van den Meiracker Ah

Role of nitric oxide in modulating systemic pressor responses to different vasoconstrictors in man.

Objective Animal studies suggest that nitric oxide (NO) attenuates responses to endogenous vasoconstrictors. We investigated whether this also holds true in man by monitoring pressor responses to different vasoconstrictors during nitric oxide synthase (NOS) inhibition. Methods Systemic hemodynamic responses to intravenous infusions of three doses (each for 5 min) of angiotensin II (AngII) (2, 4 and 8 ng/kg per min), noradrenaline (NOR) (10, 30 and 70 ng/kg per min) and phenylephrine (PE) (0.5, 1.0 and 1.5 μg/kg per min) were monitored in 44 healthy subjects during saline. A second dose–response curve was obtained during NOS inhibition with a subpressor dose of NG- nitro-L-arginine-methyl ester (L-NAME) (5 μg/kg per min) or during a systemic NO clamp using combined systemic infusions of L-NAME (12.5 μg/kg per min) and nitroprusside. Blood pressure was measured in the brachial artery and other hemodynamic parameters were derived from this signal. Results Mean arterial pressure (MAP) increased 2 ± 2, 6 ± 1 and 16 ± 2 mmHg in response to AngII during saline, 7 ± 6, 15 ± 5 and 26 ± 6 mmHg during the subpressor dose of L-NAME (P < 0.05) and 11 ± 10, 18 ± 7 and 25 ± 6 mmHg during the systemic NO clamp (P < 0.001). These augmented responses of MAP were due to enhanced increments in systemic vascular resistance. Infusions of NOR and PE during saline resulted in dose-dependent increments in MAP and systemic vascular resistance. These increments were of comparable magnitude as those seen during AngII, but were not affected by NOS inhibition. Conclusion Our findings show that the systemic pressor response evoked by AngII, but not by NOR or PE, is enhanced during NOS inhibition, suggesting that AngII is associated with increased NO release that counteracts its blood pressure rising effect.

Potentiation of L-NAME-induced systemic and renal vasoconstrictor responses by alpha1-adrenoceptor antagonism.

Background Acute inhibition of nitric oxide synthase results in systemic and renal vasoconstriction, which might be attributable to unopposed activity of the sympathetic nervous (SNS) and the renin–angiotensin system (RAS). We studied the effects of NG-nitro-L-arginine methyl ester (L-NAME) during α1-adrenoceptor blockade and concomitant angiotensin II type 1 (AT1)-receptor blockade in hypertensive individuals pretreated with hydrochlorothiazide (Hct; 25 mg once daily). Methods Thirteen individuals (47 ± 9 years) were studied during administration of placebo, and after pretreatment with Hct + doxazosin (Dox; 8 mg twice daily for 9 days), with Hct + Dox + losartan (Los; 50 mg twice daily for 9 days), or (n = 5) with doxazosin or Dox + Los without hydrochlorothiazide. Mean arterial pressure (MAP) and cardiac output were derived from the finger blood pressure signal recorded by Finapres. Systemic vascular resistance (SVR) was calculated as MAP/cardiac output. Five renal clearance studies of 40 min were performed. Renal vascular resistance (RVR) was calculated as MAP divided by renal blood flow (RBF). L-NAME (12.5 μg/kg per min intravenously) was given during the third clearance period. Results MAP was 113 ± 11 mmHg at baseline and decreased to 99 ± 10 mmHg during the administration of Hct + Dox and to 92 ± 10 mmHg during Hct + Dox + Los. This decrease in MAP was caused by a decrease in SVR (P = 0.0009). Pretreatment with Hct + Dox or Hct + Dox + Los had no effect on glomerular filtration rate or RBF. Infusion of L-NAME during the administration of Hct + Dox resulted in an augmented (P < 0.0001) increase in MAP (18%), SVR (61%) and RVR (70%) compared with those observed with placebo (8, 30 and 49%, respectively). This augmentation was abolished by losartan. Conclusion L-NAME-induced systemic and renal vasoconstrictor responses are potentiated during α1-adrenoceptor blockade. This potentiation was abolished by AT1-receptor antagonism. In man, unopposed activity of the SNS or SNS and RAS is not involved in the systemic and renal vasoconstriction induced by L-NAME.

Acute and long-term effects of acebutolol on systemic and renal hemodynamics, body fluid volumes, catecholamines, active renin, aldosterone, and lymphocyte β-adrenoceptor density

