Search

OBJECTIVE--Heart failure is common in individuals with type 2 diabetes, and early detection of individuals at risk may offer opportunities for prevention. We aimed to explore 1) prospective associations of [...]

OBJECTIVE--We investigated whether the antiproteinuric effect of the direct renin inhibitor aliskiren is comparable to that of irbesartan and the effect of the combination. RESEARCH DESIGN AND METHODS--This was a [...]

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 [...]

Renin–angiotensin–aldosterone system blockade is a cornerstone in cardiovascular protection. Angiotensin-converting enzyme (ACE)-DD genotype has been associated with resistance to angiotensin-converting enzyme inhibition (ACEi), but data are conflicting. As sodium intake modifies the effect of ACEi as well as the genotype–phenotype relationship, we hypothesize gene–environment interaction between sodium-status, the response to ACEi, and ACE genotype.

Human ‘new pressor protein’ (NPP), related to coagulation beta-factor XIIa (ß-FXIIa), potently releases sympathoadrenal catecholamines in bioassay rats, with concurrent elevation of systolic and diastolic blood pressure (SBP/DBP) and heart rate (HR). Elevated plasma NPP/ß-FXIIa levels in hypertensive anephric pediatric patients on hemodialysis associated with fluid status and blood pressure changes were previously reported, suggesting that NPP/ß-FXIIa contributed to their hypertension.

To study the effects of addition of spironolactone to angiotensin-converting enzyme (ACE) inhibition or angiotensin II (AngII) receptor antagonism on proteinuria, blood pressure (BP) and renal function in overt type 2 diabetic nephropathy.

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).

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.

Angiotensin-converting enzyme (ACE) inhibitors provide effective intervention for cardiovascular and renal disease. Changes in angiotensin-(1-7) have been proposed to be involved in the mechanism of action of ACE inhibition (ACEi). In particular, an altered balance between angiotensin II and angiotensin-(1-7) might be involved. A shift in sodium status modifies the activity of the renin–angiotensin–aldosterone system and the effects of ACEi, but its effects on angiotensin-(1-7) are unknown. We therefore studied the effect of a shift in sodium intake on angiotensin-(1-7), during placebo and ACEi.

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.

BackgroundHuman 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.

High sodium intake blunts the efficacy of angiotensin (Ang)-converting enzyme (ACE) inhibition (ACEi), but the underlying mechanism is incompletely characterized. High sodium has been reported to increase vascular expression and vascular activity of ACE. To investigate whether high-dietary sodium–induced effects on vascular conversion of Ang I might be involved in the sodium-induced blunting of the response to ACEi, the authors studied the vasoconstrictor responses to Ang I and Ang II of isolated aortic rings from healthy rats on low dietary sodium (LS 0.05 NaCl) and high dietary sodium (HS 2.0 NaCl) after 3 weeks of ACEi (lisinopril 75 mg/L) or vehicle (CON). Blood pressure was similar in LS and HS in CON, but HS blunted the blood pressure response to ACEi. Functional conversion of Ang I was assessed as the difference in dose–response curves to Ang I and Ang II in parallel aortic rings. Sodium intake did not affect the dose–response curves to Ang I and Ang II in CON. In the ACEi groups, a significant difference was present between the curves for Ang I and Ang II on LS (EC50, 6.7 n M; range, 2.2–13 n M; P< 0.01) but not on HS (EC501.3 n M; range, 0.0–4.1 n M, median interquartile range, NS). Thus, HS blunts the ACEi-induced reduction of functional vascular Ang I conversion compared with LS. Whether the blunted functional vascular conversion is causally related to the blunted blood pressure response remains to be elucidated.

Beta-blocker therapy has been shown to be associated with an increase in the plasma concentration of A-type natriuretic peptide (ANP). Whether the plasma concentration of B-type natriuretic peptide (BNP), which is mainly derived from ventricular tissue, is also increased and whether this increase is caused by increased production or decreased metabolism by down-regulation of the natriuretic peptide-clearance receptor remains to be established. In a double-blind crossover study effects of 8 weeks' treatment of bisoprolol,10 mg once daily, and losartan, 50 mg once daily, on plasma concentrations of ANP, BNP, and N-terminal (Nt)-ANP and ambulatory blood pressure (ABP) were measured in 24 hypertensive patients. With bisoprolol plasma concentrations of ANP and BNP increased (P< 0.001) by 93 ± 88 (mean ± SD) and 148 ± 117, whereas these parameters did not change with losartan. Nt-ANP, which is not metabolized by the NP clearance receptor, increased by 83 ± 45, and increments in ANP and Nt-ANP were related (r 0.77, P< 0.001). The decrease in ABP was greater with bisoprolol than with losartan. Monotherapy with bisoprolol, but not with losartan, is associated with substantial increments in plasma concentrations of ANP, Nt-ANP, and BNP. As the magnitude of the increase in ANP and Nt-ANP was comparable, the -blocker–induced increase in NPs is not likely to be explained by a decrease in NP clearance receptor density.

