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Biomedical subjects

Frans Boomsma

Publications and source records attributed to Frans Boomsma.

At least 37 records · Page 2Linked to original sources
PubMed2005

Beneficial impact of spironolactone in diabetic nephropathy.

BACKGROUND: Aldosterone has been suggested to play a role in the initiation and progression of diabetic nephropathy. Currently recommended treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers [renin-angiotensin system (RAS) blockade] does not suppress circulating aldosterone sufficiently. We therefore aimed to evaluate the short-term effect of aldosterone antagonism with spironolactone on albuminuria and blood pressure in diabetic nephropathy. METHODS: Twenty Caucasian type 1 diabetic patients with persistent macroalbuminuria despite antihypertensive treatment, including RAS blockade, completed this double-masked, randomized cross-over trial. Patients were treated in random order with spironolactone 25 mg once daily and matched placebo for two months, respectively, on top of usual antihypertensive treatment. After each treatment period albuminuria, 24-hour blood pressure, and glomerular filtration rate (GFR) were determined. RESULTS: Spironolactone on top of usual antihypertensive treatment induced a 30% (95% CI 17 to 41) reduction in albuminuria from [geometric mean (95% CI)] 831 (624 to 1106) mg/24-hour on placebo treatment (P < 0.001), and a reduction in fractional albumin clearance of 35% (20 to 46, P < 0.001). Twenty-four-hour blood pressure showed an insignificant reduction of [mean reduction (95% CI)] 8 (-1 to 17)/3 (-0.2 to 7) mm Hg (P < 0.10). There was an insignificant reversible reduction in GFR during treatment with spironolactone. On spironolactone treatment, one patient was excluded due to hyperkalemia (plasma potassium 5.7 mmol/L) and one due to orthostatic dizziness. Otherwise treatment was well tolerated. CONCLUSION: Our results suggest that spironolactone treatment on top of recommended antihypertensive treatment reduces blood pressure and may offer additional renoprotection in type 1 diabetic patients with diabetic nephropathy.

Adult↗
PubMed2005

Liver X receptors alpha and beta regulate renin expression in vivo.

The renin-angiotensin-aldosterone system controls blood pressure and salt-volume homeostasis. Renin, which is the first enzymatic step of the cascade, is critically regulated at the transcriptional level. In the present study, we investigated the role of liver X receptor alpha (LXR(alpha)) and LXR(beta) in the regulation of renin. In vitro, both LXRs could bind to a noncanonical responsive element in the renin promoter and regulated renin transcription. While LXR(alpha) functioned as a cAMP-activated factor, LXR(beta) was inversely affected by cAMP. In vivo, LXRs colocalized in juxtaglomerular cells, in which LXR(alpha) was specifically enriched, and interacted with the renin promoter. In mouse models, renin-angiotensin activation was associated with increased binding of LXR(alpha) to the responsive element. Moreover, acute administration of LXR agonists was followed by upregulation of renin transcription. In LXR(alpha) mice, the elevation of renin triggered by adrenergic stimulation was abolished. Untreated LXR(beta) mice exhibited reduced kidney renin mRNA levels compared with controls. LXR(alpha)LXR(beta) mice showed a combined phenotype of lower basal renin and blunted adrenergic response. In conclusion, we show herein that LXR(alpha) and LXR(beta) regulate renin expression in vivo by directly interacting with the renin promoter and that the cAMP/LXR(alpha) signaling pathway is required for the adrenergic control of the renin-angiotensin system.

Animals↗
PubMed2005

Beneficial effects of adding spironolactone to recommended antihypertensive treatment in diabetic nephropathy: a randomized, double-masked, cross-over study.

