Redistribution of blood volume in type I diabetes.

AIMS/HYPOTHESIS: Impaired activity of endothelium-derived nitric oxide in Type I (insulin-dependent) diabetes mellitus will cause an increased vascular tone. Considering the lower production of nitric oxide in veins than in arteries, an impaired activity would have less vasoconstrictive effect in veins. The reported minimally changed total plasma volume in diabetes might, therefore, indicate a redistribution of blood volumes from the arterial to the venous side of the circulation. This could be more pronounced in patients with microalbuminuria. METHODS: In 16 normoalbuminuric and 16 microalbuminuric Type I diabetic patients and 16 individually matched healthy control subjects, venous and arterial blood volumes, venous myogenic response and arterial distensibilities were assessed in the upper arm using an electrical bio-impedance method. RESULTS: In diabetic patients, the venous blood volume and venous myogenic response were increased (p < 0.02 and p < 0.05, respectively), whereas the arterial blood volume did not change. Moreover, in diabetic patients the distensibility of the large arteries was decreased (p < 0.05) but increased in the total arterial bed (p < 0.05). Therefore, the distensibility of the small arteries must have been increased. No differences were found between normoalbuminuric and microalbuminuric diabetic patients. CONCLUSION/INTERPRETATION: The increase in venous blood volume and myogenic response and the decrease in distensibility of the large arteries in the upper arm are in agreement with the expected shift towards venous blood volume distribution in Type I diabetes with and without microalbuminuria. Furthermore, they support the haemodynamic hypothesis of the pathogenesis of diabetic microangiopathy.

Reversal of pathophysiologic changes with long-term lisinopril treatment in isolated systolic hypertension.

The purpose of this study was to evaluate in a prospective, double-blind, placebo-controlled study the effect of long-term (2-year) lisinopril treatment on cardiovascular end-organ damage in patients with previously untreated isolated systolic hypertension (ISH). All patients with ISH were derived from a population screening program. End-organ damage measurements, done initially and after 6 and 24 months of treatment, included measurements of aortic distensibility and echocardiographic left ventricular mass index (LVMI) and diastolic function. Blood pressure was measured by office and ambulatory measurements. Of the 97 subjects with ISH selected from the screening, 62 (30 lisinopril) completed the study according to protocol. Office blood pressure decreased in both groups, but ambulatory results significantly decreased with lisinopril-treatment only. Aortic distensibility increased significantly with lisinopril, as opposed to a decrease in placebo-treated subjects. The main effect of increased distensibility occurred between 6 and 24 months, whereas ambulatory blood pressure changed mainly in the first 6 months of treatment. LVMI decreased in both treatment groups, with a significantly higher reduction in lisinopril-treated subjects. Left ventricular diastolic function showed no significant changes in either group. The vascular pathophysiologic alterations of ISH-a decreased aortic distensibility-can be improved with long-term lisinopril treatment, whereas values deteriorate further in placebo-treated subjects. These results, in one of the first studies including subjects with previously untreated ISH only, indicate that lisinopril treatment might favorably influence the cardiovascular risk of ISH.

Effects of initial and long-term lipid-lowering therapy on vascular wall characteristics.

Several studies have demonstrated the beneficial effects of 3 hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors on vascular properties, but little is known about treatment intensification. We compared patients in whom statins were started (INITIAL, n=30) for hypercholesterolaemia (>6.5 mmol l(-1)) with a matched patient group of long-time statin users, with similar baseline characteristics for lipids, intima-media thickness (IMT), and pulse wave velocity, in whom treatment with statins was intensified (LONG-TERM, n=54). At baseline and after 1 year, lipid profile, IMT of the carotid and femoral arteries, aortic distensibility using pulse-wave velocity and various properties of the peripheral vascular bed using a recently developed bio-impedance method were measured. After 1 year the relative changes in lipid profile were significantly better in the INITIAL compared with the LONG-TERM-group. The relative changes in IMT of the mean internal carotid and common femoral arteries significantly differed between the INITIAL and LONG-TERM-group (-8 and +11%, -11 and +22%, respectively). After 1 year, in both groups, most other vascular wall characteristics were unaltered compared with baseline. In conclusion, the beneficial structural alterations of the vascular wall were greater after starting than after intensifying already existing lipid-lowering treatment. This suggests that other effects of HMG-CoA reductase inhibitors than lipid-lowering alone must be involved in vascular changes.

The vagal cardiac accelerator system in the reflex control of heart rate in conscious dogs.

