Intrauterine growth restriction and shallower implantation site in rats with maternal hyperinsulinemia are associated with altered NOS expression.

Nitric oxide synthase (NOS) plays an important role in hypertensive disorders of pregnancy. In the context of the known association between hyperinsulinemia and hypertension, we studied the expression of the 3 isoforms of NOS (neuronal-nNOS, inducible-iNOS, and endothelial-eNOS) in the placenta and implantation site of our insulin-induced intrauterine growth restriction (IUGR) rat model in which the normal gestational blood pressure decline is abrogated. The fetuses of hyperinsulinemic dams were significantly smaller than those of normal pregnant dams (male fetal weight=4.8+/-0.5 g vs. 5.4+/-0.4 g, hyperinsulinemic vs. control, respectively; female fetal weight=4.5+/-0.5 g vs. 5.1+/-0.4 g, hyperinsulinemic vs control, respectively, p<0.0001). Their placentas weighed less than those of normal pregnant dams (0.44+/-0.08 g in hyperinsulinemic dams vs. 0.50+/-0.09 g, p<0.0001) and their implantation site, designated the mesometrial triangle, was also smaller. Endovascular trophoblasts were found more often and in greater depth in normal pregnant dams. Possibly as a compensatory mechanism, the endovascular trophoblasts formed cell groups rather than a monolayer and occupied a larger portion of the arterial perimeter in arteries of hyperinsulinemic dams. iNOS expression increased by 80% (p<0.0001) and 180% (p=0.045) in placenta and mesometrial triangle of hyperinsulinemic dams, respectively. The expression of eNOS was reduced by 17% (p=0.048) in the placenta and did not change significantly in the mesometrial triangle (p>0.05). nNOS expression was decreased by 37% (p=0.03) in the placenta and increased by 53% (p=0.035) in the mesometrial triangle of hyperinsulinemic dams. Immunohistochemistry revealed prominent expression of iNOS in the placental junctional zone and in interstitial and endovascular trophoblasts in the mesometrial triangle. Assuming a role in trophoblastic invasion, the increased expression of iNOS in hyperinsulinemic dams explains the "compensatory" pattern of trophoblastic invasion. Expression of eNOS was prominent in endothelial cells and weak in endovascular trophoblasts. In our model of gestational hyperinsulinemia-induced IUGR, we found not only differing expression of the 3 NOS isoforms in the cellular elements of the placenta and mesometrial triangle, but also divergent modes of altered NOS isoform expression. These findings suggest, in accordance with other publications, that each isoform may have a distinct function in the placenta and placental bed. The differing expression of the 3 NOS isoforms in the placenta and in the mesometrial triangle in rat IUGR seems to result from the hyperinsulinemia and the resulting IUGR phenotype.

A modified ambulatory arterial stiffness index is independently associated with all-cause mortality.

Dependence of the ambulatory arterial stiffness index (AASI) on data scattering interferes with its potential clinical relevance. We assessed the correlates and all-cause mortality associations of a modified AASI (s-AASI). AASI was derived from the 24-h diastolic vs. systolic blood pressure linear regression line, whereas s-AASI was derived by symmetric regression (bisecting the line of diastolic vs systolic and systolic vs. diastolic). Of 2918 patients 55% were women; age was 56 +/- 16 years and body mass index was 27.3 +/- 4.5 kg/m(2). Average 24-h ambulatory blood pressure was 138 +/- 16/78 +/- 10 mm Hg. Applying the modified method for calculating AASI yielded a different measure: the negative correlation between AASI and blood pressure dipping (r = -0.304, P < 0.0001) was abolished (r = +0.223, P < 0.0001), s-AASI was more dependent on age (r = 0.266 vs. r = 0.089 for AASI), and prediction of all-cause mortality was enhanced; hazard ratio (95% confidence intervals) 1.17 (1.00-1.36) per 1 s.d. increase in s-AASI in the fully adjusted model as compared with 1.15 (0.97-1.36) for AASI.

Normal ambulatory blood pressure: a clinical practice-based comparison of two recently published definitions.

