Significant Changes In Mean Arterial Blood Pressure Research Articles

Evaluation of Two Injection Techniques in Combination with the Local Anesthetics Lidocaine and Mepivacaine for Piglets Undergoing Surgical Castration.

Simple SummaryPain elimination during the surgical castration of male piglets is an important animal welfare issue. Bans on castration without pain relief are pending in most pork-producing European countries. Surgical castration of suckling piglets without anesthesia has been prohibited in Germany since January 2021. Boar fattening, gonadotropin-releasing hormone (GnRH) vaccination and surgical castration under isoflurane or injection anesthesia are permitted as legal alternatives. These alternatives have advantages and disadvantages, and a feasible and simple method is still needed. The legal basis for another alternative, i.e., the application of a local anesthetic by the farmer prior to castration, has been created in Germany, but evidence of its efficacy remains controversial. The present study developed a feasible and effective method for local anesthesia in piglet castration. Two different injection techniques in combination with the local anesthetics lidocaine and mepivacaine were investigated using nociceptive parameters, injection pressure and tissue distribution. Both injection techniques significantly reduced the nociceptive parameters regardless of the local anesthetic used and achieved similar distribution patterns and injection pressures. One method performed slightly better in the experimental setup, based on injection duration and handling.The present study evaluated the effects of two injection techniques in combination with lidocaine or mepivacaine for piglets undergoing castration. To improve ease of use, a cannula with side holes (one-step fenestrated (F)) was invented to simultaneously deliver a local anesthetic into the testis and scrotum and was compared to a two-step injection technique. The distribution of a lidocaine/contrast agent mixture using the two methods was examined using computed tomography. Piglets were randomly divided into treatment groups: handling, castration without pain relief and castration after lidocaine or mepivacaine injection using the one-step F or two-step method. Acute physiological responses to noxious stimuli were evaluated by measuring the mean arterial blood pressure (MAP), heart rate (HR) and nocifensive movements. Fos protein expression in the spinal dorsal cord was semi-quantitatively analyzed. Both injection techniques achieved similar distribution patterns. The one-step F method was faster and easier. Injection was not associated with significant changes in MAP or HR, but Mepi1 and NaCl elicited significantly increased nocifensive movements. Both techniques significantly reduced MAP and nocifensive movements when the spermatic cords were cut, regardless of the local anesthetic type. Compared to NaCl, only the lidocaine treatments significantly reduced HR during skin incision. Lido2 significantly reduced Fos protein expression.

Local anesthesia in piglets undergoing castration-A comparative study to investigate the analgesic effects of four local anesthetics on the basis of acute physiological responses and limb movements.

Surgical castration of male piglets without analgesia is a painful procedure. This prospective, randomized and double-blinded study aimed to evaluate the analgesic effects of four different local anesthetics for piglet castration during the first week of life. In total, 54 piglets aged 3 to 7 days were distributed into 6 treatment groups: handling (H); castration without pain relief (sodium chloride, NaCl); and castration with a local anesthetic: 4% procaine (P), 2% lidocaine (L), 0.5% bupivacaine (B) or 20 mg/ml mepivacaine (M). By excluding stress and fear as disruptive factors via a minimum anesthesia model, all piglets received individual minimum alveolar concentration (MAC) isoflurane anesthesia. Twenty minutes before castration, all treatment groups except group H received one injection per testis. Then, 0.5 ml of a local anesthetic or NaCl was injected intratesticularly (i.t.), and 0.5 ml was administered subscrotally. Acute physiological responses to noxious stimuli at injection and castration were evaluated by measuring blood pressure (BP), heart rate (HR), cortisol, epinephrine, norepinephrine and chromogranin A (CgA); limb movements were quantified. The results confirm that castration without analgesia is highly painful. Surgical castration without pain relief revealed significant changes in mean arterial blood pressure (MAP) and HR. Local anesthetic administration significantly reduced changes in BP and HR associated with castration. Piglets receiving a preoperative local anesthetic exhibited the fewest limb movements during castration, while the NaCl group exhibited the most. Injection itself was not associated with significant changes in MAP or HR. However, many piglets exhibited limb movements during injection, indicating that the injection itself causes nociceptive pain. No significant differences were found between groups regarding parameters of plasma cortisol, catecholamines and CgA. In conclusion, all four local anesthetics administered are highly effective at reducing signs of nociception during castration under light isoflurane anesthesia. However, injection of a local anesthetic seems to be painful.