Background:Hypovolemia is thought to have an important role in the pathogenesis of dialysis-related hypotension. Methods:We studied the effect of hypovolemia simulated by lower body negative pressure (LBNP) in 11 hypotension-prone (HP) and 11 hypotension-resistant (HR) hemodialysis patients. LBNP was applied stepwise from 0 to −20 to −40 mm Hg. Systolic arterial pressure, heart rate, and central venous pressure (CVP) were recorded continuously after cannulation of the right jugular vein. Stroke volume index was measured at each step echocardiographically. At the end of each level of LBNP, blood samples were obtained to measure norepinephrine (NE), epinephrine (E), and atrial natriuretic peptide (ANP) levels. Results:At baseline, CVP (12 ± 5 and 16 ± 7 mm Hg), heart rate (72 ± 9 and 70 ± 13 beats/min), cardiac index (2.3 ± 0.6 and 2.5 ± 0.9 L/min), NE (median, 341 pg/mL [range,198 to 789 pg/mL] and 365 pg/mL [range, 177 to 675 pg/mL] or 2.02 nmol/L [range, 1.17 to 4.66 nmol/L] and 2.16 nmol/L [range, 1.05 to 4.00 nmol/L]), E (median, 46 pg/mL [range, 18 to 339 pg/mL] and 58 pg/mL [range, 21 to 122 pg/mL] or 251 pmol/L [range, 98 to 1,951 pmol/L] and 317 pmol/L [range, 115 to 666 pmol/L]) were similar, whereas systolic arterial pressure (141 ± 26 versus 164 ± 22 mm Hg) and ANP (median, 441 pg/mL [range, 152 to 1,330 pg/mL] versus 804 pg/mL [range, 517 to 3,560 pg/mL] ng/L) were lower (P< 0.05) in HP patients. In response to LBNP (−40 mm Hg), CVP decreased by 6.5 ± 4.0 mm Hg in the HP group and 4.9 ± 4.9 mm Hg in the HR group. In HP patients, this decrease was associated with a greater decrease in SI (37% ± 16% versus 27% ± 16%) and systolic arterial pressure (19% ± 21% versus 4% ± 14%) than in HR patients. Plasma ANP levels did not change, whereas increases in NE and E levels were similar in HP and HR patients. Conclusion:Patients who frequently experience episodes of hypotension during dialysis also are prone to develop hypotension during LBNP, which results from reduced myocardial contractile reserve and/or inadequate sympathetic tone.

Experimental evidence suggests that in conditions associated with an activated renin–angiotensin system, unopposed activity of angiotensin II underlies the marked renal vasoconstrictor response to nitric oxide synthase inhibition. In the present study, we investigated whether this holds true in hypertensive subjects pretreated with hydrochlorothiazide (HCT).

