How early should blood pressure control be achieved for optimal cardiovascular outcomes?

As a consequence of the aging population and the increasing prevalence rates for conditions such as type 2 diabetes and chronic kidney disease (CKD), management of hypertension will be focusing more and more on the high-risk patient. Clinical practice guidelines for managing hypertension in the United States recommend a target blood pressure (BP) <130/80 mm Hg in patients with diabetes or CKD, notably lower than the 140/90-mm Hg threshold for the general hypertensive population. However, the optimal timeframe from initiation of antihypertensive therapy to attaining these levels of BP control and influencing cardiovascular outcomes is not as well defined. Overall, a series of landmark BP intervention trials in patients with hypertension and additional cardiovascular risk factors collectively support that achieving prompt BP control, ideally within 1-3 months, translates into improved cardiovascular outcomes. Although the consistency of the findings is encouraging, the strength of this conclusion is limited by the available data, which were derived from studies not designed to determine the definition or benefits of early BP reduction. In several of these studies, using a treatment approach with initial monotherapy or combination therapy has clearly demonstrated pronounced BP lowering and high BP control rates within an intensive timeframe of 3-6 months of therapy. Although these studies were not conducted exclusively in high-risk patients, subgroup analyses have demonstrated that the observed outcomes in the overall study populations apply to the diabetic and CKD subsets.

Effectiveness of initiating treatment with valsartan/hydrochlorothiazide in patients with stage-1 or stage-2 hypertension.

This prospective, 6-week, multicenter, double-blind study examined the benefits of initiating treatment with combination valsartan/hydrochlorothiazide (HCTZ) compared with initial valsartan monotherapy for 648 patients with stage-1 or stage-2 hypertension (age=52.6+/-10 years; 54% male; baseline blood pressure (BP)=161/98 mm Hg, 32% stage 1). Patients were randomized to valsartan 80 mg (V-low), valsartan 160 mg (V-high) or valsartan/HCTZ 160/12.5 mg (V/HCTZ), and electively titrated after weeks 2 and 4 to the next dosage level (maximum dose valsartan/HCTZ 160/25 mg) if BP remained >140/90 mm Hg. At end of the study, patients initiated with V/HCTZ required less titration steps compared with the initial valsartan monotherapy groups (63 vs 86% required titration by study end, respectively) and reached the target BP goal of <140/90 mm Hg in a shorter period of time (2.8 weeks) (P<0.0001) vs V-low (4.3 weeks) and V-high (3.9 weeks). Initial combination therapy was also associated with higher BP control rates and greater reductions in both systolic and diastolic BP from baseline (63%, -27.7+/-13/-15.1+/-8 mm Hg) compared with V-low (46%, -21.2+/-13/-11.4+/-8 mm Hg, P<0.0001) or V-high (51%, -24.0+/-13/-12.0+/-10 mm Hg, P<0.01). Overall and drug-related AEs were mild to moderate and were similar between V/HCTZ (53.1 and 14.1%, respectively) and the two monotherapy groups, V-low (50.5 and 13.8%) and V-high (50.7 and 11.8%). In conclusion, initiating therapy with a combination of valsartan and low-dose HCTZ results in early, improved BP efficacy with similar tolerability as compared with starting treatment with a low or higher dose of valsartan for patients with stage-1 and stage-2 hypertension.

Effects of mechanical unloading/loading on respiratory loop gain and periodic breathing in man.

We investigated the effect of mechanical unloading and loading on Cheyne-Stokes respiration (CSR) in seven intubated patients with preexisting CSR. For mechanical loading patients had to breathe against the resistance of the endotracheal tube. For mechanical unloading patients were supported with a volume-proportional pressure support in the proportional assist ventilation (PAV) mode whilst the flow-dependent (nonlinear) endotracheal tube resistance was continuously compensated for by means of the automatic tube compensation (ATC) mode. Mechanical unloading aggravated CSR as revealed by a prolongation of apnea time and by an increase in the so-called strength index whereas mechanical loading shortened apnea time and decreased strength index. To test whether the observed changes are caused by the effect of mechanical unloading/loading on respiratory loop gain (relationship between minute ventilation and arterial CO2 tension), the response of respiratory loop gain on mechanical unloading/loading was determined in five healthy subjects (without CSR). In each subject, mechanical unloading increased respiratory loop gain whereas mechanical loading decreased it.