Effect of TRPA1 activator allyl isothiocyanate (AITC) on rat dural and pial arteries.

Transient receptor potential ankyrin 1 (TRPA1) channels may have a role in migraine as some substances known to cause headache activate the channel. In the craniovascular system such activation causes a calcitonin gene-related peptide (CGRP)-dependent increase in meningeal blood flow. TRPA1 channels in the endothelium of cerebral arteries cause vasodilation when activated. The headache preventive substance feverfew inhibits activation of TRPA1 channels. In this study we aim to compare and characterize the effect of the TRPA1 agonist allyl isothiocyanate (AITC) on the diameter of rat dural and pial arteries in vivo. The genuine closed-cranial window technique in rats was used to examine changes in dural and pial artery diameter and mean arterial blood pressure (MABP) after intracarotid infusion of AITC. Blockade experiments were performed by intravenous infusion of olcegepant, HC-030031, sumatriptan or capsazepine immediately after infusion of AITC, in four different groups of rats. AITC caused a significant dilation of dural arteries, which was inhibited by HC-030031, olcegepant and sumatriptan, but not by capsazepine. In pial arteries AITC caused a significant dilation, which was not inhibited by any of the pre-treatments, suggesting a poor penetration of the blood-brain barrier or autoregulation due to dimethyl sulfoxide (DMSO) mediated decrease in MABP during HC-030031 infusion. AITC did not cause a significant change in MABP. AITC causes dilation of dural arteries via a mechanism dependent on CGRP and TRPA1 that is sensitive to sumatriptan. AITC causes a small but significant dilation of pial arteries.

Vasopressin V1a receptors are present in the carotid body and contribute to the control of breathing in male Sprague-Dawley rats

Vasopressin (AVP) maintains body homeostasis by regulating water balance, cardiovascular system and stress response. AVP inhibits breathing through central vasopressin 1a receptors (V1aRs). Chemoreceptors within carotid bodies (CBs) detect chemical and hormonal signals in the bloodstream and provide sensory input to respiratory and cardiovascular centers of the brainstem. In the study we investigated if CBs contain V1aRs and how the receptors are involved in the regulation of ventilation by AVP.We first immunostained CBs for V1aRs and tyrosine hydroxylase, a marker of chemoreceptor type I (glomus) cells. In urethane-anesthetized adult Sprague-Dawley male rats, we then measured hemodynamic and respiratory responses to systemic (intravenous) or local (carotid artery) administration of AVP prior and after systemic blockade of V1aRs. Immunostaining of CBs showed colocalization of V1aRs and tyrosine hydroxylase within glomus cells. Systemic administration of AVP increased mean arterial blood pressure (MABP) and decreased respiratory rate (RR) and minute ventilation (MV). Local administration of AVP increased MV and RR without significant changes in MABP or heart rate. Pretreatment with V1aR antagonist abolished responses to local and intravenous AVP administration.Our findings show that chemosensory cells within CBs express V1aRs and that local stimulation of the CB with AVP increases ventilation, which is contrary to systemic effects of AVP manifested by decreased ventilation. The responses are mediated by V1aRs, as blockade of the receptors prevents changes in ventilation. We hypothesize that excitatory effects of AVP within the CB provide a counterbalancing mechanism for the inhibitory effects of systemically acting AVP on the respiration.

Abstract 216: Hdac2 Modulates Atherosclerosis

Objective: We recently described a novel regulatory role for histone deacetylase 2 (HDAC2) in vascular endothelial cell protection against the known endothelial injury stimulus Oxidize Low Density Lipoprotein (OxLDL). The goal of current study is to determine the effects of endothelial-specific HDAC2 overexpression on endothelial dysfunction and atherogenesis in vivo . Approach and Results: To study the effect of endothelial HDAC2 overexpression on vascular function and atherogenesis, we generated and characterized an endothelial specific human HDAC2 overexpressing transgenic mouse (HDAC2-Tg) under the control of the tie2 promoter. The founder HDAC2-overexpressing mice appear to have a normal phenotype- normal weight, mean arterial blood pressure (MAP) and pulse wave velocity (PWV). Isolated intact aortas from endothelial-specific overexpressing HDAC2 transgenic mice (HDAC2-Tg) exhibited a healthier vascular function profile with higher nitric oxide levels and less OxLDL-mediated vascular dysfunction. Further, we induced atherogenesis in C57BL6 and HDAC2-Tg mice by injecting adeno-associated viruses (AAV) encoding PCSK9 (D377Y) under the control of a liver-specific promoter by tail vein injection followed by high fat diet regimen for 12 weeks and measured endothelium-dependent vasorelaxation in isolated blood vessels, pulse wave velocity, an index of vascular stiffness and mean arterial blood pressure. HDAC2-Tg exhibited protected endothelial dependent vascular relaxation and no significant changes in MAP and PWV as compared to control mice. Conclusion: HDAC2 is a critical regulator of endothelial function. Overexpression or activation of HDAC2 represents a novel therapy for endothelial dysfunction and atherosclerosis.