Background/Aim:Renal vasodilation in response to L-arginine has been reported to be diminished in hypertensive (HT) subjects. If this diminished renal vasodilator response indicates disturbance of the renal NO pathway, a diminished renal vasoconstrictor response to NO synthase inhibition may be present in HT subjects as well. The present study was conducted to compare the effects of L-arginine and NG-nitro-L-arginine methyl ester (L-NAME) on renal and systemic hemodynamics between HT and normotensive (NT) subjects. Methods:The responses of renal and systemic vascular resistances (RVR and SVR) and plasma noradrenaline and renin (NOR and PRA) to systemic NO stimulation and inhibition were studied in patients with grade 1 essential HT and age- and sex-matched NT subjects. On separate occasions, after baseline values were obtained, 40-min randomly administered intravenous infusions of L-arginine (12.5 mg·kg–1·min–1) or L-NAME (0.0125 mg·kg–1·min–1) were given. Results:Baseline values of RVR (129 ± 21 and 162 ± 10 resistance units) and SVR (15.1 ± 4.3 and 21.6 ± 5.1 resistance units) were higher (p < 0.01) in HT than in NT subjects, whereas the baseline values of NOR and PRA were similar. Infusion of L-arginine caused similar decrements in SVR (29 ± 10 and 31 ± 11%), but the decrease in RVR was smaller (22 ± 8 and 35 ± 12%, respectively; p < 0.05) in HT than in NT subjects. In response to L-NAME, the increments in RVR (66 ± 10 and 61 ± 25%) and SVR (36 ± 21 and 34 ± 18%) were similar in HT and NT subjects. In both groups, infusion of L-arginine was associated with similar increments, whereas infusion of L-NAME was associated with similar decrements in NOR and PRA. Conclusions:This study confirms the smaller renal vasodilator response to L-arginine in HT than in NT subjects. Whether this is caused by a disturbance of the renal NO pathway remains doubtful considering the observed similar L-NAME-induced increments in RVR and SVR in the two groups of subjects

Dopamine agonists have been studied in chronic heart failure, but earlier reports with non-selective compounds demonstrated unfavourable long-term effects. CHF 1035 is an orally active, new selective dopamine agonist, primarily activating DA2−and α2receptors, thereby inhibiting norepinephrine release, which may be beneficial in heart failure. We conducted a double-blind, placebo-controlled comparison of CHF 1035 (10 mg/day, n= 20) and placebo (n= 9) in patients with mild to moderate chronic heart failure (left ventricular ejection fraction <0.45). Patients were clinically stable on diuretics and angiotensin converting enzyme inhibitors. Both acute and chronic assessments were made, including plasma neurohormones and 24-hr Holter monitoring for heart rate variability analysis. CHF1035 was generally well tolerated during the study. After 10 days, there were no significant changes between the groups regarding heart rate and blood pressure. Compared to placebo, plasma norepinephrine levels decreased on CHF1035, both in the first 4 hours and after 10 days (p< 0.05 between groups). Other neurohormones (natriuretic peptides, renin, aldosteron and endothelin) were not significantly affected. Heart rate variability parameters generally increased on CHF1035, but were unaffected by placebo (p< 0.05 between groups). Short-term treatment with the selective dopaminergic agonist CHF1035 is well tolerated, reduces plasma norepinephrine concentrations and increases heart rate variability in mild chronic heart failure.

OBJECTIVES

The deletion (D) allele of the angiotensin-converting enzyme (ACE) is associated with high ACE levels. Subjects homozygous for the D allele should therefore exhibit enhanced angiotensin I-induced vasoconstrictor responses and diminished bradykinin-induced vasodilator responses as compared with subjects homozygous for the insertion (I) allele. In eight II and eight DD normotensive male subjects, angiotensin I, bradykinin, and angiotensin II were infused in the forearm. Changes in forearm blood flow were registered with venous occlusion plethysmography. Blood was sampled to quantify angiotensin I to II conversion. Plasma ACE levels were 60% higher, and DD subjects showed an enhanced response to angiotensin I infusion (p < 0.05). No differences in angiotensin I to II conversion, angiotensin II vasoconstriction, and bradykinin vasorelaxation were found. The ACE-inhibitor enalaprilate inhibited angiotensin I-induced vasoconstriction, but did not significantly affect bradykinin-induced vasodilation. The AT1-receptor antagonist losartan (3,000 ng/kg/min) inhibited angiotensin II-induced vasoconstriction. In conclusion, subjects with the DD genotype display an enhanced vasoconstrictor response to angiotensin I, which cannot be explained on the basis of a similarly enhanced angiotensin I to II conversion rate or a difference in vascular reactivity. Possibly therefore, differences in angiotensin I to II conversion occur within the vascular wall only, at a site that does not readily equilibrate with blood plasma.

Objectives. To determine dose-related clinical and neurohumoral effects of angiotensin-converting enzyme (ACE) inhibitors in patients with chronic heart failure (CHF), we conducted a double-blind, placebo-controlled, randomized study of three doses (2.5 mg, 5 mg and 10 mg) of the long-acting ACE inhibitor imidapril.