The European Society of Hypertension (ESH) has issued guidelines for the detection and treatment of hypertension. According to these guidelines, normal 24-h ambulatory blood pressure (ABP) is defined as lower than 125/80 mmHg. Another publication of ESH recommendations for blood pressure (BP) measurement defines normal awake and asleep blood pressure as lower than 135/85 and 120/70 mmHg, respectively. Our aim was to investigate the compatibility of these two recently proposed ABP cutoffs in clinical practice. We analysed 1495 consecutive ABP measurements. In all, 56% of the subjects were female; age 58 +/- 16 years; body mass index 27 +/- 4 kg/m(2); clinic BP 151+/-22/84 +/- 13 mmHg. Two-thirds were treated for hypertension, and 11% for diabetes. Subjects were classified as having normal 24-h BP if the corresponding value was <125/80 mmHg. Normal awake-sleep BP was diagnosed if awake BP was <135/85 mmHg and sleep BP was <120/70 mmHg. Concordance between the cutoffs was found in 93% of the subjects. Among the 7% discordant subjects, 4.5% were hypertensive applying the 24 h, but not awake-sleep, BP values, whereas only 2.5% were hypertensive according to awake-sleep, but not 24 h, BP values (P < 0.005). In Conclusion, in real-life ABP measurement, a good agreement was found between two recently issued ABP normality definitions. However, some subjects are classified as hypertensive only according to one of these methods, more often by the 24-h cutoff of 125/80. This discordance may be significant in large-scale clinical BP monitoring.

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.

Dipping status may be determined by nocturnal urination.

Nondipping, ie, failure to reduce blood pressure by >/=10% during the night, is considered an important prognostic variable of 24-hour ambulatory blood pressure monitoring. However, some people wake up at night to urinate. Usually, 24-hour ambulatory blood pressure monitoring-derived blood pressure includes these rises in the nighttime blood pressure mean. We identified 97 subjects undergoing 24-hour ambulatory blood pressure monitoring who reported waking up at night to urinate. We assessed the 24-hour ambulatory blood pressure monitoring first using total daytime and total nighttime means and then using actual daytime awake and nighttime asleep (as reported by the patient) means. Nocturnal decline in blood pressure was 14.4+/-8.5/11.8+/-6.1 mm Hg with the first method and 17.1+/-8.3/13.8+/-5.9 mm Hg with the second one (P<0.00001). Although the absolute difference between the nocturnal blood pressure declines calculated by the 2 methods was small, the effect on nocturnal dip was profound. Average systolic blood pressure dipping was 10.1% by the total day-total night method and 12.0% by the actual day awake-night asleep method (P

Atrophy or hypertrophy in chronic renal ischemia: role of the IGF-I system.

To examine the role of insulin-like growth factor-1 (IGF-1) in renal atrophy of rats with two-kidney, one-clip (2K1C), in which the clipped kidney atrophies, and in the one-kidney, one-clip (IK1C) model of renovascular hypertension, in which it hypertrophies, we studied levels of IGF-I, mRNA, and protein in 2K1C, IK1C, and unilateral nephrectomy (NPX) in rats by solution-hybridization RNase protection, and radioimmunoassay, respectively, both cross-reactively and longitudinally at 3, 10, and 30 days after clipping. Three days after clipping, there were no differences in blood pressure or kidney size; however, 10 and 30 days postoperation, the clipped kidney shrank in the 2K1C model. The nonclipped 2K1C and the clipped lK1C and unilateral nephrectomy kidneys increased in weight (P < .05. At day 3 the IGF-I levels were lower (557 +/- 54, 335 +/- 61 ng/g in control and clipped 2K1C, P < .05, v 1,074 +/- 186, 1,109 +/- 54, and 1,154 +/- 200 ng/g kidney, nonclipped 2K1C, 1K1C, and NPX, respectively). At 30 days the IGF-I levels were 300 +/- 24 ng/g in control (P < .05) v clipped 2K1C, 160 +/- 19, 218 +/- 20 ng/g in nonclipped 2K1C and 406 +/- 33 and 470 +/- 34 ng/g in 1K1C and NPX, respectively (P < .05) v control and clipped 2K1C. Kidney mRNA was increased in the clipped 2K1C. In conclusion, the kidney that had higher IGF-I levels early in nonclipped 2K1C, 1K1C, and nephrectomy hypertrophied, and the kidney (clipped 2K1C) that failed to increase IGF-I atrophied. IGF-I levels are dissociated from the local mRNA message.

Subpressor dose of L-NAME unmasks hypertensive effect of chronic hyperinsulinemia.

