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The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) study demonstrated that dapagliflozin, a sodium-glucose cotransporter-2 inhibitor (SGLT2i), reduced heart failure hospitalization and cardiovascular death in patients with heart failure with reduced ejection fraction (HF-rEF), with and without type 2 diabetes mellitus. Multiple potential mechanisms have been proposed to explain this benefit, which may be multifactorial. This study aimed to quantify the contribution of the known natriuretic/diuretic effects of SGLT2is to changes in cardiac hemodynamics, remodeling, and fluid homeostasis in the setting of HF-rEF. An integrated cardiorenal mathematical model was used to simulate inhibition of SGLT2 and its consequences on cardiac hemodynamics in a virtual population of HF-rEF patients generated by varying model parameters over physiologically plausible ranges and matching to baseline characteristics of individual DAPA-HF trial patients. Cardiovascular responses to placebo and SGLT2i over time were then simulated. The baseline characteristics of the HF-rEF virtual population and DAPA-HF were in good agreement. SGLT2i-induced diuresis and natriuresis that reduced blood volume and interstitial fluid volume, relative to placebo within 14 days. This resulted in decreased left ventricular end-diastolic volume and pressure, indicating reduced cardiac preload. Thereafter, blood volume and interstitial fluid volume again began to accumulate, but pressures and volumes remained shifted lower relative to placebo. After 1 year, left ventricle mass was lower and ejection fraction was higher than placebo. These simulations considered only hemodynamic consequences of the natriuretic/diuretic effects of SGLT2i, as other mechanisms may contribute additional benefits besides those predictions., (© 2020, The American College of Clinical Pharmacology.)

Background and Purpose: The purpose of this study was to assess cerebral perfusion changes following systemic administration of the recreational drug 3,4-methylendioxymethamphetamine (MDMA 'ecstasy') to rats., Experimental Approach: Cerebral perfusion was quantified using bolus-tracking arterial spin labelling (btASL) MRI. Rats received MDMA (20 mg·kg(-1); i.p.) and were assessed 1, 3 or 24 h later. Rats received MDMA (5 or 20 mg·kg(-1); i.p.) and were assessed 3 h later. In addition, rats received MDMA (5 or 10 mg·kg(-1); i.p.) or saline four times daily over 2 consecutive days and were assessed 8 weeks later. Perfusion-weighted images were generated in a 7 tesla (7T) MRI scanner and experimental data was fitted to a quantitative model of cerebral perfusion to generate mean transit time (MTT), capillary transit time (CTT) and signal amplitude., Key Results: MDMA reduces MTT and CTT and increases amplitude in somatosensory and motor cortex 1 and 3 h following administration, indicative of an increase in perfusion. Prior exposure to MDMA provoked a long-term reduction in cortical 5-HT concentration, but did not produce a sustained effect on cerebral cortical perfusion. The response to acute MDMA challenge (20 mg·kg(-1); i.p.) was attenuated in these animals indicating adaptation in response to prior MDMA exposure., Conclusions and Implications: MDMA provokes changes in cortical perfusion, which are quantifiable by btASL MRI, a neuroimaging tool with translational potential. Future studies are directed towards elucidation of the mechanisms involved and correlating changes in cerebrovascular function with potential behavioural deficits associated with drug use., (© 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society.)

The integrity of the blood-brain barrier (BBB) is critical to normal brain function. Traditional techniques for the assessment of BBB disruption rely heavily on the spatiotemporal analysis of extravasating contrast agents. However, such methods based on the leakage of relatively large molecules are not suitable for the detection of subtle BBB impairment or for the performance of repeated measurements in a short time frame. Quantification of the water exchange rate constant (WER) across the BBB using strictly intravascular contrast agents could provide a much more sensitive method for the quantification of the BBB integrity. To estimate WER, we have recently devised a powerful new method using a water exchange index (WEI) biomarker and demonstrated BBB disruption in an acute stroke model. Here, we confirm that WEI is sensitive to even very subtle changes in the integrity of the BBB caused by: (i) systemic hypercapnia and (ii) low doses of a hyperosmolar solution. In addition, we have examined the sensitivity and accuracy of WEI as a biomarker of WER using computer simulation. In particular, the dependence of the WEI-WER relation on changes in vascular blood volume, T1 relaxation of cellular magnetization and transcytolemmal water exchange was explored. Simulated WEI was found to vary linearly with WER for typically encountered exchange rate constants (1-4 Hz), regardless of the blood volume. However, for very high WER (>5 Hz), WEI became progressively more insensitive to increasing WER. The incorporation of transcytolemmal water exchange, using a three-compartment tissue model, helped to extend the linear WEI regime to slightly higher WER, but had no significant effect for most physiologically important WERs (WER < 4 Hz). Variation in cellular T1 had no effect on WEI. Using both theoretical and experimental approaches, our study validates the utility of the WEI biomarker for the monitoring of BBB integrity., (Copyright © 2012 John Wiley & Sons, Ltd.)