The origin of endothelin-1 in patients with severe preeclampsia.

OBJECTIVE: To determine the site of origin of increased concentrations of plasma endothelin-1 in patients with severe preeclampsia. METHODS: Twelve patients with severe preeclampsia undergoing an indicated abdominal delivery had endothelin-1 levels measured from plasma specimens drawn from right and left uterine and antecubital veins before delivery and after placenta removal with uterine curettage. Twelve uncomplicated control patients undergoing abdominal delivery had endothelin-1 concentrations drawn by an identical protocol. Clinical staff members were blinded to endothelin-1 results and laboratory staff were blinded to patient group assignment and sample source. Endothelin-1 plasma concentrations were determined by radioimmunoassay and data were analyzed by paired t test. RESULTS: No difference in endothelin-1 concentration was noted with respect to placental location, central versus peripheral, or predelivery versus postdelivery sampling procedures. Overall, patients with preeclampsia had higher plasma concentrations of endothelin-1 (mean 11.0 +/- 6.6 pg/mL) compared with normotensive patients (mean 8.4 +/- 6.7 pg/mL, P < .005). CONCLUSION: The decidual-placental interface does not appear to be the source of increased plasma endothelin-1 concentrations found in severe preeclampsia. The origin of this increase remains uncertain.

Breathing pattern and additional work of breathing in spontaneously breathing patients with different ventilatory demands during inspiratory pressure support and automatic tube compensation.

OBJECTIVE: We designed a new ventilatory mode to support spontaneously breathing, intubated patients and to improve weaning from mechanical ventilation. This mode, named Automatic Tube Compensation (ATC), compensates for the flow-dependent pressure drop across the endotracheal tube (ETT) and controls tracheal pressure to a constant value. In this study, we compared ATC with conventional patient-triggered inspiratory pressure support (IPS). DESIGN: A prospective, interventional study. SETTING: A medical intensive care unit (ICU) and an ICU for heart and thoracic surgery in a university hospital. PATIENTS: We investigated two groups of intubated, spontaneously breathing patients: ten postoperative patients without lung injury, who had a normal minute ventilation (VE) of 7.6 +/- 1.7 l/min, and six critically ill patients who showed increased ventilatory demand (VE = 16.8 +/- 3.0 l/ min). INTERVENTIONS: We measured the breathing pattern [VE, tidal volume (VT), and respiratory rate (RR)] and additional work of breathing (WOBadd) due to ETT resistance and demand valve resistance. Measurements were performed under IPS of 5, 10, and 15 mbar and under ATC. RESULTS: The response of VT, RR, and WOBadd to different ventilatory modes was different in both patient groups, whereas VE remained unchanged. In postoperative patients, ATC, IPS of 10 mbar, and IPS of 15 mbar were sufficient to compensate for WOBadd. In contrast, WOBadd under IPS was greatly increased in patients with increased ventilatory demand, and only ATC was able to compensate for WOBadd. CONCLUSIONS: The breathing pattern response to IPS and ATC is different in patients with differing ventilatory demand. ATC, in contrast to IPS, is a suitable mode to compensate for WOBadd in patients with increased ventilatory demand. When WOBadd was avoided using ATC, the patients did not need additional pressure support.

Blood metabolite and catecholamine responses to prolonged exercise following either acute plasma volume expansion or short-term training.