Exocytosis from nerve terminals is triggered by depolarization-evoked Ca entry, which also activates calmodulin and stimulates protein phosphorylation. Ba is believed to replace Ca in triggering exocytosis without activation of calmodulin and can therefore be used to unravel aspects of presynaptic function. We have analysed the cellular actions of Ba in relation to its effect on transmitter release from isolated nerve terminals. Barium evoked specific release of amino acid transmitters, catecholamines and neuropeptides (EC 50 0.2-0.5 mM), similar to K/Ca-evoked release both in extent and kinetics. Ba- and Ca-evoked release were not additive. In contrast to Ca, Ba triggered release which was insensitive to trifluoperizine and hardly stimulated protein phosphorylation. These observations are in accordance with the ability of Ba to replace Ca in exocytosis without activating calmodulin. Nevertheless, calmodulin appears to be essential for regular (Ca-triggered) exocytosis, given its sensitivity to trifluoperizine. Both Ba- and Ca-evoked release were blocked by okadaic acid. Furthermore, anti-calcineurin antibodies decreased Ba-evoked release. In conclusion, Ba replaces Ca/calmodulin in the release of the same transmitter pool. Calmodulin-dependent phosphorylation appears not to be essential for transmitter release. Instead, our data implicate both Ca-dependent and -independent de phosphorylation in the events prior to neurotransmitter exocytosis.

Summary: We noted rapid breakdown at 4° and 20°C of dopamine (DA) (but not of (norepinephrine and epinine) in pig plasma, but not in human plasma. The enzyme responsible appears to be a semicarbazide-sensitive amine oxidase (SSAO) because the breakdown can be inhibited by semicarbazide, but not by pargyline, clorgy-line, EDTA, or (extra) glutathione. Among catecholamines tested, only DA and 3,4-dihydroxybenzylamine (DHBA, the internal standard of most catecholamine assays using high-performance liquid chromatography (HPLC) with electrochemical detection) were good substrates for the pig plasma SSAO. At 37°C, especially after prolonged storage, all catecholamines break down. This breakdown results from autoxidation since it can be prevented by addition of extra glutathione (but not by semicarbazide) for all catecholamines except DA and DHBA. Breakdown at 37°C of these two compounds cannot be prevented by addition of extra glutathione or semicarbazide, but only by addition of both. For reliable measurements of DA concentrations in pig plasma, blood should be collected in tubes containing not only glutathione, but also semicarbazide. The possibility of similarly high plasma SSAO activity in other species should be investigated further

For almost 50 years it has been known that hemolysed blood can increase blood pressure. Although preclinical studies suggest that this pressor response is due to an interaction of hemoglobin with endothelium-derived vasoactive substances, its mechanism in humans is unknown. We investigated the involvement of endothelin-1 in the blood pressure response to the oxygen carrier diaspirin cross-linked hemoglobin (DCLHb) in stroke patients.

We sought to assess the prognostic value of heart rate variability measures, including Poincaré plots, in patients with mild to moderate chronic heart failure.

This study aimed at the combined assessment of the serotonergic and sympathetic nervous system reactions of migraine patients before, during, and after the induction of mental stress in order to detect the possible role of these reactions in inducing a migraine attack. The responses to mental stress of the migraine patients were compared to a group of patients suffering from tension headache and a control group. Activation of the sympathoadrenomedullary system due to mental stress was successfully induced in the migraine patients (n=23), in the tension headache patients (n=18), and in the control group (n=22). The results of this study present evidence of increased cardiovascular activity in migraine patients as compared to nonmigraineurs. However, no evidence was found of a specific serotonergic, sympathoadrenomedullary, or cerebrovascular response of migraine patients to mental stress as compared to nonmigraineurs.

The possibility that sympathetic pressor responses are modulated by adrenalinemediated facilitation of neuronal noradrenaline release was explored in 17 subjects with borderline hypertension. Infusion of adrenaline, which raised plasma adrenaline by a factor of 8 to 9, augmented the rise in systolic and diastolic arterial pressure induced by standardized cold pressor and isometric exercise tests. The heart rate response to these tests was not affected. When a low dose of propranolol was given on top of the adrenaline infusion before the cold pressor test, the blood pressure response to cold exposure was not different from the response observed when the test was performed during saline infusion. Plasma noradrenaline was higher during adrenaline infusion then during saline infusion, both before and after the cold pressor and isometric exercise tests, and the effect of adrenaline on plasma noradrenaline was antagonized by propranolol. These observations are consistent with the hypothesis that stress levels of circulating adrenaline may amplify sympathetic pressor responses by facilitation of the release of transmitter noradrenaline.