Comparison of hemodynamic effects of inhaled milrinone and inhaled nitroglycerin in patients with pulmonary hypertension undergoing mitral valve surgery

Introduction Pulmonary hypertension (PH) frequently complicates the perioperative management of patients undergoing mitral valve surgery and has been shown to be a significant independent predictor of postoperative morbidity and mortality. The aim of this work is to compare the effects of inhaled milrinone and inhaled nitroglycerin on pulmonary and systemic hemodynamic responses in patients with PH undergoing mitral valve surgery. Patients and methods A total of 50 patients with PH were randomly divided into two groups with 25 patients in each group: group I patients received inhaled nitroglycerin (5 mg, 1 mg/ml) over 15 min and group II patients received inhaled milrinone (5 mg, 1 mg/ml) over 15 min through an ultrasonic nebulizer connected to the inspiratory limb of the ventilator circuit near the endotracheal tube immediately after separation from cardiopulmonary bypass. Hemodynamic parameters were measured after induction of anesthesia (T1), immediately after the end of cardiopulmonary bypass (T2), 30 min after the start of treatment, and 90 min after the start of treatment (T4). The hemodynamic variables were as follows: heart rate, mean arterial blood pressure (MAP), mean pulmonary artery blood pressure (MPAP), cardiac index (CI), systemic vascular resistance index (SVRI), pulmonary vascular resistance index (PVRI), and right ventricular stroke work index (RVSWI). Results At 30 min after the start of treatment, both groups showed a significant comparable decrease in MPAP, PVRI, and RVSWI, with no significant changes in MAP, CI, and SVRI. At 90 min after the start of treatment, MPAP, PVRI, and RVSWI returned to their values in the inhaled nitroglycerin group but remained at significantly lower values in the inhaled milrinone group. Conclusion Inhalation of nitroglycerin and milrinone produces a comparable decrease in MPAP, PVRI, and RVSWI without significant changes in heart rate, MAP, CI, and SVRI. Inhaled milrinone has a longer duration of action than inhaled nitroglycerin.

MRI with ferumoxytol: A single center experience of safety across the age spectrum.

PurposeTo summarize our single‐center safety experience with the off‐label use of ferumoxytol for magnetic resonance imaging (MRI) and to compare the effects of ferumoxytol on monitored physiologic indices in patients under anesthesia with those of gadofosveset trisodium.Materials and MethodsConsecutive patients who underwent ferumoxytol‐enhanced (FE) MRI exams were included. Adverse events (AEs) were classified according to the Common Terminology Criteria for Adverse Events v4.0. In a subgroup of patients examined under general anesthesia, recording of blood pressure, heart rate, oxygen saturation, and end‐tidal CO2 was performed. A comparable group of 23 patients who underwent gadofosveset‐enhanced (GE) MRI under anesthesia with similar monitoring was also analyzed.ResultsIn all, 217 unique patients, ages 3 days to 94 years, underwent FE‐MRI. No ferumoxytol‐related severe, life‐threatening, or fatal AEs occurred acutely or at follow‐up. Two patients developed ferumoxytol‐related nausea. Between‐group (FE‐ vs. GE‐MRI) comparisons showed no statistical difference in heart rate (P = 0.69, 95% confidence interval [CI] 96–113 bpm), mean arterial blood pressure (MAP) (P = 0.74, 95% CI 44–52 mmHg), oxygen saturation (P = 0.76, 95% CI 94–98%), and end‐tidal CO2 (P = 0.73, 95% CI 31–37 mmHg). No significant change in MAP (P = 0.12, 95% CI 50–58 mmHg) or heart rate (P = 0.25, 95% CI 91–105 bpm) was noted between slow infusion of ferumoxytol (n = 113) vs. bolus injection (n = 104).ConclusionIn our single‐center experience, no serious AEs occurred with the diagnostic use of ferumoxytol across a wide spectrum of age, renal function, and indications. Because of the limited sample size, firm conclusions cannot be drawn about the generalizability of our results. Thus, vigilance and monitoring are recommended to mitigate potential rare adverse reactions. Level of Evidence: 2J. Magn. Reson. Imaging 2017;45:804–812.