To determine the effect of acute plasma volume (PV) expansion on substrate utilization, blood metabolites and catecholamines to prolonged, moderate intensity cycle exercise, eight untrained men mean maximal oxygen uptake VO2max 4.10 (SEM 0.32) 1.min-1 were infused (10 ml.kg-1) with a 6% dextran (DEX) solution. These responses were also compared to those elicited using a short-term training (TR) protocol involving cycling for 90 to 120 min.day-1 at 60% VO2max for 3 consecutive days. In general DEX, which resulted in a calculated expansion of PV by 23.9% was without effect in modifying exercise oxygen uptake or the reduction in the respiratory exchange ratio (R) observed during prolonged exercise. In addition, the concentrations of blood glucose, glycerol, alanine and serum free fatty acids, although altered (P < 0.05) by exercise, were not altered by DEX. Blood lactate concentration was only higher (P < 0.05) at 30 min of exercise during DEX compared to the control. With the exception of blood lactate concentration, which was reduced (P < 0.05), TR did not change R or the concentrations of other blood metabolites. The concentrations of nonadrenaline and adrenaline, were depressed (P < 0.05) by DEX and TR at 60 and 90 min of exercise. These results would suggest that mechanisms as yet undefined can compensate for the estimated 10% reduction in arterial oxygen content mediated by acute PV expansion and enable prolonged exercise to be performed without adjustments in substrate selection and substrate mobilization.

Respiratory comfort of automatic tube compensation and inspiratory pressure support in conscious humans.

OBJECTIVE: To compare the new mode of ventilatory support, which we call automatic tube compensation (ATC), with inspiratory pressure support (IPS) with respect to perception of respiratory comfort. ATC unloads the resistance of the endotracheal tube (ETT) in inspiration by increasing the airway pressure, and in expiration by decreasing the airway pressure according to the non-linear pressure-flow relationship of the ETT. DESIGN: Prospective randomized single blind cross-over study. SETTING: Laboratory of the Section of Experimental Anaesthesiology (Clinic of Anaesthesiology; University of Freiburg). SUBJECTS: Ten healthy volunteers. INTERVENTIONS: The subjects breathed spontaneously through an ETT of 7.5 mm i.d. Three different ventilatory modes, each with a PEEP of 5 cmH2O, were presented in random order using the Dräger Evita 2 ventilator with prototype software: (1) IPS (10 cmH2O, 1 s ramp), (2) inspiratory ATC (ATC-in), (3) inspiratory and expiratory ATC (ATC-in-ex). MEASUREMENTS AND MAIN RESULTS: Immediately following a mode transition, the volunteers answered with a hand sign to show how they perceived the new mode compared with the preceding mode in terms of gain or loss in subjective respiratory comfort: "better", "unchanged" or "worse". Inspiration and expiration were investigated separately analyzing 60 mode transitions each. Flow rates were continuously measured. The transition from IPS to either type of ATC was perceived positively, i.e. as increased comfort, whereas the opposite transition from ATC to IPS was perceived negatively, i.e. as decreased comfort. The transition from ATC-in to ATC-in-ex was perceived positively whereas the opposite mode transition was perceived negatively in expiration only. Tidal volume was 1220 +/- 404 ml during IPS and 1017 +/- 362 ml during ATC. The inspiratory peak flow rate was 959 +/- 78 ml/s during IPS and 1048 +/- 197 ml/s during ATC. CONCLUSIONS: ATC provides an increase in respiratory comfort compared with IPS. The predominant cause for respiratory discomfort in the IPS mode seems to be lung over-inflation.

Hypertension in obese Zucker rats. Role of angiotensin II and adrenergic activity.

We designed our studies to determine whether blood pressure is elevated in obese Zucker rats compared with lean control rats and to test the importance of the renin-angiotensin and adrenergic nervous systems in long-term blood pressure control in this genetic model of obesity. We monitored mean arterial pressure 24 hours per day using computerized methods in 13- to 14-week-old lean and obese Zucker rats maintained on a fixed, normal sodium intake (3.3 mmol/d). Mean arterial pressure (average of 5 days) was higher in obese (100 +/- 1 mm Hg) than in lean (86 +/- 1) rats. Although control plasma renin activity was lower in obese than in lean rats (3.66 +/- 0.15 versus 5.48 +/- 0.11 ng angiotensin I/mL per hour), blood pressure sensitivity to exogenous angiotensin II was greater in obese than in lean rats. Blockade of endogenous angiotensin II receptors with losartan (10 mg/kg per day) for 7 days also caused a greater decrease in blood pressure in obese (36 +/- 2 mm Hg, n = 6) than in lean (25 +/- 1, n = 5) rats. However, combined alpha- and beta-adrenergic blockade with terazosin (10 mg/kg per day) and propranolol (10 mg/kg per day), respectively, for 8 days caused only modest decreases in blood pressure in obese (9 +/- 3 mm Hg, n = 8) and lean (4 +/- 2, n = 6) rats, despite effective alpha- and beta-adrenergic blockade. These results suggest that increased arterial pressure in obese Zucker rats depends in part on angiotensin II. However, additional mechanisms may also contribute to increased blood pressure in obese Zucker rats.