In a double blind, crossover study 6 h infusions of adrenaline (15 ng/kg/min; 1 ng=5·458 pmol), noradrenaline (30 ng/kg/min; 1 ng = 5·911 pmol), and a 5% dextrose solution (5·4 ml/h), were given to ten healthy volunteers in random order 2 weeks apart. By means of intra-arterial ambulatory monitoring the haemodynamic effects were followed for 18 h after the infusions were stopped. Adrenaline, but not noradrenaline, caused a delayed and protracted pressor effect. Over the total postinfusion period systolic and diastolic arterial pressure were 6 (SEM 2)% and 7 (2)%, respectively, higher than after dextrose infusion (ANOVA, p<0·001). Thus, "stress" levels of adrenaline (230 [28] pg/ml) for 6 h cause a delayed and protracted pressor effect. These findings are strong support for the adrenaline-hypertension hypothesis in man.

Acebutolol is a relatively new adrenoceptor blocking antagonist, possessing both 1adrenoceptor selectivity and partial agonist activity PAA. Its acute 24 h, 400 mg, twice daily and longterm effects 3 weeks on systemic and renal hemodynamics, body fluid volumes, hormones, and adrenoceptor density on lymphocytes were studied in a singleblind placebocontrolled trial, in 10 hypertensive patients. The initial response to acebutolol 12 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 23 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 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 longterm treatment had no effect on the density of lymphocytemembrane adrenoceptors. This could be explained by acebutolol's 1selectivity or, alternatively, this could be due to the drug's PAA.

• Some depressed patients have been shown to excrete abnormal amounts of catecholamines and their metabolites in urine. Some studies suggest that hypersecretion of epinephrine by the adrenals and of norepinephrine by the peripheral sympathetic system cause increased excretion of urinary catecholamines and their metabolites in a subgroup of patients. To evaluate the effect of increased catecholamine levels in the peripheral circulation on urinary catecholamine and metabolite levels, we infused healthy volunteers during 6 hours with epinephrine, norepinephrine, or placebo, respectively, in a three-period, double-blind, crossover design. The results indicate that (1) urinary epinephrine and norepinephrine levels were the most sensitive indicators of increased circulating epinephrine and norepinephrine levels, respectively; (2) changes in circulating epinephrine or norepinephrine levels were not readily reflected in changes in urinary vanillylmandelic acid or 3-methoxy-4-hydroxyphenylglycol levels; and (3) increased normetanephrine excretion was not only induced by infusion of norepinephrine but also by epinephrine. This last finding may be due to activation of the sympathetic nervous system by circulating epinephrine. These results may help to explain the mechanism of adrenal epinephrine and sympathetic nervous system norepinephrine hypersecretion observed in subgroups of depressed patients.

Abstract: Dose-dependent effects of intravenously administered lorazepam on psychophysiological activity during rest and mental stress were studied in order to examine differential responses to doses which may induce anxiolysis or sedation. In a double-blind randomized cross-over study, nine male volunteers participated in a placebo and a lorazepam session, during which the subjects repeatedly performed a 10-min version of the Stroop Color Word Test (CWT), with 10 min of rest between the CWTs. Lorazepam was administered before each rest period in increasing doses of 0.0, 0.06, 0.13, 0.25 and 0.5 mg (total cumulative dose: 0.94 mg). Heart rate showed a dose-dependent decrease during rest with an ED50 of 0.13 mg lorazepam, while lorazepam had no effect on the cardiovascular and plasma catecholamine response magnitudes to the CWT. Subjective fatigue and reaction time increased significantly after 0.94 mg lorazepam, while at the same dose vigor decreased; state anxiety after the CWT was not influenced by lorazepam. These data show differential effects of lorazepam on cardiovascular, biochemical and psychological function. While heart rate was suppressed at low doses during rest and reaction time and subjective fatigue increased at doses which induced sedation, state anxiety and physiological response patterns to the CWT were not influenced by lorazepam.

This study assessed the effects of digoxin and ibopamine on variables of heart rate variability in relation to neurohormonal activation.

This study evaluated cardiac beta-adrenoceptor responsiveness in the elderly.

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−1min) 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 β1-selective β-adrenoceptor blockade with atenolol, 50 mg once daily, and during nonselective β-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 < 0.01) and resting NE forearm production increased from 296 ± 48 to 529 ± 98 pg 100 ml/min−1(p < 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 < 0.05) by EPI. This enhancement was also abolished by both β-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 β-adrenoceptors and can be blocked not only by a nonselective but also by a β,-selectivev β-adrenoceptor antagonist.