The reactions of the vagal cardioaccelerator (VCA) system to changes in mean arterial pressure (MAP) were studied in five beta-adrenoceptor blocked conscious dogs. An increase in MAP was obtained by administration of vasopressin or methoxamine, a decrease by doxazosin or nitroprusside. In the first series of experiments the MAP changes were induced after muscarinic receptor blockade, in a second series both before and after muscarinic blockade. Prior to these experiments, the maximum VCA activity, defined as the difference between maximum heart rate after muscarinic blockade and the rate after additional nicotinic blockade, was determined. We hypothesized that this quantity, as a measure of VCA activity, depends on the prevailing vagal tone. In the first series of experiments, a rise in MAP evoked an increase in heart rate, a fall in MAP indicated decrease. In the second series, when prior to muscarinic blockade the vagal tone was reflexly raised, the subsequent VCA reflex response to the rise in MAP was attenuated. Prior to the muscarinic blockade the vagal tone was reflexly lowered, the VCA reflex response was enhanced. Direct chronotropic effects of MAP-varying drugs were ruled out by the absence of a heart-rate response in experiments on vagotomized animals. We concluded that the vagal cardioaccelerator system is involved in the reflex control of heart rate. Both the VCA reflex response to changes in systemic blood pressure and the maximum VCA activity however, are determined by the prevailing vagal tone.

Isolated systolic hypertension from a vascular point of view.

Due to the results of antihypertensive intervention studies, isolated systolic hypertension (ISH) has gained new interest lately. Yet, apart from increased aortic stiffness, the specific pathophysiological features of ISH have remained largely undetermined. Therefore, we investigated the elastic properties of the vascular bed of an upper arm segment in uncomplicated ISH patients and matched normotensive controls using an electrical bioimpedance technique. Compared with the controls, the compliance of the arterial bed as a whole at normotensive blood pressure level was on the average 108.0% higher (p < 0.005) in the hypertensive patients. The blood volume of the arterial bed as a whole at operating blood pressure level and that of the larger arteries were significantly higher (40.5%, p < 0.05, and 40.5%, p < 0.01, respectively). The same held true for the venous blood volume (64.4%, p < 0.05), and for the width of the arterial compliance-pressure relation (34.6%, p < 0.01). We concluded that ISH is a separate pathophysiological entity in which all parts of a peripheral vascular bed are changed and the decreased buffering function of the aorta and large arteries is partly compensated for by an increase in small artery compliance.

Arteriolar constriction in mild-to-moderate essential hypertension: an old concept requiring reconsideration?

OBJECTIVE: To investigate differences between in-vivo properties of a vascular bed in hypertensive patients and normotensive controls. DESIGN: Despite the controversy about the origin of essential hypertension and its accompanying vascular changes, it is generally assumed that the characteristic increase in peripheral resistance when hypertension progresses is caused by arteriolar constriction. Yet, there is little experimental evidence that this assumption generally holds in vivo. METHODS: A non-invasive technique was used for studying properties of the complete vascular bed of an upper arm segment under an occluding cuff in 23 previously untreated hypertensive patients and their matched normotensive controls. The method used the segment's electrical impedance to assess the volumes of extravascular fluid and of arterial and venous blood under varying arterial transmural pressures. RESULTS: Compared with that of matched normotensive controls, the compliance of the large arteries of the vascular bed was on average 50.9% lower (P < 0.001) in the hypertensive patients. The compliance of the complete arterial bed at the operating blood pressure level was also lower (40.0%, P < 0.01), but appeared to be significantly higher (45.9%, P < 0.05) at the normotensive blood pressure level. On the venous side, the patients had a higher blood volume (60.0%, P < 0.01) and an increased myogenic response (68.5%, P < 0.05). CONCLUSIONS: The increase in vascular resistance in the hypertensive patients is due primarily to changes in the large and small vessels of the arterial bed. We found no evidence for a generally increased arteriolar constriction.

Age-related differences in elastic properties of the upper arm vascular bed in healthy adults.

The significance of age-related changes in arterial stiffness has remained largely uncertain in healthy subjects. This appears to be partly due to difficulties in the interpretation of methods for measuring arterial stiffness in vivo. Therefore, a recently developed electrical bioimpedance method was used for studying elastic properties of a vascular bed as a function of age. In 66 healthy subjects, aged 22-82 years, we investigated the vascular bed of an upper arm segment. This vascular bed showed an age-related decrease in the venous blood volume (r = -0.31, p < 0.01) and in the distensibility, the inverse of stiffness, of the larger arteries (r = -0.38, p < 0.001). The distensibility of the arterial bed as a whole at normotensive blood pressure, however, appeared to increase with age (r = 0.32, p < 0.005). The arterial and venous blood volumes, arterial compliance and extravascular fluid volume were significantly higher in the males than in the females. Practically all investigated vascular properties appeared to be related with height, body mass or body mass index. We concluded that comparative studies concerning vascular properties should preferably be performed in subjects matched as to age, gender, height and body mass. In healthy subjects the smaller arteries adjust to the age-related decrease in large artery distensibility by means of an age-related increase in distensibility. These age-related changes in arterial distensibility are caused by changes in the females, and seem to be associated with age-related changes in body mass index rather than with aging per se.

Alterations in cortisol metabolism in insulin-dependent diabetes mellitus: relationship with metabolic control and estimated blood volume and effect of angiotensin-converting enzyme inhibition.