[Added work of breathing, respiratory pattern and determination of ventilator weaning readiness in inspiratory pressure support and and automatic tube compensation]. / Zusätzliche Atemarbeit, Atemmuster und Erkennbarkeit der Extubationsbereitschaft unter inspiratorischer Druckunterstützung (IPS) und automatischer Tubuskompensation (ATC).

We measured the ventilatory pattern and additional work of breathing (WOBadd) at three different levels of inspiratory pressure support [IPS 5, 10, 15 mbar above positive end-expiratory pressure (PEEP)] and in a new ventilatory mode, automatic tube compensation (ATC), in nine operative patients without lung injury nine patients ventilated for several following acute respiratory insufficiency (ARI). In ATC, endotracheal tube resistance is compensated automatically by means of closed-loop control of the calculated tracheal pressure. Pressure support in this mode, i.e. airway pressure above PEEP, is equal to the actual flow-dependent pressure drop across the endotracheal tube (ETT). Airway pressure rises at the beginning of inspiration and falls towards the end. As the tube resistance of ETT seriously hinders expiration and can cause desynchronization between ventilator and patient, airway pressure is reduced below PEEP during expiration in the same way as it is increased during inspiration. The result is a near-constant tracheal pressure at PEEP both during inspiration and during expiration. This mode could be best termed as "electronic extubation". The most striking difference between the postoperative patients and the ARI patients was their minute ventilation (17.8 +/- 1.85 l/min in ARI patients vs 7.3 +/- 3.1 l/min in the postoperative patients). In the postoperative patients augmentation of IPS from 5 to 15 mbar induced a steady increase in tidal volume (VT) and a consecutive decrease in respiratory rate (rr) compared with ATC (VTATC,postop = 463 +/- 78 ml; rrATC,postop = 16 +/- 4 min-1; VTIPS5.postop = 505 +/- 79 ml; rrIPS5,postop = 15 +/- 4 min-1; VTIPS10,postop = 562 +/- 86 ml; rrIPS15,postop = 14 +/- 4 min-1; VTIPS15.postop = 660 +/- 151 ml; rrTPS15,postop = 12 +/- 4 min-1), whereas the augmentation of IPS of 5 and 10 mbar in the ARI patients could not compensate for the increase in rr and the decrease in VT, after switching from ATC to IPS (VTATC,ARI 724 +/- 308 ml, rrATC,ARI = 24 +/- 6 min-1; VTIPS5,ARI = 649 +/- 315 ml; rrIPS5,ARI = 27 +/- 8 min-1; VTIPS10,ARI = 653 +/- 353 ml; rrIPS10,ARI = 25 +/- 8 min-1: Even IPS 15 was not able to reestablish VT at the values observed during ATC (VTIPS15,ARI = 680 +/- 312 ml). During ATC WOBadd was small in both postoperative and ARI patients (WOBadd,ATC,postop = 93 +/- 36 mJ/l, WOBadd,ATC,ARI = 116 +/- 72 mJ/l). In the postoperative patients, an inspiratory pressure support of 5 mbar was not sufficient to compensate WOBadd compared with ATC. However, IPS 10 and 15 mbar were able to compensate for WOBadd (WOBadd,ATC5.postop WOBadd,IPS5,postop = 189 +/- 77 mJ/l; WOBadd,IPS10,postop = 55 +/- 30 mJ/l; WOBadd,IPS15,postop = 21 +/- 11 mJ/l). In the ARI patients an IPS 5, 10 or 15 mbar was not sufficient to compensate for WOBadd (WOBadd,IPS 5,ARI = 1126 +/- 262 mJ/l; WOBadd,IPS 10,ARI 863 +/- 253 mJ/l; WOBadd,IPS15,ARI 763 +/- 298 mJ/l). Under ATC, WOBadd was only 15% of WOBadd under IPS of 15 mbar. All but two patients were successfully extubated after the investigation. These two patients were not extubated because they were dependent on an FIO2 > 0.5. Our results strongly indicate that ventilatory dependence in ARI patients may be caused by the ETT rather than by mechanical dysfunction of the lung. ATC is a very helpful mode to use in distinguishing between ventilatory failure caused by ETT and real ventilatory dependence.