Intravenous (i.v.) infusions (1, 2.5, 5, and 10 u.g/kg/min for 10 min) were used to evaluate the cardiovascular effects of epinine (N-methyl-dopamine) in 8 conscious pigs. Epinine is a nonselective and nonspecific dopamine (DA) agonist, that also stimulates α- and β-adrenoceptors. Epinine (1–5 μg/kg/min) increased cardiac output (CO) by up to 15 ± 5 (p< 0.05), owing to an increase in heart rate (HR, 24 ± 6), but an increase in stroke volume (SV, 16 ± 4) caused the further increase in CO at 10 n-g/kg/min. Mean arterial blood pressure decreased gradually from 100 ± 5 mm Hg to 84 ± 4 mm Hg during infusions up to 5 (μg/kg/min, but increased to 89 ± 4 mm Hg during infusion of 10 μg/kg/min (p < 0.05). Systemic vascular resistance had decreased from 36.5 ± 2.8 to 27.5 ± 3.0 mm Hg/L/min after infusion of 5 μg/kg/min but did not change further during infusion of 10 μg/kg/min. LV dP/dtmaxincreased only at 10 μg/kg/min. Myocardial blood flow did not change at any dose, owing to metabolically regulated coronary vasodilatation (myocardial work did not change). Flow to the adrenals (up to 110 ± 37) and the spleen (up to 95 ± 13) increased dose dependently. Cerebral blood flow increased only at the highest dose (15 ± 5, p < 0.05); flow to the kidneys, liver, small intestine, and skeletal muscle did not change. Flow decreased to the stomach (21 ± 5) and skin (for doses <2.5 μg/kg/min). Further studies are needed to evaluate the contribution of activation of DA receptors and β2-adrenoceptors to the epinine-induced vasodilation of the various regional vascular beds.

Forty young subjects, aged 18 to 28 years, with mildly elevated blood pressure participated in a double-blind randomized three-period crossover study of the effect of sodium restriction with and without potassium supplementation on blood pressure. Dietary sodium intake was restricted for 18 weeks in which the patients received in random sequence 'slow-sodium' (90 mmol/day), 'slow-potassium' (72 mmol/day), and placebo tablets, each for 6 weeks. Mean urinary sodium excretion was 129 mmol/24 h in the slow-sodium period, 57 mmol/24 h during placebo, and 69 mmol/24 h during slow-potassium. Mean supine systolic blood pressure in the sixth week of the slow-potassium period was 3.3 mmHg lower than that at the end of the slow-sodium period (P<0.05). There was no significant difference in systolic or diastolic blood pressure between the placebo and the slow-sodium periods. The fall in systolic blood pressure in the low sodium/high potassium period was accompanied by a fall in cardiac index of 0.4 l/min per m2 body surface area (BSA) (P0.03). Our observations suggest a small hypotensive effect of moderate sodium restriction combined with high potassium intake in young hypertensive subjects. Sodium restriction alone has little effect on blood pressure in this group. The combination of a low sodium/high potassium diet may lower blood pressure by affecting cardiac output. Reducing the dietary sodiumpotassium ratio may therefore be useful in the management of early primary hypertension.

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.

Bopindolol is a new long-acting, nonselective β-adrenoceptor antagonist with partial agonist activity. Its acute (24 hours, 2 mg, administered orally) and long-term (3 weeks, 2 to 4 mg) hemodynamic and hormonal effects were studied in a single-blind placebo-controlled trial in 10 hypertensive subjects. The initial response (mean ± SE) to bopindolol was a fall in cardiac output (−12% ± 2%) and heart rate (−11% ± 2%). Mean arterial pressure began to fall 3 to 4 hours after administration in parallel with a decrease in systemic vascular resistance, which had increased initially. Twenty-four hours after administration, mean arterial pressure and systemic vascular resistance were reduced by 12% ± 2% and 12% ± 5%, respectively. By that time heart rate and cardiac output did not differ from baseline values despite β-blockade. After 3 weeks of treatment mean arterial pressure had fallen by 9% ± 2% and renal blood flow and glomerular filtration rate were not changed. One week after withdrawal from treatment mean arterial pressure and heart rate were no longer reduced, but β-blockade could still be demonstrated, establishing the long duration of action of the drug.