Despite the widespread use of loop diuretics to treat acute decompensated heart failure (ADHF), robust data supporting their role and optimal dosing strategies are scarce. This analysis aimed to compare clinical outcomes of patients admitted with ADHF who received a diuretic dosing protocol with those who received the usual diuretic therapy. We performed an observational medical records review to compare the use of a nurse-driven diuretic dosing protocol with usual diuretic dosing for patients admitted with ADHF during a 1-year period. Using a propensity scoring model, comparisons were made between groups for total weight loss, length of stay (LOS), 30-day readmissions, in-hospital mortality, 30-day mortality, and acute kidney failure. Sixty-eight of the 596 patients admitted with ADHF during the study period received the diuretic protocol. Protocol use was associated with an additional 2.63-kg weight loss (P=.003) but a trend toward increased LOS compared with patients receiving usual care (P=.097). However, patients receiving the protocol had a significantly lower risk of 30-day readmission (odds ratio, 0.46, 95% confidence interval, 0.22-0.95). Protocol use was not associated with significant differences in kidney failure, inpatient mortality, or 30-day mortality. A diuretic dosing protocol for patients admitted with ADHF improves weight loss and may lower 30-day readmissions, at the cost of potentially increasing LOS., (© 2013 Wiley Periodicals, Inc.)

Pharmacologic MRI (phMRI) uses functional MRI techniques to provide a noninvasive in vivo measurement of the hemodynamic effects of drugs. The cerebral blood volume change (ΔCBV) serves as a surrogate for neuronal activity via neurovascular coupling mechanisms. By assessing the location and time course of brain activity in mouse mutant studies, phMRI can provide valuable insights into how different behavioral phenotypes are expressed in deferring brain activity response to drug challenge. In this report, we evaluate the utility of three different intravascular ultrasmall superparamagnetic iron oxide (USPIO) contrast agents for phMRI using a gradient-echo technique, with temporal resolution of one min at high magnetic field. The tissue half-life of the USPIOs was studied using a nonlinear detrending model. The three USPIOs are candidates for CBV weighted phMRI experiments, with r(2)/r(1) ratios ≥ 20 and apparent half-lives ≥ 1.5 h at the described doses. An echo-time of about 10 ms or longer results in a functional contrast to noise ratio (fCNR) > 75 after USPIO injection, with negligible decrease between 1.5-2 h. phMRI experiments were conducted at 7 T using cocaine as a psychotropic substance and acetazolamide, a global vasodilator, as a positive control. Cocaine acts as a dopamine-serotonin-norepinephrine reuptake inhibitor, increasing extracellular concentrations of these neurotransmitters, and thus increasing dopaminergic, serotonergic and noradrenergic neurotransmission. phMRI results showed that CBV was reduced in the normal mouse brain after cocaine challenge, with the largest effects in the nucleus accumbens, whereas after acetazolamide, blood volume was increased in both cerebral and extracerebral tissue., (Copyright © 2011 John Wiley & Sons, Ltd.)

Early imaging or blood biomarkers of tumor response is needed to customize anti-tumor therapy on an individual basis. This study evaluates the sensitivity and relevance of five potential MRI biomarkers. Sixty nude rats were implanted with human glioma cells (U-87 MG) and randomized into three groups: one group received an anti-angiogenic treatment (Sorafenib), a second a cytotoxic drug [1,3-bis(2-chloroethyl)-1-nitrosourea, BCNU (Carmustine)] and a third no treatment. The tumor volume, apparent diffusion coefficient (ADC) of water, blood volume fraction (BVf), microvessel diameter (vessel size index, VSI) and vessel wall integrity (contrast enhancement, CE) were monitored before and during treatment. Sorafenib reduced tumor CE as early as 1 day after treatment onset. By 4 days after treatment onset, tumor BVf was reduced and tumor VSI was increased. By 14 days after treatment onset, ADC was increased and the tumor growth rate was reduced. With BCNU, ADC was increased and the tumor growth rate was reduced 14 days after treatment onset. Thus, the estimated MRI parameters were sensitive to treatment at different times after treatment onset and in a treatment-dependent manner. This study suggests that multiparametric MR monitoring could allow the assessment of new anti-tumor drugs and the optimization of combined therapies., (Copyright © 2010 John Wiley & Sons, Ltd.)

Chronic pain is a major problem for the individual and for society. Despite a range of drugs being available to treat chronic pain, only inadequate pain relief can be achieved for many patients. There is therefore a need for the development of new analgesic compounds. The assessment of pain depends to date entirely on the subjective report of the patient, in contrast to many other clinical conditions where biomarkers that help determine the severity and stage of the disease enable the physician to monitor the course of the disease and treatment effects longitudinally. In this article, we illustrate that magnetic resonance-based imaging techniques have the potential to provide sensitive and specific biomarkers of the pain experience, as well as clarifying disease mechanisms. Functional magnetic resonance imaging (FMRI) is particularly suited to investigating the effects of pharmacological agents on pain processing within the human central nervous system. Combination of FMRI and drug administration is termed pharmacological FMRI (phFMRI). In addition to outlining several methodological considerations that have to be taken into account when performing phFMRI, we discuss phFMRI studies that have already used this technique to study the effects of analgesic compounds. These studies provide promising data for the use of phFMRI as sensitive tool in assessing a potential drug effect. Such pharmacodynamic readouts obtained early in the process of drug development would not only save the pharmaceutical industry substantial amounts of money, but would also avoid the unnecessary exposure of patients to molecules with limited or no therapeutic value. We are therefore optimistic that phFMRI will be used as a tool with high sensitivity and specificity for evaluating analgesic agents in early drug development and clinical studies., (Copyright 2006 John Wiley & Sons, Ltd.)