OBJECTIVE: The objective of this study was to evaluate the safety and short-term effect of adding spironolactone to conventional antihypertensive treatment including diuretics and maximally recommended doses of an ACE inhibitor or an angiotensin II receptor blocker (ARB) on albuminuria and blood pressure in type 2 diabetic patients with nephropathy. RESEARCH DESIGN AND METHODS: Twenty-one type 2 diabetic patients with nephropathy were enrolled in a randomized, double-masked, cross-over study. Patients were treated in random order with spironolactone 25 mg once daily and matched placebo for 8 weeks, respectively, in addition to ongoing antihypertensive treatment including diuretics and maximally recommended doses of an ACE inhibitor and/or an ARB. At the end of each treatment period, albuminuria, 24-h ambulatory blood pressure (ABP), and glomerular filtration rate (GFR) were determined. RESULTS: During the addition of placebo, values were as follows: albuminuria (geometric mean [range]) 1,566 [655-7,762] mg/24 h, ABP (mean +/- SE) 138 +/- 3/71 +/- 1 mmHg, and GFR (mean +/- SE) 74 +/- 6 ml/min per 1.73 m2. During the addition of spironolactone, albuminuria was reduced by 33% (95% CI 25-41) (P < 0.001), fractional clearance of albumin by 40% (24-53) (P < 0.001), and 24-h ABP by 6 mmHg (2-10) for systolic and 4 mmHg (2-6) for diastolic (P < 0.001 for both). The change in albuminuria did not correlate with the change in systolic 24-h ABP (r = 0.19, P = 0.42) or diastolic 24-h ABP (r = 0.01, P = 0.96). Spironolactone treatment induced an insignificant reversible reduction in GFR of 3 ml/min per 1.73 m2 (-0.3 to 6) (P = 0.08). One patient was excluded from the study due to hyperkalemia. Otherwise treatment was well tolerated. CONCLUSIONS: Our study suggests that spironolactone safely adds to the reno- and cardiovascular protective benefits of treatment with maximally recommended doses of ACE inhibitor and ARB by reducing albuminuria and blood pressure in type 2 diabetic patients with nephropathy.

Antihypertensive Agents↗
PubMed2005

Does angiotensin (1-7) contribute to the anti-proteinuric effect of ACE-inhibitors.

Angiotensin-converting enzyme inhibitors (ACE-I) reduce proteinuria and protect the kidney in proteinuric renal disease. During ACE-I therapy, circulating levels of angiotensin (1-7) [Ang (1-7)] are increased. As cardiac and renal protective effects of Ang (1-7) have been reported, we questioned whether Ang (1-7) contributes to the anti-proteinuric effects of ACE-I treatment. Therefore, we evaluated whether Ang (1-7) infusion reduces proteinuria in a rat model of adriamycin-induced renal disease. In addition, the effect of a selective Ang (1-7) blocker, [D-Ala7]-Ang (1-7) (A779), was investigated in rats treated with the ACE-I, lisinopril (LIS). Six weeks after induction of proteinuria, therapy was started in four different groups: control, Ang (1-7), LIS, and LIS+A779. After two weeks, the rats were sacrificed. Six weeks after injection of adriamycin, the rats had developed proteinuria of 323+/-40 mg/24 hours. The proteinuria remained stable in the control group and in the Ang (1-7) group, but was reduced in both LIS and LIS+A779-treated groups. Similarly, blood pressure (BP) was unchanged in the control and the Ang (1-7) groups, but reduced in both the LIS and the LIS+A779 groups. Plasma levels of Ang (1-7) were increased in the Ang (1-7) and in both LIS-treated groups. We conclude that systemic Ang (1-7) plays no major role in the anti-proteinuric and BPlowering effects of ACE-I in this rat model of adriamycin-induced nephrosis.

Angiotensin I↗
PubMed2004

Myocardium tolerant to an adenosine-dependent ischemic preconditioning stimulus can still be protected by stimuli that employ alternative signaling pathways.

Clinical studies on cardioprotection by preinfarct angina are ambiguous, which may involve development of tolerance to repeated episodes of ischemia. Not all preconditioning stimuli use identical signaling pathways, and because patients likely experience varying numbers of episodes of preinfarct angina of different degrees and durations, it is important to know whether myocardium tolerant to a particular preconditioning stimulus can still be protected by stimuli employing alternative signaling pathways. We tested the hypothesis that development of tolerance to a particular stimulus does not affect cardioprotection by stimuli that employ different signaling pathways. Anesthetized rats underwent classical, remote or pharmacological preconditioning. Infarct size (IS), produced by a 60-min coronary artery occlusion (CAO), was determined after 120 min of reperfusion. Preconditioning by two 15-min periods of CAO (2CAO15, an adenosine-dependent stimulus) limited IS from 69 +/- 2% to 37 +/- 6%, but when 2CAO15 was preceded by 4CAO15, protection by 2CAO15 was absent (IS = 68 +/- 1%). This development of tolerance coincided with a loss of cardiac interstitial adenosine release, whereas two 15-min infusions of adenosine (200 microg/min i.v.) still elicited cardioprotection (IS = 40 +/- 4%). Furthermore, cardioprotection was produced when 4CAO15 was followed by the adenosine-independent stimulus 3CAO3 (IS = 50 +/- 8%) or the remote preconditioning stimulus of two 15-min periods of mesenteric artery occlusion (IS = 49 +/- 6%). In conclusion, development of tolerance to cardioprotection by an adenosine-dependent preconditioning stimulus still allows protection by pharmacological or ischemic stimuli intervention employing different signaling pathways.

