Vasopressin-induced presynaptic facilitation of sympathetic neurotransmission in the pithed rat

Objective Several studies have shown that arginine vasopressin (AVP) potentiates the sympathetic nervous transmission in isolated vessels. The present study investigates such a potentiation in the pithed rat model. Methods Male Wistar rats weighing 270-310 g were used. Spinal-cord stimulation was applied, with frequencies of 0.25-4 Hz, in the presence or absence of a subpressor dose of intravenous (i.v.) AVP (1 pmol/kg per min). In addition, the effect of AVP on postsynaptic alpha-adrenoceptor-mediated responses was studied using exogenously administered noradrenaline (NA). For this purpose dose-response curves (DRCs) for NA (i.v.) were constructed. Results In the pithed rat model endogenously generated angiotensin II facilitates neurally mediated increments in vascular resistance. Without the administration of the angiotensin II type 1 (AT(1)) antagonist irbesartan, the facilitating effect of AVP was not visible. However, after the administration of the AT(1) antagonist irbesartan, the facilitating effect of AVP became apparent. The stimulation-induced rise in diastolic blood pressure (DBP) was enhanced in the presence of AVP from 63.7 +/- 4.5 to 78.6 +/- 4.2 mmHg, at a stimulation frequency of 4 Hz. The vasopressin receptor V-1 antagonist, SR-49059, completely inhibited this AVP-inDuced facilitation, whereas the V-2 antagonist, SR-1211463B, or the V-2 agonist desmopressin, did not. The DRC of exogenously administered NA was not influenced by AVP. Conclusion The stimulating effect of AVP on sympathetic neurotransmission is completely dependent on the stimulation of presynaptically located V-2 receptors. The facilitating effect of angiotensin II on the sympathetic nervous system (SNS) in the pithed rat model masks the facilitating effect of AVP in this preparation. (C) 2002 Lippincott Williams Wilkin

Influence of the nature of pre-contraction on the responses to commonly employed vasodilator agents in rat-isolated aortic rings

The relaxing properties of vasodilator drugs in vitro may depend on the characteristics of the contractile state of the vessel investigated. Rat-isolated thoracic aortas were exposed to different types of pre-contraction. The following vasoconstrictor agents were used: phenylephrine (PhE), a selective alpha(1)-adrenoceptor agonist; St 587, a partial alpha(1)-adrenoceptor stimulant; U46619 (U-46), a thromboxane A(2) agonist; and potassium ions causing receptor-independent depolarization of the membrane. After pre-contraction, various differential vasodilator drugs were investigated: methacholine (MCh, endothelium dependent), sodium nitroprusside (SNP, NO donor), forskolin (FSK, adenylyl cyclase stimulant) and nifedipine, a Ca2+-antagonist (selective L-type calcium antagonist). The vasodilator activity of these compounds was quantified by their vasodilator potency value (pD(2)) and efficacy (E-max) obtained from their concentration-response curves. PhE (0.1, 0.3, 3 mu(M)) caused isometric responses of 4.8 +/- 0.3, 6.5 +/- 0.3 and 7.8 +/- 0.5 mN, respectively. An increase of the PhE concentration from 0.1 to 3 mu(M) did not influence the response to FSK while it reduced the pD(2) of SNP (8.6 +/- 0.1 to 7.35 +/- 0.1). Under these conditions, only the E-max of MCh was reduced (96.3 +/- 4.3% to 43.3 +/- 6.9%). U46 (0.18, 0.3, 1 mu(M)) increased the contractile force by 7.4 +/- 0.4, 8.8 +/- 0.3 and 10.4 +/- 0.3 mN, respectively. Increasing the concentration of U-46 from 0.18 to 1 mu(M) affected only the efficacy of SNP (84 +/- 4.4% to 17 +/- 8.8%) and MCh (64.5 +/- 12.3% to 0.0 +/- 9.2%) and reduced the potency of FSK (7.9 +/- 0.26 to 7.15 +/- 0.10). The concentration of K+-ions from 25 to 30 and 40 mm increased the contractile force by 4.0 +/- 0.4, 7.0 +/- 0.5 and 10.8 +/- 0.4 mN, respectively. The increase in [K+] caused a potency decrease of FSK (7.1 +/- 0.0 to 5.8 +/- 0.0) whereas both efficacy and potency were reduced for SNP (95.6 +/- 1.8% to 65.8 +/- 1.9% and 8.7 +/- 0.1 to 7.2 +/- 0.1) and MCh (55.4 +/- 3.5% to 24.5 +/- 0.8% and 7.4 +/- 0.3 to 6.1 +/- 0.4). Inhibiting of the endothelial NO production by L-NAME 100 mu(M) resulted after pre-contraction with PhE and potassium in comparable differences in properties for SNP. Pre-contraction with St 587 1, 3, 10 and 30 mu(M) shows comparable results after nifedepine relaxation. The present experiments clearly demonstrate that the characteristics of the applied pre-contraction strongly, but differentially influence both the potency and efficacy of various vasodilator drugs in vitro. Accordingly, in vitro characterization of vasodilator drugs should be performed under a carefully standardized protocol of pre-contractio

Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: A randomised, controlled, open-label trial

Background: In critically ill patients, antibiotic therapy is of great importance but long duration of treatment is associated with the development of antimicrobial resistance. Procalcitonin is a marker used to guide antibacterial therapy and reduce its duration, but data about safety of this reduction are scarce. We assessed the efficacy and safety of procalcitonin-guided antibiotic treatment in patients in intensive care units (ICUs) in a health-care system with a comparatively low use of antibiotics. Methods: We did a prospective, multicentre, randomised, controlled, open-label intervention trial in 15 hospitals in the Netherlands. Critically ill patients aged at least 18 years, admitted to the ICU, and who received their first dose of antibiotics no longer than 24 h before inclusion in the study for an assumed or proven infection were eligible to participate. Patients who received antibiotics for presumed infection were randomly assigned (1:1), using a computer-generated list, and stratified (according to treatment centre, whether infection was acquired before or during ICU stay, and dependent on severity of infection [ie, sepsis, severe sepsis, or septic shock]) to receive either procalcitonin-guided or standard-of-care antibiotic discontinuation. Both patients and investigators were aware of group assignment. In the procalcitonin-guided group, a non-binding advice to discontinue antibiotics was provided if procalcitonin concentration had decreased by 80% or more of its peak value or to 0·5 μg/L or lower. In the standard-of-care group, patients were treated according to local antibiotic protocols. Primary endpoints were antibiotic daily defined doses and duration of antibiotic treatment. All analyses were done by intention to treat. Mortality analyses were completed for all patients (intention to treat) and for patients in whom antibiotics were stopped while being on the ICU (per-protocol analysis). Safety endpoints were reinstitution of antibiotics and recurrent inflammation measured by C-reactive protein concentrations and they were measured in the population adhering to the stopping rules (per-protocol analysis). The study is registered with ClinicalTrials.gov, number NCT01139489, and was completed in August, 2014. Findings: Between Sept 18, 2009, and July 1, 2013, 1575 of the 4507 patients assessed for eligibility were randomly assigned to the procalcitonin-guided group (761) or to standard-of-care (785). In 538 patients (71%) in the procalcitonin-guided group antibiotics were discontinued in the ICU. Median consumption of antibiotics was 7·5 daily defined doses (IQR 4·0-12·7) in the procalcitonin-guided group versus 9·3 daily defined doses (5·0-16·6) in the standard-of-care group (between-group absolute difference 2·69, 95% CI 1·26-4·12,