A. J. H. M. Houben

Bone metabolism during anti-thyroid drug treatment of endogenous subclinical hyperthyroidism

OBJECTIVE There is recent evidence that both exogenous and endogenous subclinical thyrotoxicoses are associated with decreased bone mineral density. Scanty information is available on bone metabolism in these conditions when euthyroidism is restored. We evaluated the effect of anti‐thyroid drug treatment on bone metabolism in endogenous subclinical hyperthyroidism.

Vascular and renal actions of brain natriuretic peptide in man: physiology and pharmacology

During the last decade brain natriuretic peptide (BNP) has received increasing attention as a potential marker of cardiovascular disease. BNP may act as a compensating mechanism in cardiovascular diseases in order to reduce preload. However, the increase in endogenous BNP is often not sufficient to compensate for volume overload in diseases like established hypertension and heart failure. The reported hemodynamic and renal effects of BNP in man differ largely between studies, because of differences in design and doses of BNP employed. In the pharmacological range, BNP has clear blood pressure and afterload lowering effects, and in the kidney blood flow and filtration is increased with concomitant natriuresis and diuresis. While in the physiological range BNP does not affect blood pressure and reduces preload only, and induces natriuresis/diuresis without changes in renal blood flow and filtration. There is increasing evidence from vascular studies that BNP preferentially acts on the venous system resulting in preload reduction, in contrast to atrial natriuretic peptide which acts preferentially on the arterial system to reduce afterload. This review summarizes our current understanding of BNP, and discuss its regulation and mechanisms of action on the vasculature and the kidneys.

Nitric oxide and potassium channels are involved in brain natriuretic peptide induced vasodilatation in man.

Objective Brain natriuretic peptide (BNP) causes vasodilatation but the mechanisms by which this is accomplished are not fully known. The aim of the present study was to determine whether, besides K+Ca2+-channels, nitric oxide (NO) is involved in BNP-induced vasodilatation. Methods We studied 10 healthy males twice, in random order, at an interval of 2 weeks. Experiments always started with infusion of BNP (8–16–32–64 pmol/dl per min) into the brachial artery. On the first day this infusion was followed by a second BNP infusion combined with the K+Ca2+-channel-blocker, tetraethylammonium (TEA, 0.1 mg/dl per min), and on the other day by BNP infusion combined with the NO-synthase inhibitor, l-NG-monomethyl arginine (l-NMMA, 0.8 μmol/dl per min). The latter was then followed by a combined infusion of BNP, l-NMMA and TEA. All infusions were separated by a 1 h washout period. Forearm blood flow (FBF) was determined by venous occlusion plethysmography. Results Mean arterial pressure and heart rate did not change during any of the experiments. BNP alone induced a dose-dependent dilatation, which was similar on both days. TEA, l-NMMA, and their combination all reduced the BNP-induced dilatation (P < 0.05). The combined infusion had a significantly greater effect than TEA alone (P = 0.005). BNP infusions were associated with a significant increase in plasma cyclic guanosine monophosphate (cGMP) and C-type natriuretic peptide (CNP) (P < 0.05). Conclusions BNP induces arterial vasodilatation not only by opening K+Ca2+-channels, but also via stimulation of NO production. In addition, BNP stimulates net CNP increase.

Quantitative analysis of retinal vascular changes in essential and renovascular hypertension.

Patients and methods A cross-sectional prospective study was performed in 10 patients with essential hypertension and nine with renovascular hypertension selected from the outpatient clinic (continuing medication) compared with eight age-matched normotensive control subjects. Fundal photography was performed in both eyes, preceded or succeeded (in random order) by 24-h ambulatory blood pressure monitoring. The fundus photographs were projected on a glass table and vascular morphometric variables were determined. Vascular density was evaluated using a stereological technique with a square grid overlay. The main outcome measures were arterial and venous diameters near the optic disc and at the first bifurcation, vessel length, angles of bifurcating arteries and veins, and peripheral arteriolar and venular density. Results Both the arterial and the venous diameter was larger in the essential hypertensives and the renovascular hypertensives compared with the controls. Vascular diameter was positively correlated with mean arterial pressure during the night and with the night: day mean arterial pressure ratio (a measure of nocturnal blood pressure decline). Venular density was decreased in essential hypertension only and was not correlated with blood pressure. Conclusions Our quantitative retinal vascular analysis method detected an increased vascular diameter in both essential and renovascular hypertensives, which was related to night-time blood pressure and, in particular, to an attenuated nocturnal blood pressure decline. Vascular rarefaction in essential hypertension was not related to blood pressure and could influence the pathogenesis of essential hypertension.