We previously found that chronic exogenous hyperinsulinemia without sugar supplementation does not elevate blood pressure. This may be partially explained by the ability of insulin to release nitric oxide and cause vasodilatation. To test this hypothesis, we studied 4 groups of rats: 9 rats (body weight, 213+/-14 g) treated with a gradual increase of a sustained-release subcutaneous insulin pellet; 9 rats (body weight, 213+/-9 g) treated with N:(G)-nitro-L-arginine methyl ester (L-NAME) in drinking water 50 mg/L; 19 rats (body weight, 217+/-11 g) treated with the combination of L-NAME and insulin; and 9 control rats (body weight, 218+/-11 g). Blood pressure was followed weekly for 6 weeks, and then rats were studied in metabolic cages. Weight gain was not different during the 6 weeks. Renal function did not differ between the 4 groups, but 24-hour urinary nitrite/nitrate excretion was lower (P<0.02) in L-NAME-treated and higher in insulin-treated rats. Plasma insulin doubled (P<0.002) in the insulin-treated rats, but there was no hypoglycemia and, by week 6, fructosamine levels were 2.1+/-0.2, 2.1+/-0.2, 2.3+/-0.1, and 2.3+/-0.2 mmol/L in control rats and rats treated with L-NAME, insulin, and L-NAME plus insulin, respectively. Systolic blood pressure, which did not differ at baseline, at week 3 was 122+/-17, 118+/-17, and 118+/-24 mm Hg in the control, L-NAME, and insulin groups and 136+/-14 mm Hg (P<0.03) in the combination group. At week 6, systolic blood pressure was 128+/-14, 127+/-15, and 118+/-13 mm Hg in the control, L-NAME, and insulin groups, respectively, and 150+/-14 mm Hg (P<0.0005) in the combination group. In a subsequent experiment, L-arginine 2 g/L abrogated the effects of L-NAME and insulin combination. In conclusion, chronic exogenous hyperinsulinemia does not affect blood pressure but may cause hypertension when endothelial function is compromised.

Chronic exogenous hyperinsulinemia in pregnancy: a rat model of pregnancy-induced hypertension.

Insulin resistance and hyperinsulinemia are associated with essential hypertension. There is also evidence of hyperinsulinemia in women who developed hypertension in pregnancy (P). The present study examines whether chronic hyperinsulinemia in pregnant rats plays a role in the development of hypertension in pregnancy. A sustained-release insulin pellet was implanted subcutaneously in 15 Wistar rats (P-INS) 1 wk before and on day 7 of pregnancy; 14 control rats were sham-implanted (P-SHAM). Tail-cuff systolic BP (SBP), serum triglycerides, glucose, insulin, renal function, and urinary excretion of Na+ and of metabolites of nitric oxide were determined throughout pregnancy. Data were analyzed by ANOVA with basal body weight as covariate analysis of covariance. Results are expressed as the mean +/- SD. Body weight; water and food intake; urine volume; creatinine clearance; and level of proteinuria at the end of pregnancy were similar in both groups. The number of fetuses was 9 +/- 2.3 in P-INS versus 11 +/- 2.4 in pregnant control rats (P < 0.05). Before mating, SBP was similar, but at the end of pregnancy SBP was 110 +/- 18 mmHg in P-INS versus 85 +/- 12 mmHg in pregnant rats (P < 0.05). Serum triglycerides and Na+ were also higher in P-INS rats. The fractional excretion of Na+ was 3.1 +/- 1.0 versus 4.4 +/- 1.5, respectively (P < 0.01). The percent increase in nitric oxide metabolite excretion was 233 +/- 14 versus 370 +/- 17%, respectively (P < 0.01). Chronic hyperinsulinemia, without sugar supplementation, and hypertriglyceridemia may cause a decrease in the synthesis of nitric oxide in P-INS rats. The development of hypertension in these rats may be associated with an impaired vasodilatation, together with an increased renal sodium reabsorption.

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.

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.

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.

Acute hypertensive response to saline induced by vanadate, an insulinomimetic agent.