1. Semicarbazide-sensitive amine oxidase is a common name for a group of heterogeneous amine oxidases which are present in various mammalian tissues, especially in vascular smooth muscle cells, cartilage and adipose tissue, but also in plasma. 2. Plasma semicarbazide-sensitive amine oxidase activity was elevated in a group of 104 patients with insulin-dependent diabetes mellitus compared with normal control subjects (555 ± 172 versus 352 ± 102 m-units/l, P < 0.0005). 3. Plasma semicarbazide-sensitive amine oxidase activity was higher in subgroups with either retinopathy or nephropathy or both [583 ± 116 (n = 34), 581 ± 229 (n = 10) and. 646 ± 249 m-units/l (n = 19), respectively] than in the subgroup without overt complications [486 ± 129 m-units/l (n = 41), P < 0.005]. 4. Plasma semicarbazide-sensitive amine oxidase activity was positively correlated with plasma glycosylated haemoglobin (r = 0.40; P < 0.0001) and with log urinary albumin excretion (r = 0.26; P < 0.025). 5. The possibility that semicarbazide-sensitive amine oxidase, by its conversion of endogenous amines like methylamine and aminoacetone into cytotoxic aldehydes, plays a role in the development of microvascular complications in diabetes mellitus, needs further investigation.

We studied hemodynamic changes, catecholamine responses, and the occurrence of improved wall thickening by echocardiography during two different dobutamine-infusion protocols. Forty-three patients were studied by using a stepwise incremental dobutamine dose-infusion protocol (10-40 μg/kg/min, 3-min intervals); a subgroup of 11 patients also underwent a continuous dobutamine-infusion protocol (10 μg/kg/min for 12 min) in random order. No patient used β-blockers. At 3-min intervals, blood pressure, heart rate, and plasma concentrations of dobutamine, epinephrine, and norepinephrine were measured. The echocardiographic improvement of wall thickening was analyzed only in paired protocols by visual assessment in left ventricular regions with normal wall motion at rest. The mean heart rate increased in the continuous and stepwise protocols from 73 to 99 and 74 to 132 beats/min. There was no significant change in blood pressure response between the two protocols. The mean plasma dobutamine concentrations during the continuous and stepwise protocols at 0, 3, 6, 9, and 12 min were 0/0; 31/38; 80/203; 106/448; and 120/692 ng/ml, respectively. In each patient, a response curve was constructed for the plasma dobutamine concentration versus heart rate. The heart rate increment and dobutamine concentration at which wall thickening was detected were similar with both protocols (14 ± 5 vs. 12 ± 7 beats/min) and (80 ± 40 vs. 92 ± 48 ng/ml; mean ± SD). Wall thickening was noted in two of 11 patients between 0 and 3 min and 11 of 11 patients between 3 and 6 min in both protocols. Catecholamine responses during the continuous and stepwise protocols were epinephrine, 23 versus 28/28 versus 36, and norepinephrine 301 versus 323/347 versus 519. Only norepinephrine plasma concentrations increased significantly during the stepwise protocol. A 6-min dobutamine infusion was sufficient during both protocols to reach an adequate plasma dobutamine concentration, which induced a detectable increase of wall thickening in all patients. There is a significant differences between the two protocols with regard to the plasma catecholamine changes, so some of the hemodynamic effects during the stepwise dobutamine-infusion protocol may be mediated through release of endogenous catecholamines.

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.

Stimulation of prejunctional β2-adrenoceptors on sympathetic nerve terminals increases vasoconstrictor nerve activity by facilitating release of noradrenaline. Therefore, man's endogenous β2-adrenoceptor agonist adrenaline has been implicated in the pathogenesis of hypertension. To test this hypothesis, adrenaline (15 ng/kg per min), noradrenaline (30 ng/kg per min) and saline (0.9 NaCl, 5.4 ml/h) were infused in 10 supine, resting healthy volunteers for 6 h (1000–1600 h) in random order 2 weeks apart in a double-blind crossover fashion. During infusion of noradrenaline and adrenaline, venous plasma concentrations rose to 705 ± 58 (mean ± s.e.m) and 230 ± 28 pg/ml, respectively. Mean arterial pressure rose by 4 (P< 0.001) during noradrenaline and fell by 5 (P< 0.001) during the adrenaline infusion compared with the saline infusion. In the postinfusion period (1600–0900 h) mean arterial pressure was 7 higher (P< 0.01) after adrenaline compared with the saline infusion, whereas after the noradrenaline infusion, values of mean arterial pressure were not different from those during the saline infusion. The pressor effect of adrenaline could not be explained by a central mechanism or by activation of the renin-angiotensin system. Thus, `stress levels' of adrenaline mediate a delayed and protracted pressor effect. This is most likely due to stimulation of prejunctional β2-adrenoceptors, since `stress levels' of noradrenaline are devoid of such activity. Our data support the `adrenaline-hypertension‘ hypothesis in man.