Adaptation, Physiological↗
PubMed2004

Contribution of endothelin to coronary vasomotor tone is abolished after myocardial infarction.

Left ventricular dysfunction in swine with a recent myocardial infarction (MI) is associated with neurohumoral activation, including increased catecholamines and endothelin (ET). Although the increase in ET may serve to maintain blood pressure and, hence, perfusion of essential organs such as the heart and brain, it could also compromise myocardial perfusion by evoking coronary vasoconstriction. In the present study, we tested the hypothesis that endogenous ET contributes to perturbations in myocardial O2 balance during exercise in remodeled myocardium of swine with a recent MI. For this purpose, 26 chronically instrumented swine (10 with and 16 without MI) were studied at rest and while running on a treadmill at 1-4 km/h. After MI, plasma ET increased from 3.2 +/- 0.4 to 4.9 +/- 0.3 pM (P < 0.05). In normal swine, blockade of ETA (by EMD-122946) or ETA-ETB (by tezosentan) receptors resulted in an increase in coronary venous PO2, i.e., coronary vasodilation at rest, which decreased during exercise. In contrast, neither ETA nor ETA-ETB receptor blockade resulted in coronary vasodilation in swine with MI. Coronary vasoconstriction to intravenous ET-1 infusion in awake resting swine was blunted after MI. To investigate whether factors released by cardiac myocytes contributed to decreased vascular responsiveness to ET, we performed ET-1 dose-response curves in isolated coronary arterioles (70-200 microm). Vasoconstriction to ET-1 in isolated arterioles from MI swine was enhanced. In conclusion, the vasoconstrictor influence of endogenous as well as exogenous ET on coronary circulation in vivo is reduced. Because the response of isolated coronary arterioles to ET is increased after MI, the reduced vasoconstrictor influence in vivo suggests modulation of ET receptor sensitivity by cardiac myocytes, which may serve to maintain adequate myocardial perfusion.

Animals↗
PubMed2004

Extracellular signal regulated kinase and SMAD signaling both mediate the angiotensin II driven progression towards overt heart failure in homozygous TGR(mRen2)27.

Angiotensin (Ang) II is a key player in left ventricular (LV) remodeling and cardiac fibrosis. Its effects are thought to be transferred at least in part by mitogen-activated protein kinases (MAPK), transforming growth factor (TGF) beta1, and the Smad pathway. In this study we sought to elucidate whether Ang II related effects on LV dysfunction and fibrosis in vivo are mediated via MAPK or rather via Smad stimulation. We treated homozygous REN2 rats (7-11 weeks) with placebo, Ang II type 1 (AT1) receptor blocker or tyrphostin A46 (TYR), an inhibitor of epidermal growth factor receptor tyrosine kinase that blocks extracellular signal-regulated kinase (ERK) activity. REN2 rats had LV hypertrophy (LVH) and LV dysfunction that progressed to heart failure between 10 and 13 weeks. Blood pressure normalized over time. Renin, N-terminal atrial natriuretic peptide (N-ANP), and ERK were activated while p38 MAPK was not. Treatment with AT1 receptor blockade prevented LVH and right ventricular hypertrophy, normalized systolic and diastolic d P/d t, N-ANP levels, and reduced collagen apposition. Similarly, TYR reduced LVH, N-ANP levels, and collagen apposition. Myocardial ERK activation did not depend on AT1 receptor signaling as it was not affected by AT1 receptor blockade. TYR abolished myocardial ERK activity. Smad2 activation was inhibited by AT1 receptor blockade but was unaltered by TYR. Ang II induced LV remodeling and fibrosis are dependent on both ERK and Smad2 activation. This process is prevented by both AT1 receptor blockade and TYR, and therefore inhibition of either pathway is equally efficacious in restoring LV function and architecture.