1. The study investigated whether endothelin (ET) contributed to the diabetes-associated alterations in volume reflex and characterised the receptor subtype that might be involved. The influence of renal sympathetic nerves on these aspects of ET was also examined. 2. Groups of nondiabetic and streptozotocin-induced diabetic rats were subjected to an acute isotonic saline volume expansion (VE), 10% body wt in the presence and absence of ET antagonists. 3. Cumulative urine sodium excretion (CuU(Na)V) after VE in diabetic rats reached values of 116+/-10 in the denervated and 74+/-6 micromol min(-1) g kidney wt(-1) in the innervated kidneys, which were both less (both P<0.001) than those achieved in the nondiabetic rats, at 267+/-9 in the denervated and 183+/-10 micromol min(-1) g kidney wt(-1) in the innervated kidney, respectively. 4. Diabetic rats pretreated with a nonselective ET(A)/ET(B) antagonist had an enhanced CuU(Na)V in the denervated kidneys by 37% (P<0.01) compared to that of untreated diabetic rats. At both doses of SB209670 these increments were less than the values obtained previously in nondiabetic rats (both P<0.01). The ET(A)/ET(B) antagonist had no meaningful effect on CuU(Na)V in the innervated kidneys of the diabetic rats, whereas previous studies in nondiabetic rats showed the response to be depressed. The CuU(Na)V responses to VE in diabetic rats given the selective ET(A) antagonist were not different from those observed in untreated diabetic rats, irrespective of whether or not the renal nerves were present. In nondiabetic rats, the ET(A) antagonist had an action similar to the mixed antagonist. 5. These findings demonstrate that activation of ET(B) receptors contributes to the depressed ability to excrete a saline load in diabetes mellitus, but its impact is obscured by the influence of the renal nerves.

Frusemide reduces pulmonary vascular pressures in resting horses and attenuates exercise-induced increases in these pressures in exercising horses. The mechanism underlying these effects of frusemide is unclear. We tested the hypothesis that the haemodynamic effects of frusemide are dependent on diuresis by examining the effect of frusemide in anaesthetised horses in which diuresis was prevented by ligation of ureters. Twenty four horses were assigned randomly to one of 4 treatments: 1) frusemide (1 mg/kg bwt i.v.) and intact ureters; 2) frusemide and ligated ureters; 3) saline placebo and ligated ureters; and 4) frusemide and phenylbutazone (4.4 mg/kg bwt i.v. 12 h and 15 min before frusemide) and ligated ureters. Frusemide administration to anaesthetised horses with intact ureters increased plasma total protein concentration and reduced mean right atrial, pulmonary artery and aortic pressures. There was no significant effect of frusemide administration on haemodynamic variables or plasma total protein concentration in horses with ligated ureters. The combination of frusemide and phenylbutazone increased mean right atrial, pulmonary artery and aortic pressures in horses with ligated ureters. This study demonstrates that, in anaesthetised horses, the haemodynamic effect of frusemide is dependent upon diuresis. We interpret these results as providing further evidence that the haemodynamic effect of frusemide in horses is attributable to a reduction in plasma and blood volume.

1. This study examined the role of endothelin ET(A) and ET(B) receptors on haemodynamic compensation following haemorrhage (-17.5 ml kg(-1)) in thiobutabarbitone-anaesthetized rats. Rats were divided into four groups (n=6 each): time-control, haemorrhage-control, haemorrhage after treatment with FR 139317 (ET(A)-receptor antagonist), and haemorrhage after treatment with BQ-788 (ET(B)-receptor antagonist). 2. In the time-control rats, there were no significant changes in any haemodynamics for the duration of the experiments. Relative to the time-control rats, rats given haemorrhage had reduced mean arterial pressure (MAP), cardiac output (CO) and mean circulatory filling pressure (MCFP), but increased systemic vascular resistance (R(SV)). Venous resistance (R(V)) was slightly (but insignificantly) reduced by haemorrhage. MAP, however, gradually returned towards baseline (-17+/-4 and -3+/-2 mmHg at 10 and 60 min after haemorrhage, respectively) as a result of a further increase in R(SV). 3. Pre-treatment with FR 139317 (i.v. 1 mg kg(-1), followed by 1 mg kg(-1) h(-1)) accentuated haemorrhage-induced hypotension through abolition of the increase in R(SV). FR 139317 did not modify haemorrhage-induced changes in CO, MCFP and R(V). 4. Pre-treatment of BQ-788 (3 mg kg(-1)) did not affect MAP or MCFP following haemorrhage; however, CO was lower, and R(SV) as well as R(V) were higher relative to the readings in the haemorrhaged-control rats. 5. These results show that following compensated haemorrhage, ET maintains arterial resistance and blood pressure via the activation of ET(A) but not ET(B) receptors.

Objectives: A double blind randomized controlled trial was performed at the tertiary hospital in Harare, Zimbabwe to compare oral misoprostol with intramuscular oxytocin in the management of third stage of labor., Methods: A total of 499 women were randomized to receive either 400 microg misoprostol orally or 10 IU oxytocin intramuscularly. The incidences of postpartum hemorrhage and side effects were examined., Results: The demographic and labor characteristics were comparable. Postpartum hemorrhage occurred in 15.2% of women given misoprostol and in 13.3% of those given oxytocin (P=0.534). Measured blood loss of more than 1000 ml occurred in 3.7% of the misoprostol group compared with 2% in the oxytocin group (P=0.237). There was no significant difference in the need for additional oxytocic drugs or blood transfusion in women given misoprostol (P values 0.137 and 0.600, respectively). Significant side effects of misoprostol were shivering [RR=1.32 (95% CI 1.11-1.58); P=0.002) and a rise in temperature [RR=2.02 (95% CI 1.75-2.33); P<0.001]., Conclusions: Oral misoprostol is as effective as intramuscular oxytocin in the prevention of PPH. Shivering and transient pyrexia were specific side effects of misoprostol. Misoprostol has potential in reducing the high incidence of PPH in developing countries.