Comparative effects of acute volume expansion and short-term training on thermal and cardiovascular responses to prolonged exercise.

To investigate the hypothesis that increases in plasma volume (PV) are crucial to the cardiovascular and thermal adaptations resulting from training, eight moderately active males (Vo2max = 4.10 +/- 0.32 L/min; mean +/- SE) performed prolonged cycle exercise at 60% Vo2max during a control test (CON) and following infusion (10 mL/kg) of a 6% dextran solution (DEX). These responses were also compared with short-term training (TR) involving 3 days of cycling for 90-120 min at moderate intensity (60% Vo2max). During DEX, exercise cardiac output (Q) and stroke volume (SV) were persistently higher (p < 0.05) than CON, while heart rate (HR) was unchanged. In comparison, TR resulted in a lower (p < 0.05) HR at constant Q. In contrast with TR, in which the exercise response was unchanged from CON, the DEX condition produced a lower total peripheral resistance. Rectal temperature (Tre) was lowered (p < 0.05) both by DEX and TR, but the conditions differed in the time at which the reduction occurred. For DEX, the lower Tre was manifested early and persisted throughout exercise, whereas for TR the Tre was only lower later in exercise. Forearm blood flow, mean skin temperature, and sweat rate were not affected by DEX or TR. It is concluded that acute PV expansion does not affect the time-dependent response in cardiovascular function or thermoregulation during prolonged exercise in ambient conditions. The primary effects appear to be manifested during rest or soon after the onset of exercise.

Cardiac output and renal function during insulin hypertension in Sprague-Dawley rats.

Hyperinsulinemia has been reported to cause hypertension in rats; however, the renal and hemodynamic mechanisms are not known. In this study, changes in renal function, cardiac output (CO), and total peripheral resistance (TPR) were measured during chronic insulin infusion in eight rats (approximately 350 g). After a 4-day control period, a 7-day insulin infusion was begun (1.5 mU.kg-1.min-1 iv), together with glucose (22 mg.kg-1.min-1 iv) to prevent hypoglycemia. Mean arterial pressure (MAP), CO, TPR, and heart rate were measured 24 h/day. MAP increased from 92 +/- 1 to 100 +/- 2 mmHg on day 1 and was 108 +/- 4 mmHg by day 7 of insulin. CO tended to decrease during insulin infusion, although not significantly, averaging 94 +/- 4% of the control value of 121 +/- 7 ml/min. Heart rate did not change significantly from the control value of 384 +/- 8 beats/min. TPR increased significantly to 122 +/- 11% of control by day 7. In five rats, glomerular filtration rate and effective renal plasma flow decreased to 73 +/- 4 and 66 +/- 5% of control, respectively, during insulin. Urinary sodium excretion averaged 2.6 +/- 0.1 and 2.7 +/- 0.1 meq/day during the control and insulin-infusion periods, respectively. These results indicate that insulin hypertension in rats is initiated by an increase in TPR rather than by increased CO. Also, the fact that sodium balance was maintained at elevated arterial pressure suggests that the ability of the kidneys to excrete sodium was impaired chronically during insulin infusion.