Angiotensin II↗
PubMed2004

Impaired renal function in patients with ischemic and nonischemic chronic heart failure: association with neurohormonal activation and survival.

BACKGROUND: Renal dysfunction is a strong predictor of mortality in chronic heart failure (CHF). Most patients with CHF have atherosclerotic vascular disease, and several authors have suggested that impaired renal function is only a marker of advanced atherosclerosis. We compared renal function in patients with ischemic and nonischemic CHF and examined associations with prognosis and extent of neurohormonal activation. METHODS: In a large survival study (1906 patients), patients with documented coronary artery disease (CAD, n = 995), were compared with patients with idiopathic dilated cardiomyopathy (IDC, n = 429). In a smaller substudy, plasma neurohormones were determined in 270 patients and 37 patients (CAD and IDC, respectively). All patients had advanced CHF (New York Heart Association functional class III-IV). At baseline, the mean patient age was 64 +/- 10 years, and the mean left ventricular ejection fraction was 0.26 +/- 0.08. The baseline glomerular filtration rate was calculated with the Cockcroft-Gault equation (GFRc). RESULTS: GFRc was a strong predictor for mortality in both groups on multivariate analysis. The relative risk was 3.04 for patients with IDC (P < or =.01, for the lowest quartile < or =53 mL/min), and the relative risk for patients with CAD was 1.81 (P =.01 for the lowest quartile < or =42 mL/min). Plasma neurohormones showed a relation with GFRc in both groups. CONCLUSIONS: GFRc is related to survival and plasma neurohormones in both patient groups. In patients with IDC, this association appears to be at least as strong as in patients with CAD.

Aged↗
PubMed2004

Atrial natriuretic peptides during experimental atrial tachycardia: role of developing tachycardiomyopathy.

INTRODUCTION: Atrial tachycardia and chronic heart failure (CHF) are associated with elevated levels of atrial natriuretic peptide (ANP) and its amino terminal part NT-ANP. Chronic high atrial rates may cause CHF due to a rapid ventricular response. The aim of this study was to establish the contribution of elevated atrial rate and of high ventricular rate, resulting in CHF, on ANP and NT-ANP levels during chronic atrial tachycardia. METHODS AND RESULTS: Thirteen goats (AV-paced group) were subjected to 4 weeks of rapid AV pacing with an atrial and ventricular rate of 240 beats/min. Another five goats (A-paced group) were subjected to 4 weeks of atrial pacing at 240 beats/min while the ventricular rate was kept low and regular at 80 beats/min. Pacing was interrupted only for measurement of right atrial (RA) and left ventricular (LV) diameter and sampling for ANP, NT-ANP, and renin. In the AV-paced group, RA and LV diameter reached 152% and 109% of baseline values, respectively. Both ANP and NT-ANP (8.3 +/- 9.2 pmol/L and 0.5 +/- 0.4 nmol/L at baseline, respectively) increased progressively (53.1 +/- 37.9 pmol/L and 2.0 +/- 0.9 nmol/L, respectively, after 4 weeks). There was a significant correlation between the magnitude of atrial dilation and natriuretic peptide levels after 3 days. In A-paced goats, however, RA and LV diameters did not change. Furthermore, ANP and NT-ANP levels (9.1 +/- 6.0 pmol/L and 0.8 +/- 0.2 nmol/L at baseline, respectively) were unchanged after 4 weeks (5.3 +/- 3.4 pmol/L and 0.6 +/- 0.2 nmol/L, respectively). CONCLUSION: Elevated levels of ANPs during chronic atrial tachycardia are related to a high ventricular rate rather than a high atrial rate alone. Rather than atrial tachycardia, the atrial hemodynamic burden is an important determinant of the sustained ANP response.

Animals↗
PubMed2004

Role of bradykinin B2-receptor in the sympathoadrenal effects of 'new pressor protein' related to human blood coagulation factor XII fragment.

