Effect of testosterone on ex vivo vascular reactivity in man

2006 ◽  
Vol 111 (4) ◽  
pp. 265-274 ◽  
Author(s):  
Christopher J. Malkin ◽  
Richard D. Jones ◽  
T. Hugh Jones ◽  
Kevin S. Channer
Keyword(s):  
Heart Failure ◽  
Vascular Reactivity ◽  
Ex Vivo ◽  
Testosterone Replacement ◽  
Androgen Deficiency ◽  
Resistance Arteries ◽  
Patients With Heart Failure ◽  
Dose Dependent ◽  
Concentration Curves

Testosterone is reported to have an acute vasodilating action in vitro, an effect that may impart a favourable haemodynamic response in patients with chronic heart failure. However, the effect of chronic testosterone exposure on general vascular reactivity is poorly described. In the present study, fresh subcutaneous resistance arteries were obtained from patients with heart failure (n=10), healthy controls (n=9) and men with androgen-deficiency (n=17). All arteries were studied using a wire myograph to examine the effect of cumulative additions of testosterone (1 nmol/l–100 μmol/l) compared with vehicle control following maximal pre-constriction with KCl (1–100 μmol/l). The vascular reactivity of arteries from androgen-deficient patients was examined further by recording tension concentration curves to cumulative additions of noradrenaline (1 nmol/l–100 μmol/l) and U46619 (1–300 nmol/l), followed by relaxation concentration curves to additions of ACh (acetylcholine; 10 nmol/l–30 μmol/l) and SNP (sodium nitroprusside; 10 nmol–30 μmol/l) respectively. In all cases, statistical analysis was performed by ANOVA. Patients with proven androgen-deficiency were treated according to clinical recommendations for a minimum of 3 months and further arteries (n=19) were taken for experimentation using the same protocol. In all groups, testosterone was confirmed to be an acute concentration-dependent vasodilator at concentrations ≥1 μmol/l (P=0.0001). The dilating effect of testosterone was augmented in patients with androgen-deficiency prior to treatment, and this effect was abrogated following appropriate testosterone replacement. Testosterone therapy significantly reduced the normal vascular dilating response to ACh and SNP (P<0.01) and significantly increased the contractile response to noradrenaline (P<0.01), but not U46619. Testosterone is an acute dose-dependent vasodilator of resistance arteries. Physiological testosterone replacement attenuates general vascular reactivity in androgen-deficient subjects. The numerous perceived benefits of testosterone replacement may be offset by a decline in vascular reactivity and, therefore, further studies and careful monitoring of patients is recommended.

scholarly journals Vasoresponsiveness in patients with heart failure (VASOR): protocol for a prospective observational study

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Marieke E. van Vessem ◽  
Saskia L. M. A. Beeres ◽  
Rob B. P. de Wilde ◽  
René de Vries ◽  
Remco R. Berendsen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Surgery ◽  
Cardiopulmonary Bypass ◽  
Observational Study ◽  
Vascular Reactivity ◽  
Prospective Observational Study ◽  
Ex Vivo ◽  
Phase 1 ◽  
Resistance Arteries ◽  
Patients With Heart Failure

Abstract Background Vasoplegia is a severe complication which may occur after cardiac surgery, particularly in patients with heart failure. It is a result of activation of vasodilator pathways, inactivation of vasoconstrictor pathways and the resistance to vasopressors. However, the precise etiology remains unclear. The aim of the Vasoresponsiveness in patients with heart failure (VASOR) study is to objectify and characterize the altered vasoresponsiveness in patients with heart failure, before, during and after heart failure surgery and to identify the etiological factors involved. Methods This is a prospective, observational study conducted at Leiden University Medical Center. Patients with and patients without heart failure undergoing cardiac surgery on cardiopulmonary bypass are enrolled. The study is divided in two inclusion phases. During phase 1, 18 patients with and 18 patients without heart failure are enrolled. The vascular reactivity in response to a vasoconstrictor (phenylephrine) and a vasodilator (nitroglycerin) is assessed in vivo on different timepoints. The response to phenylephrine is assessed on t1 (before induction), t2 (before induction, after start of cardiotropic drugs and/or vasopressors), t3 (after induction), t4 (15 min after cessation of cardiopulmonary bypass) and t5 (1 day post-operatively). The response to nitroglycerin is assessed on t1 and t5. Furthermore, a sample of pre-pericardial fat tissue, containing resistance arteries, is collected intraoperatively. The ex vivo vascular reactivity is assessed by constructing concentrations response curves to various vasoactive substances using isolated resistance arteries. Next, expression of signaling proteins and receptors is assessed using immunohistochemistry and mRNA analysis. Furthermore, the groups are compared with respect to levels of organic compounds that can influence the cardiovascular system (e.g. copeptin, (nor)epinephrine, ANP, BNP, NTproBNP, angiotensin II, cortisol, aldosterone, renin and VMA levels). During inclusion phase 2, only the ex vivo vascular reactivity test is performed in patients with (N = 12) and without heart failure (N = 12). Discussion Understanding the difference in vascular responsiveness between patients with and without heart failure in detail, might yield therapeutic options or development of preventive strategies for vasoplegia, leading to safer surgical interventions and improvement in outcome. Trial registration The Netherlands Trial Register (NTR), NTR5647. Registered 26 January 2016.