Functional MRI of rat brain was performed at 2 Tesla following intravenous injection of cocaine in order to 1) determine if changes in CBV and changes in BOLD signal were regionally coupled in brain parenchyma, and 2) compare the sensitivities of these imaging methods across different brain structures. Percent changes in CBV and BOLD relaxation rate were spatially and temporally coupled during this graded brain activation. The use of contrast agent increased functional sensitivity in all parenchymal brain structures, with a strong but predictable dependence on the resting-state blood volume fraction. Magn Reson Med 45:443-447, 2001., (Copyright 2001 Wiley-Liss, Inc.)

The intracranial effects of acetazolamide on flow velocities can be monitored noninvasively by transcranial Doppler (TCD) sonography. Extracranial volume flow changes can now reliably be measured with color duplex M-mode systems. The authors tested the volumetric effects of acetazolamide in patients with high-grade unilateral carotid disease to quantify the amount of flow changes. Patients in group 1 had a high-grade > 70% internal carotid artery (ICA) stenosis, without collateral flow through the ophthalmic artery (OA). Patients with occluded ICA were included in group 2 (patent OA collateralization) or group 3 (no OA collateralization) (n = 6 per group). In group 1, common carotid artery (CCA) volume flow in the stenotic (normal contralateral) side increased from 271 (388) ml/min by 52 (54%) with 1 g aceta-zolamide intravenously. Simultaneously, middle cerebral artery (MCA) flow velocities increased from 54 (56) cm/s by 47 (53%). In group 2, extracranial volume flow increased from 166 (444) ml/min by 19 (52)%. MCA flow velocities increased from 43 (65) cm/s by 13 (30)%. In group 3, volume flow increased from 159 (467) ml/min by 2 (46)%. Intracranial flow velocities rose from 49 (54) cm/s by 27 (41)%. Volume flow data showed the expected decline in patients with high-grade ICA stenosis and even more pronounced in patients with occlusion of the vessel. Cerebral reserve capacity was less sufficient in patients with a patent OA, despite an additional supply of 30 ml/min, indicating a hemodynamically critical situation.

In animal models of stroke the promise of a therapy is commonly judged from infarct size measurements, assuming that a reduction in infarct size results in reduction of the functional deficits. We have evaluated the validity of the concept that structural integrity translates into functional integrity during the acute post-stroke period (24 h). Unilateral permanent middle cerebral artery occlusion (pMCAO) in Fischer F344 rats leads to infarcts comprising the ipsilateral striatum and cortical structures, including the somatosensory cortex. Infarct volumes were assessed using magnetic resonance imaging (MRI) methods (T(2), diffusion, perfusion MRI). The functional integrity of the somatosensory cortex was assessed by functional MRI (fMRI) measuring changes in local cerebral blood volume, and by assessing the forelimb grip strength and the beam-walking performance of the animals. Treatment with the calcium antagonist isradipine (2.5 mg/kg injected s.c. immediately after pMCAO) reduced the total infarct size by more than 40% compared to vehicle-injected controls. In particular, the ipsilateral somatosensory cortex appeared normal in diffusion- and T(2)-weighted MRI images. In sham-operated rats simultaneous electrical stimulation of both forepaws led to similar activation of both somatosensory cortices, while in pMCAO animals given vehicle only the contralateral cortex showed an fMRI response. Similarly, in pMCAO rats treated with isradipine, functional activation following bilateral electrical stimulation was only detected in the contralateral somatosensory cortex despite the normal appearance of the ipsilateral cortex in MRI images. Furthermore, fMRI responses to pharmacological stimulation with bicuculline were virtually absent in the ipsilateral somatosensory cortices both in vehicle- and isradipine-treated rats. Finally there was no significant difference between vehicle- and isradipine-treated animals upon the performance of beam-walking test or in forelimb grip strength. It is concluded that during the acute (24 h) post-occlusion period, structural integrity in the somatosensory cortex revealed by MRI does not translate into preservation of function., (Copyright 2000 John Wiley & Sons, Ltd.)

Background and Objectives: Although indocyanine green can be used to estimate cardiac output and blood volume independently, a recirculatory multicompartmental indocyanine green model enables description of these and additional intravascular events. Our model was used to describe the effect of propranolol on blood volume and flow distribution in humans., Methods: Indocyanine green disposition was determined twice in four healthy adult men, once during a propranolol infusion that decreased cardiac output. After injection of indocyanine green, arterial blood was collected frequently for 2 minutes and less frequently thereafter. Plasma indocyanine green concentrations were measured by HPLC. The recirculatory pharmacokinetic model incorporates data from both the initial transient oscillations and the later post-mixing portions of the blood indocyanine green concentration versus time curves to characterize not only blood volume and cardiac output but also their distribution among a central blood volume and fast and slow peripheral volumes in lumped parallel circuits. Flow through the central circulation (cardiac output) is described by two parallel Erlang distribution functions generated by two linear chains of compartments in parallel., Results: Propranolol reduced cardiac output from 10.6 to 4.1 L/min. Most of the decrease in cardiac output was at the expense of blood flow to the fast peripheral circuit, which represented nonsplanchnic circulation. Propranolol also reduced the blood volume of the fast peripheral circuit by more than half., Conclusion: Our indocyanine green model is able to derive estimates of blood volume and cardiac output, as well as their systemic distribution during different physiologic conditions.