Acebutolol is a relatively new beta-adrenoceptor blocking antagonist, possessing both beta 1-adrenoceptor selectivity and partial agonist activity (PAA). Its acute (24 h, 400 mg, twice daily) and long-term effects (3 weeks) on systemic and renal hemodynamics, body fluid volumes, hormones, and beta-adrenoceptor density on lymphocytes were studied in a single-blind placebo-controlled trial, in 10 hypertensive patients. The initial response to acebutolol (1-2 h) was a fall in heart rate (HR) (-9.6 +/- 2.7%), cardiac output (-16.0 +/- 3%), and stroke volume (SV) (-10.7 +/- 0.2%), and an increase in systemic vascular resistance (SVR) (18.0 +/- 3.9%). Mean arterial pressure (MAP) began to fall 2-3 h after dosing in parallel with a decrease in SVR. At the end of the acute study, MAP and SVR were decreased by 18.1 +/- 2.7% and 15.6 +/- 5.6%, respectively. By that time, HR and SV had returned to control values despite blockade of beta-adrenoceptors. After 3 weeks of treatment (mean dose of acebutolol 480 mg twice daily), the fall in MAP was 10.1 +/- 2.7% and HR was decreased by 13.0 +/- 2.3%. Renal blood flow and glomerular filtration rate did not change. Acute and long-term treatment had no effect on the density of lymphocyte-membrane beta-adrenoceptors. This could be explained by acebutolols beta 1 selectivity or, alternatively, this could be due to the drugs PAA.

Epinephrine-induced enhancement of sympathetic activity in humans: inhibition by nonselective as well as beta 1-selective beta-adrenoceptor blockade.

To collect further evidence that epinephrine (EPI) facilitates norepinephrine (NE) release in humans, the effect of a low-dose intravenous (i.v.) infusion of EPI (20 ng kg-1/min) on arterial levels of NE and on local production of NE in the forearm was studied both before and during isometric exercise, cold provocation, head-up tilting, and mental stress in 10 subjects with borderline to mild hypertension. Studies were performed during placebo, during beta 1-selective beta-adrenoceptor blockade with atenolol, 50 mg once daily, and during nonselective beta-blockade with bopindolol, 1 mg once daily. Atenolol and bopindolol were administered for 1 week, 2 weeks apart, in a randomized double-blind cross-over design. During infusion of EPI, which increased plasma EPI levels to within the high physiologic range, resting levels of NE increased from 214 +/- 20 to 263 +/- 26 pg/ml (p less than 0.01) and resting NE forearm production increased from 296 +/- 48 to 529 +/- 98 pg 100 ml/min-1 (p less than 0.01). The enhancement of these two indices of sympathetic activity by EPI, observed during placebo, was abolished by bopindolol as well as by atenolol. The response of arterial NE, but not the response of forearm NE production, to three of the four stress tests was also enhanced (p less than 0.05) by EPI. This enhancement was also abolished by both beta-adrenoceptor antagonists. Our findings support the hypothesis that physiologic levels of EPI are capable of enhancing sympathetic activity in humans. This effect is mediated by beta-adrenoceptors and can be blocked not only by a nonselective but also by a beta 1-selective beta-adrenoceptor antagonist.

8C.03: A KEY ROLE FOR ENDOTHELIN-1 IN THE PATHOGENESIS OF PREECLAMPSIA AND THE ASSOCIATED SUPPRESSION OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM.

Objective: Women with preeclampsia (PE) display low renin-angiotensin-aldosterone system (RAAS) activity and a high anti-angiogenic state, the latter characterized by high levels of soluble Fms-like tyrosine kinase-1(sFlt-1) and reduced levels of placental growth factor (PlGF). In the present study, we hypothesized that the RAAS suppression in PE is the consequence of the disturbed angiogenic balance. Design and method: In a group of pregnant women with hypertensive disease of pregnancy and a group of healthy pregnant women, matched for gestational age (GA) we measured mean arterial blood pressure (MAP), urinary protein-to-creatinine ratio (PCR), and the plasma levels of sFlt-1, PlGF, albumin, creatinine, endothelin-1 (ET-1), renin (concentration and activity, PRC and PRA), angiotensinogen, and aldosterone. Since initial analysis revealed that these parameters strongly correlated with each other, multiple regression analysis was applied to establish independent determinants of ET-1, PRC, aldosterone and PCR. A sFlt-1/PlGF ratio >85 was considered to be representative for a high anti-angiogenic state. Results: Of the 103 pregnant women included, 65 had a sFlt-1/PlGF ratio <85 and 38 had a ratio >85. Plasma ET-1 and creatinine levels were increased in women with a high ratio, whereas PRA and the plasma levels of renin, angiotensinogen, aldosterone and albumin were decreased in these women. The PRA-aldosterone relationship was identical in both groups. Multiple regression analysis revealed that PRC correlated independently with MAP and plasma ET-1 (R2 0.30). In turn, plasma ET-1 correlated positively with sFlt-1 and negatively with PRC (R2 0.52). Independent determinants of plasma aldosterone were GA and PRA (R2 0.56). Finally we found that plasma PlGF, plasma ET-1 and MAP determined PCR (R2 0.69). Conclusions: The high anti-angiogenic state in PE induces ET-1 activation. Together with the increased MAP in PE this factor suppresses renin release, and in parallel (via PRA reduction) aldosterone synthesis. The identical reduction in PRA and aldosterone argues against studies reporting that a high anti-angiogenic state, via a reduction of adrenal capillary density, selectively suppresses aldosterone. Since ET-1 also was a major determinant of PCR, our data reveal a key role for ET-1 in the pathogenesis of PE.

Effects of ibopamine on postural hypotension in pure autonomic failure.