Two patients with congenital dopamine β-hydroxylase (DBH) deficiency were treated with d,l-threo-3,4-dihydroxyphenylserine (DOPS), 500 mg twice daily. In this orthostatic syndrome the functional integrity of the sympathetic noradrenergic neuron is probably intact, but dopamine instead of noradrenaline is released as the neurotransmitter. In vitro l-DOPS may serve as a substrate for aromatic-l-amino-acid decarboxylase (ALAAD) to form physiological (-)-noradrenaline. During infusion of d,l-threo-DOPS, 400 mg in 4 h, noradrenaline appeared in plasma and blood pressure rose, whereas plasma dopamine and the elevated venous:arterial ratio of plasma dopamine decreased. During chronic treatment supine blood pressure rose from 100–115/55–65 to 140–145/80–85 mmHg and orthostatic hypotension disappeared. After 12 and 6 months of treatment the patients are free of symptoms and they live a normal life. During chronic treatment, d,l-threo-DOPS, like plasma noradrenaline and dopamine, rose after standing, indicating release of the precursor after neuronal stimulation. After administration of tyramine plasma noradrenaline, dopamine and d,l-threo-DOPS and their respective venous:arterial ratios rose; this is further evidence of neuronal release. Thus, in DBH deficiency, dopamine instead of noradrenaline is released as a neurotransmitter, but the integrity of the sympathetic neuron is otherwise intact. Acting as an alternative substrate for ALAAD in the production of noradrenaline, DOPS is taken up by the neuron, restoring sympathetic control and thereby curing the orthostatic hypotension in DBH deficiency.

Objectives: Previous studies have demonstrated a decreased flow reserve in the surviving hypertrophied left ventricle (LV) early after myocardial infarction. We hypothesized that exacerbation of hemodynamic abnormalities and neurohumoral activation during exercise could exhaust coronary flow reserve and thereby impair myocardial O2 supply. Consequently, we studied hemodynamic, neurohumoral and regional myocardial perfusion and metabolic responses to exercise in pigs with LV hypertrophic remodeling 3 weeks after a myocardial infarction produced by permanent left circumflex coronary artery ligation. Methods: Chronically instrumented pigs were exercised on a treadmill up to 85% of maximum heart rate. Pigs with a myocardial infarction (MI) had a lower cardiac output (21%), stroke volume (28%), LV dP/dtmax (18%), systemic (22%) and pulmonary (20%) vascular conductance, and increased left atrial (225%) and pulmonary artery (75%) pressures, compared to normal pigs. In MI, the exercise-induced increases in cardiac pump function, and systemic and pulmonary vasodilation were blunted compared to normals. Consequently, perfusion of visceral organs became impaired during strenuous exercise, but cerebral and skeletal muscle blood flows were maintained. Exercise-induced increases in norepinephrine and endothelin levels were exacerbated and, while relative sympathetic drive was maintained, cardiac responsiveness to norepinephrine was blunted. Despite lower capillary densities in the hypertrophied non-infarcted LV and relative subendocardial hypoperfusion during strenuous exercise, which necessitated a slight increase in O2 extraction, there was no metabolic evidence of overt myocardial ischemia during strenuous exercise as indicated by the arterio–coronary venous pH difference. Conclusions: LV dysfunction and neurohumoral activation were present in pigs with a 3-week-old infarction, particularly during exercise. However, although myocardial perfusion and O2 supply were slightly impaired, myocardial ischemia did not occur even during exercise up to 85% of maximum heart rate, suggesting that perfusion abnormalities do not contribute to LV dysfunction early after infarction.

To investigate whether the compensatory rise in renin and plasma angiotensin 1 in response to repeated angiotensin converting enzyme (ACE) inhibitor treatment results in a partial escape of ACE inhibition over a 24-h dosing interval.