Man in 't Veld Aj

Stress levels of adrenaline amplify the blood pressure response to sympathetic stimulation

The possibility that sympathetic pressor responses are modulated by adrenaline-mediated 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-vitro validation, with histology, of intravascular ultrasound in renal arteries

OBJECTIVE To investigate the feasibility of using intravascular ultrasound to characterize normal and diseased renal arteries. MATERIALS AND METHODS Forty-four renal artery specimens from 21 humans, removed at autopsy, were studied with intravascular ultrasound in vitro. From each vascular specimen, two to four sets of corresponding intravascular ultrasound images and histologic sections were subjected to qualitative analysis. The renal arterial wall was considered normal by intravascular ultrasound when the wall thickness (intima and media) was 0.5 mm or less. On intravascular ultrasound imaging, a distinction was made between bright lesions with or without peripheral shadowing (i.e. calcification). Histological sections were examined and fibromuscular lesions were scored with or without calcifications. Quantitative analysis of a multitude of intravascular ultrasound cross-sections (interval 5 mm) included assessment of the lumen area, vessel area, plaque area and percentage area obstructed. The target site (smallest lumen area) was compared with a reference site (largest lumen area before the first major side branch). RESULTS Of the 130 corresponding intravascular ultrasound images and histologic sections analysed, 55 were normal and 75 presented a bright lesion on ultrasound; in 31 lesions, peripheral shadowing was involved. The sensitivity of the intravascular ultrasound in detecting calcifications was 87%, and the specificity was 89%. Lumen area reduction at the target site was associated with vessel and plaque area enlargement in eight specimens, with plaque area enlargement in 12 specimens and with a vessel area reduction in 21 specimens. CONCLUSIONS Intravascular ultrasound is a reliable technique for distinguishing renal arteries with or without a lesion. Both plaque development and local vessel narrowing may result in renal artery stenosis.

Effect of epinine on systemic hemodynamics and regional blood flow in conscious pigs.

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/dtmax increased 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.

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.

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.

High activity of semicarbazide-sensitive amine oxidase (SSAO) : an important source of errors in the determination of the concentration of dopamine in pig plasma

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

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.