We wished to determine whether ibopamine, a dopaminergic prodrug with weak agonist activity on α-and β-adrenoceptors, improves orthostatic tolerance in autonomie insufficiency. Three subjects with severe orthostatic hypotension resulting from pure autonomie failure (PAF) were studied. Direct arterial blood pressure (ABP) and heart rate (HR) were recorded continuously. Orthostatic tolerance was evaluated by 60° passive head-up tilting. Tilting was performed before and after a single oral 100-mg dose of ibopamine. Blood samples for measurement of plasma catecholamines, free epinine (the active metabolite of ibopamine), and conjugated epinine were taken at regular intervals. In all 3 subjects, orthostatic tolerance was greatly improved by ibopamine. This improvement occurred as soon as 10–30 min after administration of ibopamine and lasted 20–50 min. α-Adrenoceptor blockade with phentolamine abolished the effect of ibopamine. The interindividual pharmacokinetics of ibopamine varied considerably: Peak plasma concentrations of ibopamine in the three subjects were 2.8, 4.5, and 35.4 ng/ml, respectively. The high level of epinine in one patient was associated with severe hypertension and tachycardia. Ibopamine may be a valuable new pharmacologic treatment for orthostatic hypotension in PAF, but in light of the highly variable interindividual pharmacokinetics further studies must be performed before use of the compound can be advocated in this disorder.

Adrenaline-induced amplification of sympathetic activity during rest and stress: inhibition by non-selective and beta 1-selective beta-adrenoceptor blockade.

In a placebo-controlled randomized cross-over trial the effects of non-selective (bopindolol, 1 mg once daily for 1 week) and of β1-selective β-adrenocptor blockade (atenolol, 50 mg once daily for 1 week) on adrenaline-induced enhancement of basal and stimulated sympathetic activity were studied in 10 hypertensive subjects. During infusion of adrenaline (20 ng/kg per min) venous plasma adrenaline levels increased into the high physiological range. Resting concentrations of arterial plasma noradrenaline and of the basal production of noradrenaline in the forearm increased significantly (P < 0.01) during infusion of adrenaline. The increases in these two indices of sympathetic activity were abolished by bopindolol and by atenolol. Arterial noradrenaline, but not noradrenaline production, also increased in response to isometric exercise, cold provocation and mental stress during infusion of adrenaline (P < 0.05). These amplifications were also abolished by both β-adrenoceptor antagonists. Our findings provide further evidence in man for a stimulatory effect of adrenaline in the physiological range on sympathetic activity. This effect, which is supposed to be mediated by prejunctional β-adrenoceptors, can be blocked not only by non-selective, but also by β1-selective β-adrenoceptor antagonists.

8C.01: SFLT-1 AND PLGF MEASUREMENTS AND THEIR RATIO FOR THE DIAGNOSIS AND PROGNOSIS OF PREECLAMPSIA IN A HIGH-RISK COHORT.

Objective: The soluble Fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio has been introduced as a biomarker for diagnosing preeclampsia (PE) and the prediction of adverse pregnancy outcome. In a cohort of pregnant women with PE or at high risk of PE, the additive value of the sFlt-1/PlGF ratio for diagnosing PE and prediction of adverse pregnancy outcomes was investigated. Design and method: From September 2011 until August 2013 patients with suspected or confirmed clinical PE were recruited at the Erasmus MC. At time of admission, blood for measurement of sFlt-1 and PlGF was obtained. A sFlt-1/PlGF ratio of >85 was considered suggestive for PE. Clinical characteristics and pregnancy outcomes were retrieved from medical records. The clinical diagnosis of PE was made based on the ISSHP criteria, whereas the fullPIERS definition was used for the rating of adverse pregnancy outcomes. Results: A total of 96 patients were included. Of the patients, 53 (55%) met the clinical criteria of PE at time of blood sampling. In 11% of these patients (n = 6) the ratio was < 85 (false-negative), whereas in 14% (n = 6) of patients without clinical PE the ratio was >85 (false positive), resulting in positive and negative predictive values of 89% and 86% respectively. Three patients without clinical PE, but with a positive ratio, developed superimposed PE and 2 developed an adverse pregnancy outcome. In 2 of the 6 patients with clinical PE but a negative ratio, an adverse pregnancy outcome was encountered. Using a binary regression model with adjustment for gestational age < 34 weeks, clinical PE was associated with a 9 times increased risk for an adverse outcome, while this was 29 times for an elevated ratio (P = 0.036). Conclusions: The additive value of an increased ratio for diagnosing PE is limited since most patients with clinical PE also have a positive ratio. An elevated ratio is superior to the clinical diagnosis of PE for predicting an adverse pregnancy outcome.

Magnetic resonance imaging: beyond cardiac evaluation.

An increase in large artery stiffness is the major determinant for the rise in pulse pressure with increasing age. In addition, a number of studies has shown that pulse-wave velocity (PWV) is a predictor of cardiovascular mortality beyond classical risk factors, both in the general population and in populations with end-stage renal disease, diabetes or hypertension [1–6]. Because of this independent predictive property, assessment of PWV for the detection of subclinical vascular damage has been included in the 2007 Guidelines of the European Societies of Hypertension and Cardiology [7].