Glutamate receptors in the hypothalamic paraventricular nucleus contribute to insulin-induced sympathoexcitation.

The sympathoexcitatory response to insulin is mediated by neurons in the arcuate nucleus (ARC) and hypothalamic paraventricular nucleus (PVH). Previous studies have reported that stimulation of ARC neurons increases sympathetic nerve activity (SNA) and arterial blood pressure (ABP) through glutamate receptor activation in the PVH. Therefore, the purpose of the present study was to determine whether glutamatergic neurotransmission in the PVH contributes to insulin-induced sympathoexcitation. Male Sprague-Dawley rats (275-400 g) were infused with isotonic saline or insulin (3.75 mU · kg(-1) · min(-1)) plus 50% dextrose to maintain euglycemia. Intravenous infusion of insulin significantly increased lumbar SNA without a significant change in mean ABP, renal SNA, heart rate, or blood glucose. Bilateral PVH injection of the excitatory amino acid antagonist kynurenic acid (KYN) lowered lumbar SNA and ABP of animals infused with insulin. Similarly, a cocktail of the NMDA antagonist DL-2-amino-5-phosphonopentanoic acid (AP5) and non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) reduced lumbar SNA and mean ABP during infusion of insulin. In a final experiment, bilateral PVH injection of AP5 only, but not CNQX, lowered lumbar SNA and mean ABP of animals infused with insulin. The peak changes in lumbar SNA and mean ABP of insulin-treated animals were not different between KYN, AP5 plus CNQX, or AP5 alone. These drug treatments did not alter any variable in animals infused with saline. Altogether, these findings suggest that glutamatergic NMDA neurotransmission in the PVH contributes to insulin-induced sympathoexcitation.

Effect of Dexmedetomidine on Brain Edema and Neurological Outcomes in Surgical Brain Injury in Rats

Surgical brain injury (SBI) is damage to functional brain tissue resulting from neurosurgical manipulations such as sharp dissection, electrocautery, retraction, and direct applied pressure. Brain edema is the major contributor to morbidity with inflammation, necrosis, oxidative stress, and apoptosis likely playing smaller roles. Effective therapies for SBI may improve neurological outcomes and postoperative morbidities associated with brain surgery. Previous studies show an adrenergic correlation to blood-brain barrier control. The α-2 receptor agonist dexmedetomidine (DEX) has been shown to improve neurological outcomes in stroke models. We hypothesized that DEX may reduce brain edema and improve neurological outcomes in a rat model of SBI. Male Sprague-Dawley rats (n = 63) weighing 280 to 350 g were randomly assigned to 1 of 4 IP treatment groups: sham IP, vehicle IP, DEX 10 mg/kg, and DEX 30 mg/kg. Treatments were given 30 min before SBI. These treatment groups were repeated to observe the physiologic impact of DEX on mean arterial blood pressure (MAP), heart rate (HR), and blood glucose on SBI naïve animals. Rats were also assigned to 4 postinjury IV treatment groups: sham IV, vehicle IV, DEX 10/5, and DEX 30/15 (DEX group doses were 10 and 30 mg/kg/hr, with 5 and 15 mg/kg initial loading doses, respectively). Initial loading doses began 20 min after SBI, followed by 2 h of infusion. SBI animals were subjected to neurological testing 24 h after brain injury by a blinded observer, promptly killed, and brain water content measured via the dry/wet weight method. All treatment groups showed a significant difference in ipsilateral frontal brain water content and neurological scores when compared with sham animals. However, there was no difference between DEX-treated and vehicle animals. Physiologic monitoring showed treatment with low or high doses of DEX significantly decreased MAP and HR, and briefly increased blood glucose compared with naïve or vehicle-treated animals. DEX administration did not reduce brain edema or improve neurological function after SBI in this study. The statistical difference in brain water content and neurological scores when comparing sham treatment to vehicle and DEX treatments shows consistent reproduction of this model. Significant changes in MAP, HR, and blood glucose after DEX as compared to vehicle and sham treatments suggest appropriate delivery of drug.