The interaction between short-term exercise training and a diuretic-induced hypovolemic stimulus.

Nine healthy untrained males [mean (SEM) age, 20.2 (1) years; peak oxygen uptake (VO2max, 48.2 (2) ml.kg-1.min-1] took part in a study to examine whether short-term exercise training (cycle exercise 2 h.day-1 for 3 days at 60% VO2max), which normally results in an expansion of plasma volume (PV), can counteract a diuretic-induced hypovolemic stimulus (100 mg triamterene + 50 mg hydrochlorothiazide.day-1 for 5 days concurrent with exercise training) and restore PV to control levels. Resting and exercise responses (90 min, 60% VO2max) in the diuretic plus exercise training condition (D+E) were compared to a control (C) and a diuretic (D) condition in which no exercise was performed. Following the short-term training, PV was still decreased (P < 0.05) below C by -8.3 (3)% in D+E and was similar (P > 0.05) to the reduction in D [-12.4 (2)%]. The reduced PV in response to the diuretic was associated with similar (P > 0.05) elevations in resting aldosterone (ALDO) and norepinephrine (NOREPI) levels (ng.100 ml-1) in D [101 (12), 61 (4)] and D+E [85 (16), 60 (10)] above (P < 0.05) C [22 (5), 37 (4)]. During exercise, ALDO levels were increased (P < 0.05) by 66 (5) and 70 (10) ng.100 ml-1 in D and D+E, respectively, and the increase was greater (P < 0.05) than C [44 (8) ng.100 ml-1]. The rise in NOREPI during exercise was lower (P < 0.05) in D+E [164 (44) ng.100 ml-1] than in D [244 (24) ng.100 ml-1] with levels similar to C [176 (25) ng.100 ml-1]. Thus, the ALDO response to the diuretic was heightened at rest and during exercise but was not additionally affected by the short-term training session. Results suggest that 3 days of exercise training are unable to counteract the hypovolemic effects of a diuretic and restore PV to control levels despite chronic elevations in NOREPI and ALDO.

Age and regulation of fluid and electrolyte balance during repeated exercise sessions.

A common response after only 3-4 days of repeated exercise in younger individuals is an expansion of plasma volume (PV); however, it is not known if older individuals have a similar response. In this study, six older (O) (67 +/- 1 yr) and six younger (Y) men (24 +/- 2 yr) cycled for 4 successive days at 50% maximal oxygen consumption (Vo2max) for 90 min in a warm environment [30 degrees C temperature dry bulb (Tdb), 24 degrees C temperature wet bulb (Twb)]. On day 4, PV was increased (P < 0.05) in Y (10.0 +/- 1%) but not (P > 0.05) in O (1.7 +/- 2%). The increased PV was associated with a greater (P < 0.05) daily fluid intake during the exercise period in Y (45 +/- 3 ml. day-1.kg body wt-1) compared with O (32 +/- 2 ml.day-1.kg body wt-1) and an increase (P < 0.05) in the total circulating protein (TCP) content in Y (0.23 +/- 0.1 g/kg body wt) but not in O (0.10 +/- 0.1 g/kg body wt). Throughout the 4-day exercise period there were similar reductions in 24-h urine flow rate (UV) and urinary sodium excretion (UNaV) in Y and O. Additionally, acute renal clearance measures made during exercise on days 1 and 4 showed similar (P > 0.05) reductions in UNaV between Y (-55 +/- 10%) and O (-44 +/- 6%). However, during exercise in O there were no changes (P > 0.05) in UV (2 +/- 12%) and urine osmolality (UOsm) (-12 +/- 6%) from resting values compared with Y, where UV was decreased (P < 0.05) by 41 +/- 9% and UOsm was increased (P < 0.05) by 39 +/- 8%. Therefore, the inability of the older subjects to increase PV after repeated days of exercise is not related to an impaired renal fluid and Na+ conservation ability, despite a reduced urine concentrating ability during exercise, but to other factors (e.g., fluid intake and TCP) that appear necessary for the hypervolemic response.

