P < .03). Glucose utilization was estimated by the uptake of [3H]deoxyglucose after its intravenous administration (2 microCi/100 g body wt) to instrumented awake animals. Heart and striated muscle uptake was, respectively, 7983 +/- 5812 and 951 +/- 731 cpm.microL/g.min in the nitrendipine-treated group versus 3532 +/- 2316 and 424 +/- 201 cpm.microL/g.min in controls (P < .02 and P < .04, respectively). [3H]Deoxyglucose plasma half-life and fasting and post-glucose load insulin levels were comparable in the two groups. The results show that nitrendipine improves glucose tolerance by increasing muscle glucose uptake. We suggest that glucose tolerance in SHR is influenced by muscle blood flow and can be improved by vasodilation.

Siesta and ambulatory blood pressure monitoring. Comparability of the afternoon nap and night sleep.

A prospective analysis of consecutive ambulatory blood pressure monitorings over a 5 month period identified 50 subjects (35%) who took an afternoon nap during the monitoring. The average duration of daytime sleep, as reported by the patients, was 1.8 +/- 0.6 h compared with the reported 7 +/- 2 h for nighttime sleep. Ambulatory blood pressure values during daytime awake periods were significantly higher compared with daytime sleep and nighttime sleep. The blood pressure decline during daytime sleep and nighttime sleep was similar. The pattern of blood pressure changes during daytime sleep was comparable in normotensive (n = 16), untreated (n = 10), and treated hypertensives (n = 24), irrespective of age, gender, and the level of blood pressure. The marked decline in blood pressure during daytime sleep suggests that sleep itself, rather than an endogenous circadian rhythm, is responsible for the blood pressure dip observed during both daytime sleep and nighttime sleep. Ignoring actual sleeping time in people who sleep during the day may greatly distort the day-night ambulatory blood pressure difference, when the latter is calculated on the basis of arbitrarily defined "day" and "night" periods.

Platelet membrane microviscosity in Sabra rats with early salt hypertension.

1. To investigate the possibility that arterial hypertension is associated with changes in the physicochemical properties of cell membranes, we have studied the effects of dietary salt loading on platelet membrane microviscosity in hypertension-prone and -resistant Sabra rats. 2. Sixteen hypertension-prone and 14 hypertension-resistant Sabra rats were submitted to either a low-salt (0.25% NaCl) or a high-salt (4% NaCl) diet for 3-4 weeks. Platelet membrane anisotropy was determined, in the presence and absence of extracellular Na+, using two fluorescent probes, diphenylhexatriene and trimethylamino-diphenylhexatriene, inserted in different areas of the cell membranes. 3. A decrease in diphenylhexatriene anisotropy was demonstrated when platelets of hypertension-prone (but not hypertension-resistant) Sabra rats were suspended in a Na(+)-free medium. This alteration in membrane dynamic properties is localized within the hydrophobic core of the platelet membranes and is independent of salt intake. It reflects an abnormal fluidizing effect of extracellular Na+ removal. 4. Platelets of hypertension-prone and hypertension-resistant Sabra rats did not differ significantly in trimethylamino-diphenylhexatriene fluorescence anisotropy, irrespective of the incubation media used. Extracellular Na+ removal caused an increase in trimethylamino-diphenylhexatriene fluorescence anisotropy in all groups, the change being greatest in salt-loaded rats. 5. This study indicates that platelet membrane microviscosity is specifically altered in the hypertension-prone Sabra rat irrespective of salt intake. This raises the question of the relation of this inherited defect with the susceptibility of this strain to dietary salt loading.

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.

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: 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: It is possible to produce mild hyperinsulinaemia without hypoglycaemia by gradually increasing subcutaneous sustained-release insulin administration without sugar supplementation. Such hyperinsulinaemia is associated with significantly higher glucose, fructosamine and triglyceride levels, and normal tail-cuff and resting intra-arterial blood pressure. Insulin may induce intolerance to acute volume loading that is not associated with Na+ retention.

Comparison of verapamil and captopril in elderly hypertensive subjects: results of a randomized, double-blind, crossover study.