Amygdala centralis cardiovascular response to angiotensin I microinjection in Goldblatt hypertensive rats

Previous studies have shown that induction of 2kidney -1clip Goldblatt hypertension (2K-1C) induction in rats eliminates hypertensive response after inactivating of the central nucleus of the amygdale (ACe). The present study investigated the possibility of alteration in local renin angiotensin system (RAS) activity in ACe after hypertension induction. Clamps were placed on the left renal arteries of a group of Wistar rats to induce 2K-1C Goldblatt hypertension. A similar surgery without clipping was done in sham group. Rats were studied six weeks after surgery. The mean arterial blood pressure (MAP) and heart rate (HR) were measured directly with indwelling arterial cannulas under urethane anesthesia. Rats received bilateral cannulation of the ACe for angiotensin I (AngI) microinjection. Before and 5,10,20,40 and 60 minutes after bilateral microinjection of Ang I (1 µL, 100 µM) into ACe, MAP and HR measured and compared between groups. In normotensive rats, significant changes in MAP or HR were not seen. Meanwhile, in hypertensive rats MAP significantly increased 5, 10, and 20 minutes after (p

Effect of Angiotensin II Type 1 receptor blocker, Candesartan, and β1adrenoceptor blocker, Atenolol, on brain damage in ischemic stroke

This work aims at studying the possible alteration of renal renin secretion after human ischemic stroke and correlating it to the post stroke neurological and renal function alterations using angiotensin II type 1(AT1) receptor blocker (ARB), candesartan, and beta 1 adrenoreceptor blocker atenolol, which inhibits renin secretion, in Wistar rats subjected to middle cerebral artery occlusion. Methods . This study comprised 21 patients with cerebral ischemic stroke. Seventeen normal persons were used for comparison. Recumbent and standing plasma renin activity (PRA), reflex plasma renin sensitivity, plasminogen activator inhibitor and creatinine clearance (Ccr) were estimated at admission and two weeks later. Moreover, 60 male Wistar rats were divided into two groups SHAM and ischemic. Each of the two groups was further subdivided into three subgroups, non-treated, atenolol treated, and candesartan treated. In all rats, mean arterial blood pressure (MAP), systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), heart rate (HR), neurobehavioral evaluation, Ccr, PRA, and infarct size were measured. Results . Together with the significant deterioration of the neurological score, focal cerebral ischemia in rats resulted in increased PRA and decreased glomerular filtration rate (GFR). In ischemic stroke patients, GFR was significantly decreased at admission and two weeks later, PRA increased at admission and two weeks later while plasma renin reflex secretion sensitivity had decreased significantly at admission relative to controls, but it increased significantly 2 weeks later. Atenolol caused significant improvement of the neurobehavioral score and renal function and decrease infarct size of rats subjected to focal cerebral ischemia whereas candesartan caused significant improvement of the neurobehavioral score and decreased infarct size with no significant change in GFR. Neither atenolol nor candesartan caused significant change in MAP, SBP, DBP, PP and HR Conclusion . (1) Ischemic stroke seems to be associated with a postischemic increase of the plasma renin secretion, which may increase the infarct size in the brain and may induce acute renal insufficiency. (2) This study confirms that Atenolol and ARBs could benefit ischemic stroke patients without altering blood pressure.

Simvastatin Reduces Pressor Response to Centrally Administered Angiotensin II

Angiotensin II (Ang II) plays a pivotal role in regulation of the circulatory system. Activation of angiotensin type 1 (AT1) receptors in several brain regions leads to an increase in blood pressure. Accumulating data suggest that statins affect the peripheral action of Ang II; however, their central effects are poorly recognized. The study was aimed to determine whether simvastatin interferes with the brain angiotensin system in rats. Twelve-week-old, Sprague-Dawley rats were divided into two groups. Untreated group was maintained on tap water, whereas simvastatin group received water containing simvastatin for the following 12 weeks. Later, both groups were subjected to experiments in which mean arterial blood pressure (MABP) and heart rate (HR) were recorded during baseline conditions and after intracerebroventricular (ICV) infusion of either saline, Ang II, or losartan. ICV infusion of Ang II elicited a significant increase in MABP in both groups. However, the pressor response in the simvastatin group was significantly smaller than that in the untreated group. There was no significant change in MABP after ICV infusion of saline or losartan. ICV infusion of Ang II elicited a significant increase in HR in the untreated group but not in the simvastatin group. There was no significant change in HR after ICV infusion of saline or losartan. The results show that simvastatin reduces the pressor response to ICV-infused Ang II in rats. This implies that statins may affect the central regulation of the circulatory system, especially when the brain angiotensin system is stimulated.