Cardiovascular actions of insulin: are they important in long-term blood pressure regulation?

1. In recent years, there has been considerable interest in the possibility that insulin may have important cardiovascular as well as metabolic actions. Perhaps the best documented cardiovascular effect of insulin is to cause peripheral vasodilation, especially in skeletal muscle. Hyperinsulinaemia also stimulates sympathetic activity and causes antinatriuresis, but these effects may be linked, at least in part, to the metabolic actions of insulin that elicit peripheral vasodilation and a tendency toward hypotension. Normal, fasting levels of insulin appear to have very little influence on peripheral vascular resistance, sympathetic activity or renal sodium excretion. 2. Decreased sensitivity of the peripheral tissues to the metabolic effects of insulin and compensatory hyperinsulinaemia have been postulated to play key roles in the pathophysiology of diseases such as hypertension and atherosclerosis. Although impaired insulin action (insulin resistance) and hyperinsulinaemia often accompany essential hypertension, especially when associated with obesity, there is currently little direct evidence for a cause and effect relationship between insulin resistance, hyperinsulinaemia and increased arterial pressure. Chronic increases in plasma insulin levels in dogs and humans have not been shown to cause hypertension, although hyperinsulinaemia raises blood pressure in rats. 3. Further research is needed to determine whether there are pathophysiological conditions or genetic factors that may predispose humans to a hypertensive effect of hyperinsulinaemia and/or insulin resistance.

Obesity and hypertension: roles of hyperinsulinemia, sympathetic nervous system and intrarenal mechanisms.

Hypertension is a well-recognized complication of obesity. However, the mechanisms for the development of obesity hypertension are not known. One mechanism proposed is that the hyperinsulinemia present in obese hypertensive patients causes hypertension via sodium retaining and/or sympathetic nervous system stimulatory effects. However, numerous studies in dogs have revealed no evidence for such chronic pressor actions of hyperinsulinemia. This is in close agreement with studies in human insulinoma patients that show marked hyperinsulinemia and normal blood pressure. The appropriateness of the dog as an experimental model is strengthened by reports from our laboratory and others that inducing obesity in dogs reproduces many of the characteristics of obesity in humans, including insulin resistance, hyperinsulinemia, sodium retention, hypertriglyceridemia and hypertension. Recent studies in obese dogs have indicated that significant increases in renal medullary cellularity and intercellular matrix deposition could contribute to the sodium retention and hypertension. Additional evidence suggests that sympathetic nervous system stimulation also may contribute to the elevated blood pressure. However, the mechanisms through which obesity induces these changes and the temporal relationship between these factors and the development of the hypertension remains to be determined.

Hemodynamic and renal responses to chronic hyperinsulinemia in obese, insulin-resistant dogs.

We previously reported that chronic hyperinsulinemia does not cause hypertension in normal insulin-sensitive dogs. However, resistance to the metabolic and vasodilator effects of insulin may be a prerequisite for hyperinsulinemia to elevate blood pressure. The present study tested this hypothesis by comparing the control of systemic hemodynamics and renal function during chronic hyperinsulinemia in instrumented normal conscious dogs (n = 6) and in dogs made obese and insulin resistant by feeding them a high-fat diet for 6 weeks (n = 6). After 6 weeks of the high-fat diet, body weight increased from 24.0 +/- 1.2 to 40.9 +/- 1.2 kg, arterial pressure rose from 83 +/- 5 to 106 +/- 4 mm Hg, and cardiac output rose from 2.98 +/- 0.29 to 5.27 +/- 0.54 L/min. Insulin sensitivity, assessed by fasting hyperinsulinemia and by the hyperinsulinemic euglycemic clamp technique, was markedly reduced in obese dogs. Insulin infusion (1.0 mU/kg per minute for 7 days) in obese dogs elevated plasma insulin from 42 +/- 12 microU/mL to 95 to 219 microU/mL but failed to increase arterial pressure, which averaged 106 +/- 4 mm Hg during control and 102 +/- 4 mm Hg during 7 days of insulin infusion. Hyperinsulinemia for 7 days in obese dogs elevated heart rate from 116 +/- 8 to 135 +/- 7 beats per minute but caused no significant changes in cardiac output, in contrast to normal dogs (n = 6), in which marked increases in cardiac output (31 +/- 5% after 7 days) and decreases in total peripheral resistance occurred during chronic insulin infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin resistance, hyperinsulinemia, and hypertension: causes, consequences, or merely correlations?