Characteristics of canine coronary resistance arteries: importance of endothelium

1989 ◽  
Vol 257 (2) ◽  
pp. H603-H610 ◽  
Author(s):  
P. R. Myers ◽  
P. F. Banitt ◽  
R. Guerra ◽  
D. G. Harrison
Keyword(s):  
Coronary Arteries ◽  
Vascular Reactivity ◽  
Maximum Response ◽  
Coronary Resistance ◽  
Resistance Arteries ◽  
Resistance Vessels ◽  
Dose Dependent ◽  
Large Coronary Arteries

Canine coronary resistance vessels were studied in vitro to examine the role of the endothelium in modulating responses to acetylcholine, vasopressin, and thrombin and to compare these responses to those found in large epicardial vessels. Acetylcholine had no effect on passively distended microvessels; however, after preconstriction with the thromboxane analogue, U 46619 caused dose-dependent vasodilation [50% effective concentration (EC50), 0.05 microM; maximum response, 97.9 +/- 2.1% relaxation]. Large epicardial arterial rings studied in organ chambers similarly relaxed to acetylcholine (EC50, 0.07 microM; maximum response, 79 +/- 5% relaxation). Hemoglobin was utilized to inactivate endothelium-derived relaxing factor (EDRF), resulting in reversal of acetylcholine vasodilation in both the microvessels (92 +/- 3.2% reversal) and the large epicardial vessels (117 +/- 9%). Hemoglobin had no effect on passively distended or preconstricted microvessels. Vasopressin constricted resistance vessels by 22.3 +/- 5.9 microns at 500 microU/ml. Hemoglobin potentiated this response by 100%, suggesting that vasopressin elicited EDRF release. In large coronary arteries, however, vasopressin elicited endothelium-dependent dilation with maximal relaxation of 36 +/- 9% at 3,000 microU/ml. Thrombin produced endothelium-dependent relaxation of large epicardial arterial rings but only constricted coronary microvessels. The response to thrombin was not altered by hemoglobin. This study demonstrates that the endothelium of coronary microvessels, like that of larger vessels, importantly modulates vascular reactivity to selected agents. Furthermore, major differences exist between large and small coronary arteries in their response to vasopressin and thrombin.

Effect of adrenomedullin on the production of endothelin-1 and on its vasoconstrictor action in resistance arteries: evidence for a receptor-specific functional interaction in patients with heart failure

2001 ◽  
Vol 101 (1) ◽  
pp. 45-51 ◽  
Author(s):  
Chris HILLIER ◽  
Mark C. PETRIE ◽  
Michael P. LOVE ◽  
Fiona JOHNSTON ◽  
Margaret R. MACLEAN ◽  
...  
Keyword(s):  
Heart Failure ◽  
Hill Coefficient ◽  
Receptor Interaction ◽  
Resistance Arteries ◽  
Functional Interaction ◽  
High Potassium ◽  
Endothelin 1 ◽  
Patients With Heart Failure ◽  
Small Resistance ◽  
The Hill

Endothelin-1 (ET-1) and adrenomedullin (ADM) are both produced in the arterial wall, but have opposing biological actions. Evidence from experimental animals suggests a functional interaction between ET-1 and ADM. We have tested this in humans. Small resistance arteries were obtained from gluteal biopsies taken from patients with chronic heart failure (CHF) due to coronary heart disease (CHD), or with CHD and preserved ventricular function. The contractile responses to big ET-1 and to ET-1 in both sets of vessels were studied in the absence (control) and presence of ADM at 20 pmol/l (low ADM) or 200 pmol/l (high ADM), using wire myography. ADM did not affect the conversion of big ET-1 into ET-1 in vessels from patients with either CHD or CHF. Low ADM did not alter the contractile response to ET-1 in vessels from patients with CHF. Low ADM was not tested in vessels from patients with CHD, but high ADM did not affect this response in arteries from these patients. High ADM did, however, significantly reduce the vasoconstrictor effect of ET-1 in vessels from patients with CHF. The maximum response, as a percentage of the response to high potassium, was 199% (S.E.M. 25%) in the control experiments (n = 14), 205% (27%) in the low-ADM (n = 7) studies and 150% (17%) in the high-ADM (n = 6) experiments (P < 0.001). Furthermore, the Hill coefficient increased from 0.57±0.05 in the absence of ADM to 1.16±0.15 in the high-ADM experiments, indicating that ADM at 200 pmol/l specifically antagonized one receptor type in vessels from patients with CHF. We conclude that there is a one-site receptor interaction between ADM and ET-1 that is specific for vessels from patients with CHF. This functional interaction between ADM and ET-1 in resistance arteries may be of pathophysiological importance in CHF.