Exogenous hydrogen sulfide produces hemodynamic effects by triggering central neuroregulatory mechanisms.

Recently, it was found that hydrogen sulfide (H2S) may serve as an important transmitter in peripheral organs as well as in the brain. The aim of the present study was to evaluate the possible function of H2S in the brain regulation of the circulatory system. Experiments were performed on conscious, male, Wistar-Kyoto rats. Mean arterial blood pressure (MABP) and heart rate (HR) were recorded continuously under baseline conditions and during infusions into the lateral cerebral ventricle (LCV) of the experimental animals. In control series LCV infusion of vehicle (Krebs-Henseleit bicarbonate-buffer) did not cause significant changes in MABP or HR. LCV infusion of H2S donor (NaHS) at the rate of 400 n/h resulted in an increase in MABP, whereas infusions at the rate of 100 n/h and 200 n/h failed to change MABP. On the other hand LCV infusion of H2S donor at the rate of 200 n/h caused a significant increase in HR while infusion at the rate of 400 n/h produced an increase in HR, which was smaller than this observed during infusion at the rate of 200 n/h. H2S donor administered at the rate of 100 n/h failed to affect HR. In conclusion, the present study demonstrates that exogenous hydrogen sulfide changes hemodynamic parameters by centrally mediated mechanisms. The hemodynamic effect seems to be dependent on H2S concentration in cerebrospinal fluid. It appears that the hypertensive response may occur at a concentration, which does not exceed twice the physiological level.

Central Hypervolemia with Hemodilution Impairs Dynamic Cerebral Autoregulation

Frequent changes in the perioperative central blood volume could affect cerebral autoregulation through alterations in sympathetic nerve activity, cardiac output, blood viscosity, and cerebral vasomotor tone. However, the effect of dynamic cerebral autoregulation has not been studied during acute wide-ranging changes in central blood volume, especially with respect to central hypervolemia with hemodilution. We evaluated dynamic cerebral autoregulation during central hypovolemia and central hypervolemia with hemodilution using spectral and transfer function analysis between mean arterial blood pressure (MBP) and cerebral blood flow (CBF) velocity variability in 12 individuals. Rapid changes in central blood volume were achieved using two levels of lower body negative pressure (-15 and -30 mm Hg) and two discrete infusions of normal saline (15 mL/kg and total 30 mL/kg). We then estimated changes in central blood volume as central venous pressure (CVP) and/or cardiac output using impedance cardiography. Steady-state CBF velocity and cardiac output decreased at -30 mm Hg lower body negative pressure (changes of CVP approximately -4 mm Hg) or were increased by each saline infusion (changes of CVP 4-6 mm Hg), without a significant change in MBP. However, transfer function gain (magnitude of transfer) between MBP and CBF velocity variability significantly increased only after saline infusion, suggesting an increased magnitude of transfer from MBP oscillations to CBF fluctuations during central hypervolemia with hemodilution. Our results suggest that, although steady-state CBF velocity changes under both central hypervolemia and hypovolemia, only hypervolemic hemodilution impairs dynamic cerebral autoregulation.

Disconnection between activation and desensitization of autonomic nicotinic receptors by nicotine and cotinine

Cotinine is the major metabolite of nicotine in humans, and the substance greatly outlasts the presence of nicotine in the body. Recently, cotinine has been shown to exert pharmacological properties of its own that include potential cognition enhancement, anti-psychotic activity, and cytoprotection. Since the metabolite is generally less potent than nicotine in vivo, we considered whether part of cotinine's efficacy could be related to a reduced ability to desensitize nicotinic receptors as compared with nicotine. Rats freely moving in their home cages were instrumented to allow ongoing measurement of mean arterial blood pressure (MAP). The ganglionic stimulant dimethylphenylpiperazinium (DMPP) maximally increased MAP by 25 mmHg. Slow (20 min) i.v. infusion of nicotine (0.25–1 μmol) produced no change in resting MAP, but the pressor response to subsequent injection of DMPP was significantly attenuated in a dose-dependent manner by up to 51%. Pre-infusion of equivalent doses of cotinine produced the same maximal degree of inhibition of the response to DMPP. Discrete i.v. injections of nicotine also produced a dose dependent increase in MAP of up to 43 mmHg after the highest tolerated dose. In contrast, injection of cotinine produced no significant change in MAP up to 13 times the highest dose of nicotine. These results illustrate the disconnection between nicotinic receptor activation and receptor desensitization, and they suggest that cotinine's pharmacological actions are either mediated through partial desensitization, or through non-ganglionic subtypes of nicotinic receptors.