BACKGROUND: Human plasma new pressor protein (NPP) increases blood pressure, heart rate and plasma adrenal medullary catecholamines in bioassay rats - all potentiated by angiotensin-converting enzyme (ACE) inhibition. High plasma NPP activity has been found in haemodialysis patients with hypertension. OBJECTIVE: To investigate whether the bradykinin B2-receptor mediates the effects of NPP. METHODS AND RESULTS: Male Wistar bioassay rats were anaesthetized with inactin, ganglion blocked with pentolinium and injected intravenously (i.v.) with human NPP (20 microl plasma equivalent) or bradykinin (100 ng/kg). Both NPP and bradykinin increased systolic (SBP) and diastolic (DBP) blood pressures, heart rate and plasma adrenaline and noradrenaline concentrations. All these responses were potentiated by the ACE inhibitor, captopril (10 mg/kg i.v.), but not by antagonism of the angiotensin II type 1 receptor with losartan (10 mg/kg i.v.). Administration of the bradykinin B2-receptor antagonist, HOE-140 (20 microg/kg i.v.), significantly attenuated the peak NPP responses as follows: SBP from 58 +/- 3 to 40 +/- 4 mmHg (decrease of 30%; P < 0.05); DBP from 22 +/- 4 to 10 +/- 1 mmHg (decrease of 55%; P < 0.05); heart rate from 124 +/- 8 to 28 +/-6 beats/min (decrease of 77%; P < 0.05); plasma adrenaline from 14297 +/- 2477 to 3318 +/- 1105 pg/ml (decrease of 77%; P < 0.05) and noradrenaline from 505 +/- 66 to 77 +/-29 pg/ml (decrease of 85%; P < 0.05). CONCLUSIONS: The haemodynamic and sympathoadrenal effects of NPP involve substantial mediation by the bradykinin B2-receptor, in addition to other mechanisms.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2004

Validation of a new automated renin assay.

BACKGROUND: Measurement of plasma renin is important for the treatment of patients with congenital adrenal hyperplasia (CAH) and in the evaluation of patients with suspected hyperaldosteronism. Immunologic assays for plasma renin offer easier implementation and standardization than enzyme-kinetic assays for plasma renin activity, but their sensitivity and specificity have been questioned. We studied a renin immunochemiluminescence assay on an automated platform. METHODS: Renin was measured by an enzymatic assay, by IRMA, and by the new Nichols Advantage Specialty System immunochemiluminometric assay (ICMA), in plasmas from unselected individuals from our outpatient departments and in samples from patients with selected diagnoses. RESULTS: The detection limit in the ICMA was 0.1 mU/L. The recovery was >90%, and the imprecision (CV) was generally <9%. Mean (SD) concentrations measured by ICMA were 32 (21)% lower than those measured by IRMA. Renin concentrations as measured by ICMA were identical in serum and EDTA-, heparin-, and citrate-anticoagulated plasmas. Prolonged incubation of whole blood at room temperature before centrifugation did not affect renin concentrations. The central 95% interval for 80 healthy adults was 6-85.5 mU/L. Plasma renin as assessed by ICMA in patients with primary hyperaldosteronism was <0.2 mU/L. CONCLUSIONS: The performance characteristics of the new renin ICMA allow its use for patients with CAH and for the diagnosis of mineralocorticoid hypertension. In view of the variability of renin concentrations, use for other forms of hypertension or physiologic research calls for the development of uniform sampling protocols.

Adolescent↗
PubMed2004

Comparison of catecholamine hormone release in patients undergoing carotid artery stenting or carotid endarterectomy.