Six horses were randomly assigned to receive either frusemide (F) (0.5 mg/kg i.v.) or an equivalent volume of saline (S) i.v., 4 h prior to treadmill exercise. Horses were instrumented to enable measurement of heart rate (HR), systolic (SAP), mean (MAP), and diastolic (DAP) carotid arterial pressures, pulmonary artery pressure (PAP), central venous pressure (CVP), pulmonary arterial temperature (TEMP), blood gases, and cardiac output (CO). Plasma (PV) and blood volumes (BV) were measured using 2 injections of Evan's Blue dye. Baseline parameters were recorded while the horse stood quietly. Horses were then administered F or S. Four hours later, they were warmed up for 3 min at 4 m/s and then exercised to the point of fatigue at 115% VO2max. Horses were anaesthetised immediately following exercise by administration of detomidine (0.04 mg/kg bwt i.v.) followed 5 min later by tiletamine-zolazepam (1.25 mg/kg bwt i.v.). After transporting the horse to a recovery stall, anaesthesia was maintained with isoflurane in 100% O2. Data were analysed using a 2-way ANOVA with repeated measures with post hoc differences identified using the Student-Newman-Keul's procedure. Exercise was associated with increases in HR, SAP, MAP, DAP, PAP, CVP, TEMP, PCV, and BV, and decreases in PV, pH, arterial bicarbonate and base excess. Anaesthesia was associated with marked hypercapnia, a decrease in HR following detomidine administration, and persistent pulmonary hypertension despite carotid arterial pressure which returned to baseline. No effects attributable to F were identified at any time during the study.

An NMR method is applied for separating blood volume and magnetic susceptibility effects in response to neuronal stimulation in a rat model. The method uses high susceptibility contrast agents to enhance blood volume induced signal changes. In the absence of exogenous agent, the dominant source of signal change on neuronal activation is associated with the signal increase from the blood oxygen level dependent (BOLD) effect. The relative negative contribution of blood volume changes to BOLD changes is maximally estimated to be 34%. The blood volume changes associated with median nerve stimulation (7 Hz) in the motor cortex are 26+/-7% and the corresponding blood susceptibility changes are 0.021+/-0.006 ppm. These methods can be applied to enhance the sensitivity of fMRI signal response and provide accurate quantitative measures of blood volume response to stimulation.

The effect of blood volume repletion after frusemide administration on the right atrial and pulmonary artery pressure responses of horses to exercise has not been reported. We examined right atrial and pulmonary artery pressure and plasma atrial natriuretic peptide concentration (ANP) responses to an incremental exercise test in 6 Standardbred mares. Horses were treated, in a 3 way cross over design, with isotonic saline, frusemide (1 mg/kg bwt, i.v.), and frusemide followed 3 h later by lactated Ringer's solution (12 ml/kg bwt, i.v.). Three and a half hours after saline or frusemide administration the horses completed a standard exercise test. Frusemide significantly affected the right atrial and pulmonary artery pressure and ANP responses to exercise. Fluid administration decreased plasma total protein concentrations at rest and during running and abolished the effects of frusemide on the haemodynamic and ANP responses to exercise. These results suggest that the haemodynamic effect of frusemide in running horses is mediated, in large part, by a reduction in plasma and blood volume.

To understand whether the NO-dependent vasodilator L-arginine was effective upon a chronically hypertensive cerebral capillary endothelium, dynamic susceptibility contrast MRI was used to measure the relative cerebral blood volume (rCBV) changes in nonischemic spontaneously hypertensive rats (SHRs). rCBV was measured in 11 rats at 4.7 T using fast gradient echo imaging with intravenous injection of Gd-DTPA. Images were acquired before, immediately after, and up to 90 min after the infusion of 300 mg/kg L-arginine (n = 7) or of an equivalent volume of saline (n = 4). L-arginine increased rCBV in cortex beginning 10 min after infusion and reached significance after 30 min (P < 0.01), reached a peak of 1.24 +/- 0.06 (mean +/- SEM) times pre-injection level after 50 min, and was sustained throughout the 90 min observation period. In contrast, the rCBV in the deeper gray matter (striatum) showed no statistically significant change over the 90 min observation period. While this is consistent with previous studies showing that L-arginine infusion can directly modulate vascular tone and cerebral hemodynamics, it demonstrates that the effect is present only in cortex, and that it can occur also in the setting of a disturbed capillary endothelium.

A three-dimensional (3D) T1-weighted sequence was used to acquire high spatial resolution whole brain images in rats before and after the injection of an intravascular contrast agent. These T1-weighted images were used to estimate regional cerebral blood volume (rCBV) as a percentage of blood volume in each voxel. Ventilation was manipulated to investigate the effects of altered arterial carbon dioxide tension (PaCO2) on rCBV. In addition, different doses of a hypertonic mannitol solution were used to investigate the sensitivity of the proposed method in a serial monitoring paradigm. An rCBV of 2.40% +/- 0.34% was obtained before any physiological manipulation, in good agreement with literature values using alternative techniques. Using this method, it was found that there exists a linear relationship between PaCO2 and rCBV (R2 = 0.77) and that rCBV increased in a dose and time dependent fashion in mannitol-treated rats. High signal-to-noise was available due to the substantial increase in blood signal from the intravascular contrast agent.