Hemodynamic Benefits of Matrix Metalloproteinase-9 Inhibition by Doxycycline During Experimental Acute Pulmonary Embolism

The authors examined whether acute pulmonary embolism (APE) increases lung matrix metalloproteinase (MMP)-2 and MMP-9 activities and whether inhibition of MMPs with doxycycline attenuates the hemodynamic changes associated with APE. Anesthetized male Wistar rats were monitored for mean arterial blood pressure (MAP) and heart rate (HR). Rats in the control group (n = 5) received only saline IV; rats in the embolism (Emb) group (n = 8) received saline IV followed 10 minutes later by an injection of Sephadex microspheres (9 mg/kg) IV; rats in the doxycycline (Doxy) group (n = 4) received only doxycycline (30 mg/kg) IV, followed 10 minutes later by an injection of saline IV; rats in the Doxy + Emb group (n = 8) received the same dose of doxycycline followed 10 minutes later by the same amount of microspheres described above. Lung samples were homogenized and assayed by SDS-polyacrilamide gel electrophoresis gelatin zymography to evaluate lung MMP-2 and MMP-9 activities. Saline or doxycycline produced no significant changes in MAP, HR, and in MMP-2 and MMP-9 activities. Conversely, lung embolization significantly reduced MAP by > 32 mm Hg and HR by > 90 bpm for more than 60 minutes, and increased MMP-9 activity by 43% (all p < 0.05). No significant differences were observed in MMP-2 activity. However, lung embolization produced only transient hypotension in rats pretreated with doxycycline. In this group, MAP returned to baseline values 5 to 10 minutes after embolization. In addition, pretreatment with doxycycline blunted the increase in lung MMP-9 activity after lung embolization (p < 0.05). This study demonstrates for the first time that MMP-9 inhibition with doxycycline attenuates APE-induced hemodynamic changes in the animal model examined. These findings indicate that MMP-9 activation plays a role in the pathophysiology of APE and suggest that pharmacologic strategies targeting specific MMPs with selective inhibitors may prevent the detrimental acute hemodynamic consequences of APE.

Central stresscopin modulates cardiovascular function through the adrenal medulla in conscious rats

Stresscopin (SCP or urocortin III), a member of the corticotropin-releasing factor (CRF) neuropeptide family, is a high-affinity ligand for the type 2 CRF receptor (CRF 2). When administered peripherally, SCP suppresses food intake, delays gastric emptying and decreases heat-induced edema. Central administration of CRF produces marked hypertension and increased plasma catecholamine. However, the effects of SCP on the cardiovascular system are unknown. Thus, the present study compared the effects of intracerebroventricular (i.c.v.) administration of CRF and SCP on cardiovascular function. Central administration of SCP (0.05 or 0.5 nmol) elicited transient increases in mean arterial blood pressure (MABP) and heart rate (HR), and the higher dose of SCP (0.5 nmol) resulted in increased plasma epinephrine. In contrast, central administration of CRF provoked long-lasting increases in MABP, HR and plasma catecholamine levels (norepinephrine and epinephrine). Intravenously administered CRF and SCP (0.5 nmol) did not elicit significant changes in MABP and HR. Therefore, these data suggest that centrally administered SCP modulates cardiovascular function, likely through the sympatho-adrenal-medullary (SAM) system.

Results of a phase I trial evaluating a liver support device utilizing albumin dialysis