Resistance to the metabolic effects of insulin and compensatory hyperinsulinemia have been postulated to mediate human essential hypertension, especially when associated with obesity. Evidence supporting this hypothesis has come mainly from epidemiological studies showing correlations between insulin resistance, hyperinsulinemia, and blood pressure, and from short-term studies suggesting that insulin has renal and sympathetic effects that could raise blood pressure if the effects were sustained. However, there have been no studies demonstrating a direct causal relationship between chronic hypertension and insulin resistance or hyperinsulinemia in humans. The few long-term studies that have been conducted in dogs and humans do not support the hypothesis that hyperinsulinemia causes hypertension or potentiates the hypertensive effects of other pressor agents such as angiotensin II or increased adrenergic tone. To the contrary, multiple studies in dogs and in humans suggest that the vasodilator action of insulin tends to reduce blood pressure. Although resistance to insulin's metabolic effects has been suggested to be essential for hyperinsulinemia to cause hypertension, chronic increases in plasma insulin concentrations do not cause hypertension in dogs or humans even in the presence of insulin resistance. Also, recent studies have also shown that the blood pressure-lowering effects of antihyperglycemic agents, initially believed to lower blood pressure by decreasing insulin resistance, may be unrelated to their effects on insulin sensitivity. Obesity appears to be a key factor in accounting for correlations between insulin resistance, hyperinsulinemia, and hypertension, but increased blood pressure in obesity does not appear to be mediated by insulin resistance and hyperinsulinemia. Although insulin resistance and hyperinsulinemia may not be directly linked to hypertension, there is increasing evidence that metabolic abnormalities associated with insulin resistance may increase the risk of cardiovascular disease (e.g., coronary artery disease) associated with hypertension and Type II diabetes. For this reason, further studies of the long-term effects of insulin resistance on cardiovascular, renal, and metabolic functions are needed.

Effect of age on renal blood flow during exercise.

The present study examined the effect of age on the control of renal blood flow (RBF; PAH clearance) and renal vascular conductance (RVC = RBF/mean arterial pressure) during and after a bout of dynamic exercise in a warm environment. Six healthy fit older men (O; 67 +/- 1 years) and 6 young men (Y; 24 +/- 2 years) were matched for body size, adiposity, and maximal oxygen uptake (VO2max). Subjects exercised at approximately 50% of VO2max for 90 minutes in an environment of 30 degrees C, 60% humidity on each of 4 consecutive days, with data collected on days 1 and 4. There was no effect of repeated days of exercise on RBF or RVC, despite a 4% expansion of blood volume in Y (< 1% in O). On each day, resting RBF was significantly lower in O (e.g., Y = 1127 +/- 67, O = 852 +/- 114 mL/min on day 1; p < 0.05). During exercise, Y decreased RBF to a significantly (p < 0.05) greater extent [-508 (-45%) and -365 (-36%) mL/min on days 1 and 4, respectively] than the O [-98 (-12%) and -83 (-12%) mL/min]. RVC followed a similar pattern, decreasing by 52% and 37% during exercise for Y vs only 15% and 13% for O. The relationships between delta RBF and HR and delta RBF and plasma norepinephrine concentration were independent of age, implying similar sympathetic control during exercise. During recovery, RBF and RVC increased as expected in Y, but continued to decrease in O, falling significantly below exercise values (p < 0.05). Compared to young men, fit healthy older men redistribute less blood flow away from the kidneys during dynamic exercise in the heat, an effect which appears to result from the existence of a smaller resting RBF rather than differential sympathetic control. On the other hand, chronological age seems to be associated with altered control of RBF and RVC during recovery from exercise.