11 beta-Hydroxysteroid dehydrogenase (11 beta HSD) catalyzes the interconversion of cortisol and its inactive metabolite, cortisone, and protects the mineralocorticoid receptor from activation by cortisol. Sodium and fluid retention is a well documented phenomenon in insulin-dependent diabetes mellitus (IDDM), but it is not known whether diabetes-associated alterations in cortisol metabolism contribute to its pathogenesis. Therefore, we evaluated some aspects of cortisol metabolism by measuring urinary metabolites of cortisol and cortisone in eight microalbuminuric and eight normoalbuminuric IDDM patients and eight matched control subjects. In both IDDM groups, the overnight excretion of tetrahydrocortisol (THF), allo-tetrahydrocortisol (allo-THF), and tetrahydrocortisone (THE) was lower than that in the control group (P < 0.05 to P < 0.01). Both the allo-THF/THF ratio, a parameter of 5 alpha/5 beta-reduction of cortisol, and the cortisol to cortisone metabolite ratio (THF+allo-THF/THE), which reflects the overall direction of the cortisol to cortisone interconversion, were lower in the IDDM groups (P < 0.05 to P < 0.01). In the combined subjects (n = 24), allo-THF, allo-THF/THF, and THF+allo-THF/THE were inversely correlated with hemoglobin A1c (r = -0.69, P < 0.001; r = -0.61, P < 0.01; and r = -0.58, P < 0.01, respectively). Upper arm segmental blood volume, estimated by an electrical impedance technique, was positively correlated with the cortisol to cortisone metabolite ratio in both the control subjects (r = 0.77; P < 0.05) and the IDDM patients in whom it was measured (r = 0.56; P < 0.05; n = 13), whereas the regression line was shifted leftward in IDDM (i.e. a lower ratio at the same blood volume; P < 0.03, by analysis of covariance). In seven microalbuminuric IDDM patients, the angiotensin-converting enzyme inhibitor, enalapril (10 mg daily for 6-12 weeks), resulted in a moderate further lowering of the cortisol to cortisone metabolite ratio (P < 0.05). The present data suggest a chronic hyperglycemia-related impairment in the reduction of corticoids to tetrahydro metabolites and an imbalance in 11 beta HSD. Altered 11 beta HSD activity is unlikely to be primarily responsible for the sodium and fluid retention in IDDM. Moreover, an additional mechanism of action of angiotensin-converting enzyme inhibition might be provided by an effect on 11 beta HSD activity.

Investigation of the arterial and venous upper arm vascular bed.

Studies concerning vascular changes in hypertension and exercise have shown an increasing need to investigate the properties of a complete vascular bed in vivo. In this study, the repeatability of a non-invasive method for quantifying properties of the vascular bed of an upper arm segment, was investigated in two groups of volunteers (age 22-55 years). One group of subjects (n = 9) were measured twice at a 15 min interval. The other group (n = 8) were measured 4 times with each subject measured daily at the same time. The estimated quantities included the arterial and venous blood volume, the static arterial compliance, the myogenic response of the arm veins and the extravascular fluid volume of the tissue under an occluding cuff at the upper arm. They not only describe properties of the arterial vascular bed as a whole but also of different sized arteries functioning at different intra-arterial pressure. They were derived from the fluid shifts under the occluding cuff that arise when cuff pressure changes, as determined by electrical impedance and blood pressure measurements. The repeatability of the method was well within the physiologically acceptable range and of the same order of magnitude as that of established methods. Established methods however, provide less information about the properties of a vascular bed and result in controversial estimates of the dynamic arterial compliance. Furthermore, the method eliminates the need to match subjects in comparative studies for arterial blood pressure. These features and the sensitivity of the method for (patho)physiological changes, offer the possibility to investigate in vivo many still unknown aspects of the peripheral circulation.

Estimation of blood pressure-related parameters by electrical impedance measurement.

In 13 healthy volunteers a computerized experimental set-up was used to measure the electrical impedance of the upper arm at changing cuff pressure, together with the finger arterial blood pressure in the contralateral arm. On the basis of a model for the admittance response, the arterial blood volume per centimeter length (1.4 +/- 0.3 ml/cm), the venous blood volume as a percentage of the total blood compartment (49.2 +/- 12.6%), and the total arterial compliance as a function of mean arterial transmural pressure were estimated. The effective physiological arterial compliance amounted to 2.0 +/- 1.3 microliters.mmHg-1.cm-1 and the maximum compliance to 33.4 +/- 12.0 microliters.mmHg-1.cm-1. Additionally, the extravascular fluid volume expelled by the occluding cuff (0.3 +/- 0.3 ml/cm) was estimated. These quantities are closely related to patient-dependent sources of an unreliable blood pressure measurement and vary with changes in cardiovascular function, such as those found in hypertension. Traditionally, a combination of several methods is needed to estimate them. Such methods, however, usually neglect the contribution of extravascular factors.