Background. We have previously reported the clearance of protein-bound and water-soluble hepatic toxins, in vitro and in an animal model, using albumin dialysis as an extracorporeal hepatic support (ECHS) device. Objective. The objective of this study was to evaluate albumin dialysis through a phase I clinical trial. We hypothesized that albumin dialysis would (1) decrease elevated levels of hepatic toxins, (2) increase the Fischer ratio, and (3) decrease hepatic encephalopathy (HES) and intracranial pressure (ICP), while (4) maintaining stable hemodynamics. Methods. Patients with acute liver failure were treated with an ECHS device utilizing continuous hemodiafiltration with continuous albumin dialysis. Mean arterial blood pressure (MAP), heart rate (HR), systemic venous oxygen saturation (Svo2), ICP, and HES were recorded. Blood samples were evaluated for hepatic toxins and factor VII levels. Results. Nine patients were enrolled (status I, n = 5; status IIA, n = 4). There was no significant change in MAP, HR, or Svo2 (MAP: Pre = 81 ± 5.6 mm Hg, Post = 79 ± 5.9 mm Hg, P =.70; HR: Pre = 104 ± 5.2 bpm, Post = 107 ± 6.2 bpm, P =.62; Svo2: Pre = 72 ± 3.5, Post = 71 ± 1.7, P =.77). There was a decrease in the ammonia and total bilirubin levels (NH3: Pre = 129.8 ± 23.8 mg/dL, Post = 63.9 ± 16.1 mg/dL, P =.01; total bilirubin: Pre = 20.3 ± 2.5 mg/dL, Post = 17.6 ± 2.7 mg/dL, P =.4). There was a significant increase of the Fischer ratio and factor VII levels (Fischer ratio: Pre = 0.98 ± 0.2, Post = 2.17 ± 0.5, P =.038; factor VII: Pre = 13.9 ± 4.9, Post = 23.2 ± 4.8, P =.015). There was a significant decrease in the HES and ICP (HES: Pre = 3.8 ± 0.1, Post = 2 ± 0.7, P =.02; ICP: Pre = 37 ± 3.9, Post = 13.3 ± 2.8, P =.048). Of 5 status I patients, 1 recovered native hepatic function and 3 were bridged to transplantation. Conclusions. This phase I study suggests that albumin dialysis as a liver support device is safe and effective in clearing hepatic toxins, with an associated decrease in the HES and ICP. This encouraging efficacy data warrant further investigation with a phase II/III trial. (Surgery 2001;130:354-62.)

Cardiorespiratory effects of l-glutamate microinjected into the rat ventral medulla

We investigated the cardiorespiratory effects elicited by microinjections of l-glutamate ( l-glu, 25 nmol, 200 nl) at various sites in the ventral medulla (VMS) of urethane-anesthetized rats. The results demonstrated that regions responsive to the drug are located along a column in the VMS extending from the VI cranial nerve to the first cervical nerve in the caudal medulla. Within this column three breathing patterns were elicited from four distinct areas. In the most rostral and caudal portion of this hypothetical column, the breathing patterns observed in response to l-glu were similar and characterized by increases in minute ventilation, tidal volume, inspiratory drive, respiratory frequency, mean arterial blood pressure (MAP) and heart rate (HR). In the regions located between the areas described above two different breathing patterns were obtained without significant changes in MAP or HR. These patterns were characterized by decreases and increases in the respiratory indices analyzed, with the exception of respiratory frequency, which decreased in both regions. These results suggest that within the VMS discrete areas may act as functional units modulating cardiorespiratory responses while in others these functions are spatially segregated.

Efficacy and safety of divided dose administration of mivacurium for a 90-second tracheal intubation

Study Objective: To compare the safety and effectiveness of 0.25 mg divided doses of mivacurium chloride to succinylcholine for a 90-second tracheal intubation. Design: Randomized, double-blind, multicenter study in two groups. Setting: Operating rooms at four university medical centers. Patients: 200 healthy ASA status I and II adult patients scheduled for elective surgery with general anesthesia and endotracheal intubation. Interventions: Patients were premedicated with 1 to 2 mg midazolam and 2 μg/kg fentanyl. Anesthesia was induced with 2 mg/kg propofol. Group A received 0.25 mg/kg mivacurium given as a divided dose (0.15 mg/kg followed in 30 seconds with 0.1 mg/kg). Group B (control) received 1.5 mg/kg succinylcholine (SCh) preceded two minutes earlier by 50 μg/kg d-tubocurarine (dtc). Measurements and Main Results: Tracheal intubation grading, train-of-four response of the adductor pollicis, heart rate (HR), and mean arterial blood pressure (MAP) were measured and evaluated. Chi-square analysis was performed for comparison between Group A and Group B with respect to the frequency distribution of intubation using the scores excellent, good, and poor and not possible (combined). Group B had a significantly higher excellent score of intubation than Group A, 84% versus 56% ( p < 0.0001). No significant difference was found between the two groups when the scores excellent and good were combined (Fisher's Exact test, p = 0.28). The changes in MAP and HR were similar for the two groups. Conclusions: When Sch is not desirable, mivacurium 0.25 mg/kg given as a divided dose provides good to excellent intubation conditions 90 seconds after the initial dose without significant changes in MAP or HR. It can be an appropriate alternative for short surgical procedures. It must be emphasized that this conclusion does not apply to rapid-sequence induction-intubation.