OBJECTIVE: To investigate whether the reported insulin-like properties of vanadate may have hypertensinogenic actions in Sabra rats. DESIGN: Comparison of [3H]-deoxyglucose muscle uptake as well as blood pressure and its response to acute volume expansion and pressors infusions in 16 vanadate-treated (VT) and 12 control rats. METHODS: Rats drank either tap water or 0.2 g/l vanadate for 4 weeks. A trace amount of [3H]-deoxyglucose was administered intravenously to evaluate its plasma half-life and tissue uptake. Intra-arterial blood pressure was recorded in response to acute intravenous saline (4 ml/100 g body weight) and to incremental bolus injections of noradrenaline and angiotensin II (Ang II). RESULTS: Skeletal muscle uptake of [3H]-deoxyglucose was significantly higher in VT than in control rats. There was no difference between the blood pressure of VT or control rats; however, 2 h after saline loading the mean intra-arterial blood pressure was significantly higher in VT than in control rats. The Ang II-induced blood pressure rise was also significantly higher in VT rats. CONCLUSION: The insulin-like activity of vanadate may be associated with salt-sensitive hypertension.

Cardiac hypertrophy developing during DOCA-salt treatment is dissociated from systemic and regional hemodynamics.

Systemic and regional hemodynamics were studied in DOCA-treated Sabra hypertensive (SBH) and normotensive (SBN) rats. In SBH rats, mean arterial pressure (MAP) and total peripheral resistance index (TPRI) increased significantly. In SBN rats, MAP remained stable and TPRI decreased. Cardiac output and heart rate were unchanged. Opposed changes in TPRI were mediated mainly by changes in vascular resistance of the skin, skeletal muscles and splanchnic organs. Both strains developed significant biventricular hypertrophy. We conclude that SBH and SBN rats' susceptibility or resistance to DOCA-salt hypertension are associated with opposed changes in TPRI. The development of biventricular hypertrophy is apparently dissociated from systemic hemodynamic changes.

Effects of DOCA-salt treatment on the urinary prostaglandins in Sabra rats.

To determine whether the increased renal synthesis of thromboxane (Tx)A2 found in genetically hypertensive rats also occurred in rats with a sodium-dependent form of hypertension, the urinary excretion of 6-keto-prostaglandin F1 alpha (6KPGF1 alpha) and of TxB2 was measured by a sensitive and specific radioimmunoassay in hypertension-prone (SBH), -resistant (SBN) and unselected (SB) female rats of the Sabra strains. Rats of the three strains were studied before (9 weeks of age) and after five weeks of deoxycorticosterone (DOCA)-salt treatment. Before treatment, the urinary 6KPGF1 alpha did not differ among the three strains while a higher TxB2 excretion was seen in the SBN rats. After treatment, the urinary excretion of TxB2 increased significantly in SBH and SB but not in SBN rats, while the urinary 6KPGF1 alpha remained unchanged in SBH, increased moderately in SB and markedly in SBN controls. Consequently, DOCA-salt-induced changes in blood pressure and in urinary 6KPGF1 alpha observed in the three strains of rats were inversely related (r = -0.78; P less than 0.001). It is concluded that the high blood pressure developed after DOCA-salt treatment in SBH rats is more likely to depend upon a defect in the renal production of prostacyclin rather than upon an increased synthesis of thromboxane A2.

Nitrendipine prevents the development of cardiac hypertrophy in DOCA-salt-treated hypertension-prone (SBH) and -resistant (SBN) rats through nonhemodynamic mechanisms.

Recent studies indicate that cardiac and renal hypertrophy develop during desoxycorticosterone acetate (DOCA)-salt (DOC) treatment in hypertension-prone (SBH) and -resistant (SBN) rats, irrespective of systemic hemodynamic changes. The effect of nitrendipine on the development of left and right ventricular hypertrophy (LVH and RVH, respectively) was evaluated in 16-week-old rats. Members of each strain were divided into six groups (n = 10): 1--control; 2--nitrendipine treated for 3 weeks; 3, 4, and 5--DOC for 10 days, 3 weeks, and 6 weeks, respectively; 6--DOC for 6 weeks and nitrendipine for the last 3 weeks. Cannulae were inserted into the left ventricle and abdominal aorta. The radioactive reference sample microsphere technique was used to measure cardiac index. Mean arterial pressure (MAP) and total peripheral resistance index (TPRI) were unchanged in all six groups of SBN rats, whereas MAP and TPRI increased progressively in the DOC-treated SBH groups. Concomitant administration of nitrendipine in Group 6 was associated with a reduction of MAP and TPRI to control levels. Cardiac index and heart rate did not change in any group. Despite the different hemodynamic changes, both SBH and SBN rats developed LVH and RVH. The concomitant administration of nitrendipine prevented the progression of LVH and allowed regression of RVH in both strains. It is concluded that nitrendipine can affect the pathogenesis of LVH through nonhemodynamic mechanisms.