Influence of SIN-1 on Platelet Ca2+ Handling in Patients with Suspected Coronary Artery Disease: Ex Vivo and In Vitro Studies

2000 ◽  
Vol 83 (05) ◽  
pp. 752-758 ◽  
Author(s):  
Claude Le Feuvre ◽  
Annie Brunet ◽  
Thuc Do Pham ◽  
Jean-Philippe Metzger ◽  
André Vacheron ◽  
...  
Keyword(s):  
Superoxide Anion ◽  
Vascular Tone ◽  
Ex Vivo ◽  
Suspected Coronary Artery Disease ◽  
In Vitro Studies ◽  
H2o2 Formation ◽  
Artery Disease ◽  
Dose Dependent

SummaryThe 3-morpholinosydnonimine (SIN-1) generates both nitric oxide (NO) and superoxide anion (O2−). It elicits dose-dependent vasodilation in vivo, in spite of the opposite effects of its breakdown products on vascular tone and platelet aggregation.This study was designed to investigate the influence of intravenous SIN-1 injection on platelet Ca2+ handling in patients undergoing coronary angiography. SIN-1 administration reduced cytosolic [Ca2+] in unstimulated platelets by decreasing Ca2+ influx. It attenuated Ca2+ mobilization from internal stores evoked by thrombin or thapsigargin. In vitro studies were used as an approach to investigate how simultaneous productions of NO and O2− from SIN-1 modify thrombin- or thapsigargin-induced platelet Ca2+ mobilization. Superoxide dismutase, the O2− scavenger, enhanced the capacity of SIN-1 to inhibit Ca2+ mobilization but catalase had no effect.This suggests that the effects of SIN-1 on platelet Ca2+ handling resemble those of NO, but are modulated by simultaneous O2− release, independently of H2O2 formation.

“Dose-dependent” Impact of Recurrent Cardiac Events on Mortality in Patients with Heart Failure

2009 ◽  
Vol 122 (2) ◽  
pp. 162.e1-162.e9 ◽  
Author(s):  
Douglas S. Lee ◽  
Peter C. Austin ◽  
Thérèse A. Stukel ◽  
David A. Alter ◽  
Alice Chong ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Events ◽  
Patients With Heart Failure ◽  
Dose Dependent

Effect of Low-Molecular-Weight Heparin (Tinzaparin) and Unfractionated Heparin on Platelet Aggregation

1996 ◽  
Vol 2 (3) ◽  
pp. 209-212 ◽  
Author(s):  
Hanne B. Ravn ◽  
Claus Bregengaard ◽  
Henrik Vissinger ◽  
Per Østergaard ◽  
Jan Holst ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Platelet Aggregation ◽  
Unfractionated Heparin ◽  
Low Molecular Weight Heparin ◽  
Ex Vivo ◽  
Subcutaneous Administration ◽  
Low Molecular Weight ◽  
Pronounced Difference ◽  
Dose Dependent

A low-molecular-weight heparin (LMWH), when anti-IIa activity was compared. In the ex vivo part Tinzaparin, was compared with unfractionated heparin of the study, a significant enhancement of ADP-induced (UFH) for their effects on platelet aggregation in vitro and platelet aggregation was observed after i.v. administra ex vivo. Both heparins showed a dose-dependent proag- tion of both Tinzaparin and UFH with no difference in gregatory effect on ADP- and collagen-induced platelet potency. Subcutaneous administration of Tinzaparin in aggregation in vitro, but LMWH was less potent. The two different doses did not have any effect on platelet differences in potency between Tinzaparin and UFH de- activity. In conclusion, Tinzaparin appears, like other pended on how the compounds were compared. The most LMWHs, to have less proaggregatory effect on platelets pronounced difference was found when molar concentra- than UFH both in vitro and ex vivo.

Metabolic and Pharmacologic Interaction of Ethanol and Metronidazole in the Rat

1972 ◽  
Vol 50 (6) ◽  
pp. 476-484 ◽  
Author(s):  
H. Kalant ◽  
A. E. LeBlanc ◽  
M. Guttman ◽  
J. M. Khanna
Keyword(s):  
Incidental Finding ◽  
Repeated Administration ◽  
Volatile Material ◽  
Alcohol Dehydrogenase Activity ◽  
Liver Homogenates ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Concentration Curves ◽  
Central Depressant

Metronidazole, added in vitro, did not act either as an inhibitor or as a substrate for the alcohol dehydrogenase activity of rat liver homogenates. Concentration curves of ethanol and acetaldehyde in the blood after an oral dose of ethanol were not altered by pretreatment with metronidazole; in contrast, disulfiram caused marked elevation of acetaldehyde levels. When given once only, metronidazole (or possibly a metabolite of it) exerted a mild central depressant effect of its own and produced a dose-dependent increase in the intoxicant effect of ethanol. After repeated administration of metronidazole, synergism with ethanol was not seen. An incidental finding was the production of a volatile material during incubation of solutions containing NAD, which gives an acetone-like peak in gas-liquid chromatograms.

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