Effects of brain natriuretic peptide on forearm vasculature: comparison with atrial natriuretic peptide

OBJECTIVE The aim of the present study was to determine the vasoactive effects of brain natriuretic peptide (BNP) as compared to those of atrial natriuretic peptide (ANP) in normal man. METHODS Ten healthy male subjects (median age 21 (20-23) year) were studied twice. In the first study equimolar doses (1, 3, and 10 pmol/dl/min) of both BNP and ANP (in random order and double blind) were infused into the brachial artery of the non-dominant arm with a 1-h wash-out period in between. In the second study two BNP (n = 5) or ANP (n = 5) dose-response curves were performed in order to assess the repeatability of the BNP/ANP infusions. To this end, BNP and ANP were infused in the same equimolar doses as in the first protocol. Forearm blood flow (FBF) was determined by venous occlusion plethysmography before and during infusions. RESULTS BNP increased the FBF ratio (infused/contralateral arm) by 6%, 17%, and 48%, respectively (p < 0.05), while ANP increased the FBF ratio by 4%, 58%, and 133% (p < 0.001). The slopes of the BNP dose-response curves differed significantly from those of the ANP curves (18.1 versus 43.2; p = 0.022). No differences were observed between the repeated dose-response curves of either BNP or ANP. CONCLUSIONS The present data demonstrate that BNP induces a dose-dependent vasodilatation in man. On a molar basis, however, this vasodilatation is significantly less than the vasodilatation induced by ANP. These differences may be related to differences in natriuretic-peptide-receptor affinity. Furthermore, our data show that the vasoactive effects of both BNP and ANP are repeatable in time.

Microvascular Abnormalities in Chronic Heart Failure: A Cross-Sectional Analysis

Objectives: Similar to what has been found in hypertension, elevated peripheral resistance in chronic heart failure (CHF) might be related to microvascular constriction and rarefaction. Our objective was to evaluate both structural and functional microvascular changes in patients with CHF in relation to left ventricular function and neurohumoral activation.

Asymmetry of Renal Blood Flow in Patients With Moderate to Severe Hypertension

Abstract—It is generally assumed that renal blood flow is symmetric in the absence of renal artery stenosis. The aim of the present study was to evaluate whether this is really the case. From a group of consecutive hypertensive patients who had undergone renal angiography, we selected those with patent renal arteries. In all of them selective renal blood flow (RBF) measurements (133Xenon washout technique) had been performed with blood sampling from aorta and both renal veins (n=148). Asymmetry of RBF, defined as ≥25% difference in RBF between left and right kidney, was present in 51% of the patients. Subjects with and without asymmetry did not differ in age, body mass index, blood pressure, creatinine clearance, renal volume, or activity of the renin-angiotensin system. The presence of asymmetry coincided with an increased rate of false-positive results on renal scintigraphy. Preliminary data suggest that there may be a relation between asymmetry and renal sympathetic nerve activity. This study demonstrates that asymmetry of RBF is a frequent finding in essential hypertension, which may confound the results of diagnostic tests for renal artery stenosis. Furthermore, the present results underscore the importance of studying the function of both kidneys separately, because it cannot be assumed that they are functionally equal.

Phase-Contrast Magnetic Resonance Flow Quantification in Renal Arteries: Comparison With 133Xenon Washout Measurements