PURPOSE: To investigate the pattern of catecholamine response in patients undergoing carotid endarterectomy (CEA) or carotid artery stenting (CAS). METHODS: Adrenaline, noradrenaline, and renin levels were measured at 5 time points in 12 patients undergoing 13 CEAs (1 bilateral) and 13 patients undergoing unilateral CAS. Arterial blood samples were taken at the following time points: (1) after induction in CEA patients or 5 minutes following first contrast injection in CAS patients, (2) 5 minutes following ICA clamp release in surgical patients or deflation of the balloon in the CAS cohort, (3) 60 minutes following ICA clamp release in surgical patients or deflation of the balloon in the CAS cohort, and (4) 24 hours following the procedure. Intraoperative blood pressure and heart rate were recorded using radial arterial monitoring. Changes in adrenaline, noradrenaline, and renin levels are expressed as ratios versus baseline. RESULTS: Patterns of adrenaline and noradrenaline release were significantly different in patients undergoing CAS and CEA, with much higher and more variable surges of adrenaline and noradrenaline occurring in CEA patients. Adrenaline and noradrenaline levels increased significantly over baseline following carotid artery clamping in patients undergoing CEA (noradrenaline ratio before clamping: 1.54+/-1.25, 24 hours after unclamping: 8.38+/-16.35 [p<0.001]; adrenaline ratio before clamping: 1.12+/-0.49, 60 minutes after unclamping: 17.59+/-19.14 [p<0.001]). Conversely, in patients undergoing CAS, catecholamine levels remained unchanged (noradrenaline ratio before dilation: 0.96+/-0.23, 24 hours after the procedure: 0.92+/-0.32 [p=NS]; adrenaline ratio before dilation: 0.83+/-0.33, 60 minutes after balloon deflation: 0.56+/-0.32 [p=NS]). CONCLUSIONS: CAS is associated with a significantly less marked catecholamine response than CEA, which may reflect down-regulation of the sympathetic nervous system in response to carotid sinus stimulation during carotid angioplasty.

Aged↗
PubMed2004

Responsivity to stress in chronic posttraumatic stress disorder due to childhood sexual abuse.

The purpose of this study was to investigate psychological, cardiovascular, and neuroendocrine reactivity to standardized stress tests (orthostatic challenge, Stroop Color Word Test) in drug-free adult women with chronic PTSD due to repetitive childhood sexual abuse. At baseline, the 11 patients showed significantly higher mean scores on the Symptom Check List-90 and the Profile of Mood States than 13 healthy female controls, whereas baseline cardiovascular or hormonal parameters showed no differences between the groups. Also, no significant differences were found between the two groups in cardiovascular and hormonal responsivity to the stress tests. Thus, in the presence of robust psychological differences, the patients with chronic PTSD due to childhood sexual abuse did not show alterations in baseline values of neurobiological parameters, nor did they react differently to a physical and mental stress test when compared to healthy controls.

Adult↗
PubMed2003

Are cardiovascular and sympathoadrenal effects of human "new pressor protein" preparations attributable to human coagulation beta-FXIIa?

"New pressor protein" (NPP) derived from normal human plasma is an extra renal enzyme that shares strong sequence homology with human coagulation beta-FXIIa. Under our bioassay conditions, human NPP (10-20 microl plasma equivalent/ approximately 300 g rat iv) can raise the systolic blood pressure (SBP) by 40-50 mmHg, the diastolic blood pressure (DBP) by 15-20 mmHg, and the heart rate (HR) by 70-90 beats/min. Plasma epinephrine (of adrenal medullary origin) and norepinephrine rise by about 50- and 10-fold, respectively. Because beta-FXIIa is not normally associated with pressor properties, we endeavored to substantiate that the hypertensive effects of impure NPP preparations used in our experiments are attributable to their content of beta-FXIIa. We carried out comparisons with highly purified (>90%) commercial human beta-FXIIa and found that by gel filtration (Sephadex G-100 and G-75), NPP bioactivity appeared in the approximately 30-kDa elution zone, consistent with the molecular mass of beta-FXIIa. Retention time using fast-protein liquid chromatography anion exchange chromatography was identical. Molecular mass and comigration were confirmed by SDS-PAGE gel electrophoresis, and the recovered approximately 30-kDa protein bands yielded beta-FXIIa fragments identified by mass spectrometry. Matched doses of the NPP preparations produced dose-response curves very similar to those elicited by beta-FXIIa with respect to increments of SBP, DBP, and HR, whereas plasma catecholamine increments were generally comparable. We propose that beta-FXIIa is substantially, if not exclusively, responsible for the observed effects of our NPP preparations and that this points to a novel axis connecting the FXII coagulation cascade and the sympathoadrenal gland to other cardiovascular regulatory mechanisms.

Amino Acid Sequence↗
PubMed2003

Contribution of endothelin and its receptors to the regulation of vascular tone during exercise is different in the systemic, coronary and pulmonary circulation.