The effectiveness and tolerability of captopril and verapamil SR were compared in a double-blind, crossover study in 23 elderly hypertensives [15 males and 8 females, aged (mean +/- SEM) 68 +/- 1 years]. After 2 weeks of placebo run-in, patients were randomized to a starting dose of captopril, 12.5 mg b.i.d. or verapamil SR, 120 mg q.d. plus matched placebo of the opposite drug. Medication was titrated up over 6 weeks to a maximum dose of 75 mg of captopril or 360 mg of verapamil SR to achieve a sitting diastolic blood pressure of < 90 mm Hg. After 2 weeks of placebo washout, captopril and verapamil were crossed over. In the 20 patients who completed the study, the dose at the end of the respective treatment periods averaged 63 +/- 4 mg of captopril and 270 +/- 21 mg of verapamil SR. Blood pressure at the end of the run-in and washout placebo periods were comparable: 164 +/- 4/97 +/- 1 and 163 +/- 4/98 +/- 2 mm Hg, respectively. However, the blood pressure was significantly lower after verapamil, i.e., 147 +/- 4/86 +/- 2 mm Hg, than after captopril, i.e., 155 +/- 4/90 +/- 1 mm Hg (p < 0.05, ANOVA). There was no significant change in heart rate and laboratory parameters and no orthostatic hypotension. Captopril-treated patients reported a positive change in well being compared with placebo, although there was no overall difference between the drugs in any of the ten quality of life measurements. Three patients discontinued treatment, two because of constipation (verapamil) and one due to lack of efficacy (captopril).(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin resistance in spontaneously hypertensive rats but not in deoxycorticosterone-salt or renal vascular hypertension.

OBJECTIVE: To investigate whether the reported association between insulin resistance and hypertension in spontaneously hypertensive rats (SHR) is a primary defect or a secondary phenomenon in hypertension. DESIGN: Comparisons of glucose metabolism between three groups of hypertensive rats: deoxycorticosterone (DOCA)-salt hypertensive rats; two-kidney, one clip renovascular hypertensive (RVH) rats; SHR; and their respective control groups. There was also an additional group of weight-matched SHR and respective Wistar-Kyoto (WKY) controls. METHODS: A trace amount of 3H-deoxyglucose (3H-DOG) was administered in vivo to evaluate its plasma half-life and tissue uptake. In vitro adipose tissue segments were incubated with 14C-glucose and increasing doses of insulin. RESULTS: Compared with age-matched WKY rats, SHR had significantly higher insulin levels, longer plasma half-life and lower 3H-DOG uptake by heart and striated muscle. Plasma glucose levels and incorporation of 14C-glucose into CO2, triglycerides and glycogen by adipose tissue in response to increasing insulin concentrations was similar for both groups of SHR and WKY rats. No differences were found between hypertensive rats and controls in either the DOCA or RVH groups. CONCLUSION: Evidence of insulin resistance in spontaneous, but not secondary, rat hypertension indicates that the resistance is a primary rather than a secondary event in hypertension.

Improved kidney function with cilazapril in hypertensive type II diabetics with chronic renal failure.

The purpose of this study was to determine efficacy and safety of the angiotensin converting enzyme inhibitor, cilazapril, in the treatment of hypertensive diabetics with renal insufficiency. Fifteen type II diabetics with hypertension and chronic renal insufficiency aged (mean +/- SD) 64 +/- 7 years were studied in a regional clinic and university hospital hypertension unit. The blood pressure was measured biweekly. Urinary collections were done after 2 weeks of placebo and 8 weeks of cilazapril treatment. The blood pressure decreased from 176 +/- 15/105 +/- 9 to 164 +/- 11/95 +/- 9 mm Hg and serum creatinine from 197 +/- 69 to 179 +/- 73 mumol/L. The creatinine clearance rose from 41.6 +/- 11.4 to 47.4 +/- 14.9 ml/min, while protein excretion decreased from 0.8 +/- 1.3 to 0.5 +/- 0.8 g/24 h (p less than 0.05). The blood pressure change was inversely correlated with the creatinine clearance change (r = -0.5, n = 15, p less than 0.05). In these high-risk patients, 8 weeks of cilazapril treatment improved both blood pressure control and renal function but renal function improved most in the patients whose blood pressure changed the least.

Sodium regulation in the affinity of renal alpha 2-adrenoceptors for epinephrine in Sabra salt-sensitive and salt-resistant rats.

Sodium ions markedly decreased in vitro renal alpha 2-adrenoceptor affinity for epinephrine in Sabra hypertensive (SBH) but not in normotensive (SBN) rats. Under these conditions, affinity of alpha 1-adrenoceptor for epinephrine was unchanged in SBH and SBN rats. If these data could be confirmed in vivo, the sodium ion, by acting as an inhibitor, could modify the effect of agonists on renal alpha 2-adrenoceptors in SBH rats. Conversely, the absence of sodium regulation in SBN rats might represent a genetically mediated change responsible for the resistance to the development of salt-induced hypertension.