Abstract—To assess the accuracy of 2D phase-contrast magnetic resonance (2D PC MR) renal artery flow measurements, data obtained with this technique were compared with those acquired with the 133Xenon-washout procedure. In addition, the 2D PC MR flow data were related to functional renal information as derived from selective arterial and venous renin sampling. In 53 patients suspected of having renovascular hypertension, MR angiography of the renal arteries was performed, followed by a 3-step angiographic procedure: (1) selective venous and arterial renin sampling; (2) assessment of the renal blood flow by means of the 133Xenon washout technique, and (3) conventional renal angiography. After initial assessment, 71 kidneys were left for analysis. The overall prevalence of renovascular disease ≥50% stenosis was 18%. Mean renal blood flow as assessed with the 2D PC MR technique showed a significant correlation with the 133Xenon washout flow measurements, with a Pearson correlation coefficient of 0.69 (2-tailed;P <0.01). PC MR blood flow measurements correlated poorly with the presence and/or severity of renovascular disease on conventional angiography (r =0.1, P =0.36). Likewise, no statistically significant correlation with either renal venous renin levels or the renin ratio could be identified. Measurement of renal artery blood flow with the use of a 2D PC MR technique is technically feasible. However, the mean renal artery blood flow correlates poorly with either the presence of renovascular disease on angiography or with renin levels. Further improvement of this technique is necessary before it can be applied on a larger scale.

Diurnal variations in total forearm and skin microcirculatory blood flow in man

The aim of the present study was to determine diurnal variations in total forearm and skin microcirculatory blood flow in healthy man. At six time points between 08.00 and 18.00 hours was measured: blood pressure, forearm blood flow (FBF; strain gauge plethysmography), skin thermoregulatory blood flow (LDF; laser-Doppler fluxmetry), and skin nutritive blood flow (CBV: Capillary Blood Cell Velocity; intravital capillary microscopy) in 15 healthy, fasting, and resting men. FBF increased gradually from 2.8 in the morning to 4.3 ml 100 ml min-1 in the afternoon (p < 0.001). In contrast, LDF decreased, predominantly in the morning, from 18.3 at 09.00 hours to 13.1 at 12.00 hours and to 12.1 perfusion units at 17.30 hours (p < 0.001). However, performing the same protocol starting in the afternoon resulted in a similar initial decrease in LDF, suggesting an acclimatization phenomenon. Although not statistically significant, the decrease in CBV showed a similar pattern as compared to LDF. Blood pressure did not change. In conclusion, forearm blood flow increased during the day, probably due to diurnal variation in muscle flow. The initial decrease we observed in skin thermoregulatory blood flow is probably not related to diurnal variation but due to long-term acclimatization to the experimental conditions. These data suggest different regulatory mechanisms for the different vascular beds studied. Measurements of forearm blood flow should preferably be performed at the same time of day, and skin microcirculatory haemodynamic measurements should be performed after a standard period of acclimatization.

Changes in fibrinolytic activity after angiotensin II receptor blockade in therapy‐resistant hypertensive patients

Summary.  Background: In hypertensive patients, the activated renin–angiotensin system induces a prothrombotic state resulting from imbalance between coagulation and fibrinolysis. Although blood pressure cannot be regulated in therapy‐resistant hypertensive patients, they may still be responsive to medication that attenuates the renin–angiotensin system. Objective: Our objective was to study possible attenuating properties of angiotensin II type 1 receptor blockers (AT1RBs) on the prothrombotic state in therapy‐resistant hypertensive patients, focusing on parameters of fibrinolysis and coagulation. Methods: Fourteen therapy‐resistant hypertensive patients received AT1RB eprosartan infusion (45 and 150 μg kg–1) (study group), and 33 therapy‐resistant hypertensive patients received saline (0.9%) infusion (control group) prior to renal angiography. Baseline values of parameters of coagulation and fibrinolysis were set at 1.00, and relative changes were calculated. Results: Plasminogen activator inhibitor type 1 (PAI‐1) antigen showed non‐significant decreases in both the study group (arterial 1.00–0.45, venous 1.00–0.42) and control group (arterial 1.00–0.84, venous 1.00–0.88). PAI‐1 activity significantly decreased in the study group (arterial 1.00–0.72, venous 1.00–0.71) and control group (arterial 1.00–0.83, venous 1.00–0.94). In the study group, tissue‐type plasminogen activator (t‐PA) antigen decreased significantly (arterial 1.00–0.62, venous 1.00–0.67), whereas t‐PA activity significantly increased (arterial 1.00–6.15, venous 1.00–2.66). In the control group, t‐PA antigen remained unchanged. No changes were observed in blood pressure during and after infusion of eprosartan. Conclusion: Therapy‐resistant hypertensive patients show beneficial changes in fibrinolytic activity after infusion of a non‐pressor dose of AT1RB.