OBJECTIVES: Exercise-induced vasodilation is thought to be mediated through various vasodilator substances, but blunting the influence of vasoconstrictors such as ET may also play a role. However, the role of ET and its receptors in the regulation of systemic, pulmonary and coronary vascular resistance is incompletely understood. The aim of this study was to identify the contribution of ET-1 through the ET(A) and ET(B) receptors to the regulation of tone in the systemic, coronary and pulmonary beds at rest and during exercise. METHODS: Ten chronically instrumented swine were studied while running on a treadmill before and after ET(A) blockade (EMD122946) or ET(AB) blockade (tezosentan). RESULTS: At rest, EMD122946 resulted in vasodilation in the coronary and systemic circulation, evidenced by a decrease in coronary and systemic vascular resistance and an increase in coronary and mixed venous O(2)-saturation. These effects waned during exercise. The effect of tezosentan on the systemic vasculature was similar to that of EMD122946, whereas it was smaller in the coronary circulation. EMD122946 had no effect on the pulmonary vasculature, whereas tezosentan decreased pulmonary resistance but only during exercise. CONCLUSIONS: ET exerts a constrictor influence on the coronary and systemic circulation through the ET(A)-receptor, which decreases during exercise thereby contributing to metabolic vasodilation. ET exerts a tonic vasodilator influence on coronary resistance vessels through the ET(B)-receptor. Finally, ET exerts an ET(B)-mediated constrictor influence in the pulmonary vasculature during exercise.

Animals↗
PubMed2003

Possible role of new pressor protein in hypertensive anephric hemodialysis patients.

Unexplained hypertension was observed in three anephric children on hemodialysis. We investigated the possible involvement of a novel hypertensive extra-renal enzyme new pressor protein (NPP), related to coagulation beta-FXIIa. Currently, NPP activity can only be determined by a rat bioassay model. On study day 1, pre dialysis, patients 1, 2, and 3 were hypertensive and their plasmas raised rat systolic blood pressure (SBP) by 45, 34, and 9 mmHg, respectively. Post dialysis, patients 1 and 2 reached their estimated dry body weight and their systemic pressures dropped, while patient 3 remained hypertensive and hypervolemic. Their post-dialysis plasmas raised rat SBP by 22, 14, and 9 mmHg, respectively. On day 2, similar relationships between patient SBP, volume status, and plasma NPP-like activity in rats were observed. The characteristic rat BP responses, lack of inhibition by captopril (ruling out a renin-mediated effect), and inhibition by soybean trypsin inhibitor support co-identity with NPP. Plasma FXIIa (combined alpha-FXIIa and beta-FXIIa) was measured by immunoassay and found to be elevated in all patients. This investigation suggests that there is high endogenous NPP activity in the plasmas of these hypertensive hemodialysis patients, it changes with SBP and fluid volume, and is a possible contributor to their hypertension. Further studies are required to examine the wider applicability of these novel findings.

Adolescent↗
PubMed2003

Plasma semicarbazide-sensitive amine oxidase in human (patho)physiology.

Semicarbazide-sensitive amine oxidases (SSAO) are widely distributed enzymes, with as yet not fully elucidated functions and roles, present in many tissues but also circulating in plasma. The enzyme also functions as an adhesion molecule, the vascular adhesion protein-1. In healthy humans, plasma SSAO activity is constant from birth until 16 years of age, when it drops to lower values, gradually increasing again at advanced ages. When measuring SSAO activity, care should be taken to ensure proper preparation and storage conditions, and it should be realized that quite a few drugs unintentionally are good inhibitors, and sometimes even substrates, of SSAO. Under normal conditions SSAO activity is constant and inter-individual variation is small. In various pathophysiological conditions plasma SSAO activities are increased, most notably in diabetes mellitus (both type I and type II), in congestive heart failure and in cirrhotic liver inflammation. In patients with other vascular and inflammatory diseases plasma SSAO is normal, while it is low in children with congenital lung diseases. Interpretation of these changes is speculative, since source and regulation of plasma SSAO are as yet unknown. However, in two situations where the disease-causing process was ended (transplantation, delivery), plasma SSAO returned to normal. Many questions remain to be answered.

Amine Oxidase (Copper-Containing)↗