A susceptibility contrast agent which does not pass into the extra-cellular space was used to study the effect of changes in the relative cerebral blood volume (CBV) on the haemodynamic response to anoxia, for both normal and ischaemic brain tissue, in a rat model of acute focal ischaemia. In non-ischaemic tissue a strong CBV component was observed in the haemodynamic response, both during and after anoxia. During anoxia the change in the CBV of the non-ischaemic tissue was estimated to be 40% in the caudate putamen and 70% in the frontal-parietal cortex. For severely ischaemic tissue (ischaemic caudate putamen) there was no change in the CBV during anoxia while in areas of moderate ischaemia (ischaemic frontal parietal cortex) a change of 20% was observed. The effect of the contrast agent on spin-echo images was consistent with a small reduction in the microvascular blood volume of the ischaemic tissue.

Cerebral vasodilatory testing provides an important measure of both the hemodynamic significance of arterial occlusive disease and the adequacy of collateral pathways. This study measured the extracranial intravascular volume flow rate response to acetazolamide using phase-contrast magnetic resonance angiography. From 10 patients with unilateral carotid transient ischemic attacks (TIAs), a total of 18 extracranial carotid arteries (10 symptomatic, 8 asymptomatic, 2 occluded) and 19 extracranial vertebral arteries were studied. Patients were free of large-vessel intracranial stenoses, evident areas of ischemic infarction, evident areas of nonspecific white matter change, and hemodynamic or low-flow induction of TIA symptomatology. Asymptomatic carotid volume flow rates rose from 151 +/- 19 (standard error of mean) to 220 +/- 26 ml/min while symptomatic flow rates rose from 106 +/- 22 to 145 +/- 25 ml/min. Dominant vertebral volume flow rates rose from 128 +/- 23 to 160 +/- 22 ml/min while nondominant rates rose from 40 +/- 12 to 61 +/- 15 ml/min. Carotid volume flow rates were inversely proportional to percent stenosis for both baseline (r = 0.51, p < 0.02) and acetazolamide (r = 0.81, p < 0.001) data. Baseline-plus-acetazolamide volume flow rate techniques safely measure intravascular vasodilatory responses. Intracranial measurement techniques are being developed to further study cerebrovascular reserve using phase-contrast magnetic resonance angiography.

To evaluate MRI methods for estimating cerebrovascular reserve, we computed changes in the R2* and R2 transverse relaxation rate and apparent diffusion coefficient (ADC) at 2.0 Tesla in five rats after administration of 30 mg of acetazolamide and in four rats during inhalation of 20% carbon dioxide gas. Significant decreases in R2*, corresponding to increases in gradient echo MRI signals, occurred in both the acetazolamide (average change -8.3%, P = 0.005) and the carbon dioxide (-2.7%, P = 0.009) treated animals. The computed values for R2 and ADC were unchanged. The magnitude of the gradient echo MRI changes observed should permit anatomic mapping of blood flow reactivity patterns in normal human subjects and in patients at risk for cerebrovascular disease.

1. Sumatriptan, a 5-hydroxytryptamine (5-HT)1-like receptor agonist, is effective against the headache of migraine. The effects of sumatriptan injected via the carotid artery on the cerebral microcirculation were studied in 10 anaesthetized cats. 2. The local cerebral blood volume (CBV), mean transit time of blood (MTT) and cerebral blood flow (CBF) in the parieto-temporal cortex were measured by a photoelectric method. CBV represents the cumulative dimensions of the cerebral microvessels. 3. Sumatriptan at 5 and 50 micrograms kg-1 had no significant effects on the CBV, MTT, CBF, and mean arterial blood pressure (MABP); 500 micrograms kg-1 of sumatriptan reduced the CBV, prolonged the MTT, and decreased the CBF (approximately -20%) without affecting the MABP. Sumatriptan, 5 mg kg-1, elicited transient reductions in CBV and CBF, which were attributable to the rapid and marked falls of MABP seen with this dose. 4. Thus, while a high dose of sumatriptan (500 micrograms kg-1) exhibits direct vasoconstrictor actions on the cerebral vessels, low doses of sumatriptan, within the therapeutic range, elicit no vasoconstriction. The data do not support a vasoconstrictor action of sumatriptan playing a primary role in reversing the headache of migraine.

Eight patients with mild heart failure were treated in random order for 1 week with 2 mg bumethanide at 0800 and 1200 (treatment 1) h, 1 mg bumethanide at 0800, 1200, 1800, 2200 (treatment 2) and 5 mg bendroflumethiazide at 0800 and 1800 (treatment 3) h. The 'quality of life' did not differ significantly between the three treatment periods. At the presumed trough of the diuretic effect the circulating blood volume was largest during treatment 1; it was 6.3% smaller during treatment 2 (P < 0.02) and 6.7% lower during treatment 3 (P < 0.05). In comparison with treatment 1, the maximal increase in rate-pressure product during physical exercise was 24.6% higher in treatment 3. Compared with treatment 1 the area under the curve (AUC) for plasma lactate during physical exercise was 14% lower during treatment 2 (P < 0.05) and 18% lower during treatment 3 (P < 0.01). These findings suggest that the type of program for diuretic therapy influences the magnitude of inevitable diurnal fluctuations in body fluids, the ability of the heart to work and the ability of the body to adjust to the oxygen demand.

1. The effects of pertussis toxin on the N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) and platelet-activating factor (PAF)-induced variations in pulmonary capillary albumin exchanges, blood volume, leucocyte or platelet sequestration were studied in the guinea-pig, by use of radioactive tracers. The effects of pertussis toxin on pulmonary insufflation pressure were studied in parallel. 2. The i.v. administration of fMLP and PAF to the guinea-pig was followed by bronchoconstriction, increased lung capillary albumin exchanges (vasopermeability) sequestration of leucocytes, leucopenia and reduction of blood volume (vasoconstriction). PAF also induced platelet sequestration in lungs and thrombocytopenia. 3. Pertussis toxin (10 micrograms kg-1, i.v., 72 h before the experiment) prevented all the studied fMLP-induced effects, but failed to modify PAF-induced bronchoconstriction, lung vasoconstriction, platelet sequestration, thrombocytopenia and the increased capillary vasopermeability. In the same conditions the lung leucocyte sequestration was not significantly affected when leucopenia was partially reduced. 4. It is suggested that the effects of fMLP, but not those of PAF, involve a Gi-like protein.

Plasma concentrations of atrial natriuretic factor (ANF) and cyclic 3',5'-guanosine monophosphate (cGMP) were measured in 11 cirrhotic patients with ascites, 11 cirrhotic patients without ascites and 15 control subjects. The following were determined in 15 of the cirrhotic patients and in all the control subjects: blood volume (BV) and furosemide-induced changes in BV, plasma values of ANF, cGMP, angiotensin II (AII), aldosterone (Aldo), arginine vasopressin (AVP) and urinary excretion rates of cGMP, prostaglandin E2 (PGE2), water and sodium. Basal plasma levels of ANF and cGMP were higher in patients with cirrhosis than in controls, but were the same in both groups of cirrhotics (ANF: cirrhosis with ascites 12.7, without ascites 13.4, and in controls 5.8 pmol l-1 (medians); cGMP: 7.7, 7.4 and 4.3 nmol l-1, respectively). BV was less reduced after furosemide in the cirrhotic patients (6.0%) than in the healthy subjects (10.1%), but basal BV did not differ. Urinary sodium excretion rates after furosemide were significantly lower in the cirrhotic patients than in the controls. PGE2 excretion rate increased after furosemide in the cirrhotic patients (0.29 to 0.66 pmol min-1; P less than 0.01) but not in the controls (0.31 to 0.38 pmol min-1). After furosemide ANF and cGMP decreased slightly in both groups whereas AII and Aldo increased; AVP increased in the controls, but not in the cirrhotic patients. In conclusion, plasma values of ANF and cGMP are increased in liver cirrhosis both with and without ascites. This and the elevated PGE2 excretion after furosemide may be compensatory phenomena in order to facilitate renal sodium excretion.

We have studied the peripheral vascular effect in man of propanidid 6 mg/kg, administered as a bolus injection during cardiopulmonary by-pass with the aorta cross-clamped and at constant perfusion flow. Ten measurements in eight patients were performed. A decrease was found in systemic vascular resistance: from 150.7 +/- 16.3 to 99.5 +/- 10.1 kPa x s/1. No venous pooling occurred. It is concluded that, in man, propanidid causes a vasodilation which must contribute to the hypotension it causes.

Two-dimensional echocardiography was used to determine global and regional left ventricular function in 32 patients treated with gallopamil (methoxyverapamil) for angina pectoris. Ejection fraction (EF), pressure/volume ratio (PVR), and segmental wall motion were assessed. Evaluations were made before therapy (T1) and repeated 3 weeks later; this assessment included examination 2 and 8 hours after the morning dose (T2 and T3, respectively). Patients were randomized to either a placebo group or three study groups (25, 37.5, and 50 mg t.i.d.). In the 37.5 and 50 mg groups there was an increase in EF (T1 = 53.8% and 54.5%, T2 = 57.9% and 60.1%, and T3 = 57.6% and 60%) and PVR values (T1 = 5.2 and 7.2 mm Hg/ml/m2, T2 = 5.8 and 7.7 mm Hg/ml/m2, and T3 = 5.9 and 7.6 mm Hg/ml/m2, respectively). Wall motion remained the same or improved in 92.3% of the patients. In conclusion, gallopamil had no cardiodepressant effects in most patients. On the contrary, EF, PVR, and segmental contractility tended to improve with the higher doses.

Hemodynamic and blood volume changes, systolic time intervals, and baroreflex mechanisms were studied in 20 patients with hypertension after methyldopa (12 +/- 0.9 mg/kg/day). The drug was administered orally during 7 days' hospitalization on a normal sodium diet (110 mEq/day). There was a fall in blood pressure and in total peripheral resistance, without significant change in cardiac index, heart rate, and stroke index. There were increases in plasma and blood volume (p less than 0.05) but no change in cardiopulmonary blood volume or systolic time intervals. The unchanged heart rate was associated with an increased sensitivity ( less than 0.05) of the baroreflex mechanisms. The study supports the view that the unchanged cardiac output after methyldopa is related to important changes in control of cardiac output, including redistribution of blood volume and modifications in baroreflex mechanisms.

1. In an experimental model of haemorrhagic shock resulting in the death of all rats within 20-30 min, the intravenous (i.v.) injection of the tertiary amine cholinesterase inhibitor physostigmine (17-70 micrograms kg-1) induced a prompt, sustained and dose-dependent improvement of cardiovascular and respiratory function, with marked increase in the volume of circulating blood and survival of all treated animals, at least for the 2 h of observation. 2. Similar results were obtained with the i.v. injection of the cholinoceptor agonist oxotremorine (5-25 micrograms kg-1), while neostigmine (54 or 70 micrograms kg-1), a quaternary cholinesterase inhibitor which cannot cross the blood-brain barrier, had negligible effects. 3. The anti-shock activities of oxotremorine and physostigmine were blocked by the intracerebroventricular injection of either of the combined nicotinic and M2-muscarinic receptor antagonists gallamine and pancuronium, or of the nicotinic antagonist mecamylamine. They were also blocked by intraperitoneal injection of the adrenergic neurone blocking agent guanethidine, but they were not antagonized by either the combined M1- and M2-muscarinic receptor antagonist atropine, the M1-muscarinic receptor antagonist pirenzepine, or the M2-muscarinic receptor 4-diphenylacetoxy-N-methylpiperidine methobromide. 4. It is concluded that cholinomimetic drugs can reverse hypovolaemic shock through central activation (seemingly mediated by nicotinic receptors) of sympathetic tone, with mobilization and redistribution of the residual blood.

The antihypertensive effects of nitrendipine were evaluated in 12 subjects with hypertension, one of whom could not tolerate the drug for more than 3 days; hence hemodynamics were studied in the 11 subjects who were treated for 2 wk. In one patient taking 40 mg twice a day, blood pressure reduction was associated with a hemodynamic pattern of hyperkinetic circulation. Of the other 10 subjects, all of whom were taking 20 mg twice a day, two did not respond, but 8 had significant reduction in mean arterial pressure (136 +/- 4.3 to 106 +/- 3.2 mm Hg) resulting from a decrease in total peripheral resistance (52 +/- 3.7 to 35 +/- 2.6 U X m2). Changes in cardiac output, heart rate, and cardiopulmonary volume varied widely among subjects, such that average changes did not attain significance. Heart rate and cardiopulmonary volume, however, changed in the same direction, which suggests that the alterations in both were related to the degree of reflex sympathetic stimulation induced by nitrendipine. Plasma renin activity (PRA) increased during treatment (2.6 +/- 1.0 to 9.3 +/- 4.1 ng/ml/hr), whereas the increase in plasma aldosterone (PA) levels did not attain significance (13.7 +/- 1.6 to 21.5 +/- 4.5 ng/dl). As a result, PA/PRA decreased (16.1 +/- 4.9 to 9.4 +/- 2.6). These results suggest that calcium entry blockade might have interfered with steroidogenesis, thus blunting the effect of increased PRA. Finally, blood pressure response to nitrendipine in the whole group correlated inversely with pretreatment PRA (r = -0.88), suggesting greater activity of the drug in low-renin hypertension.

NC 7197, a new N-substituted tetrahydroisoquinoline derivative, was given in doses of 0.2 mg/kg body weight on 26 occasions to a series of 23 critically ill postoperative and posttraumatic patients who had been in moderate or severe degrees of shock. This agent was observed to improve pressure-flow and oxygen-transport variables, including increases in cardiac index, mean arterial pressure, central venous pressure, both left and right ventricular stroke work, central blood volume, systemic vascular resistance, oxygen availability, arteriovenous oxygen content difference, and oxygen consumption, and decreases in mean transit time and pulmonary vascular resistance. Previous studies on critically ill patients have suggested that these are the most commonly desired therapeutic actions for this type of patient. The agent has pronounced inotropic effect with minimal chronotropic effects, but with higher doses, chronotropic effects as well as alpha blocking effects may occur. The optimal effects may be obtained by adjusting the dose to an appropriate therapeutic range. It is concluded that, in the dose used, this agent produced both alpha and beta adrenergic actions in critically ill patients.

Hypertension develops in about 10% to 50% of patients with nephrosis or cirrhosis and peripheral edema, but the hemodynamic mechanism of the hypertension and its reversal by diuretic therapy has not been elucidated. In eight patients with marked edema and mild hypertension, diuretics (furosemide and spironolactone) decreased mean arterial pressure because of concurrent decrease in cardiac output and total peripheral resistance. Neither total blood volume nor plasma volume were decreased by the diuretics and the decrease in body weight was therefore attributed to the decrease in interstitial fluid volume. This, in turn, resulted in increased venous capacitance (as can be judged from the diuretic-induced decrease in the ratio of cardiopulmonary blood volume/total blood volume).

1. Hepatic volume was recorded by a plethysmographic technique in cats anaesthetized with pentobarbitone; the hepatic artery and portal vein remained intact. Dose-response curves were obtained for intravenous infusions of adrenaline, noradrenaline, angiotensin, vasopressin and histamine.2. Adrenaline and noradrenaline decreased hepatic blood volume and did not differ significantly in potency. Up to 40% of the hepatic blood volume was expelled by doses within the range secreted by the adrenal medullae.3. Isoprenaline, infused into the hepatic artery, had no significant effect on hepatic blood volume in doses which caused maximal vasodilatation of the hepatic arterial bed. Relaxation of hepatic capacitance vessels mediated by beta-adrenoceptors did not occur.4. Angiotensin infusions in doses previously shown to cause intestinal and splenic vasoconstriction, decreased hepatic blood volume and on a molar or microgramme basis, angiotensin was the most potent of the agents tested. Doses within the probable physiological range of endogenous production decreased hepatic blood volume by up to 20%. The responses were not significantly different when the hepatic nerves were intact or sectioned.5. Vasopressin infusions produced only small decreases in hepatic blood volume. Doses within the range secreted by the posterior pituitary which constrict the intestinal and splenic resistance vessels, did not decrease hepatic blood volume by more than 10%.6. Histamine produced no change in hepatic blood volume in doses which readily produce outflow block in dogs. Either the specific hepatic venous smooth muscle involved in outflow block is absent in the cat or it has no histamine receptors.7. After the rapid change in hepatic blood volume at the onset of the infusion, hepatic volume remained steady for the duration of each infusion. There was no evidence that these agents caused net transsinusoidal fluid movements.

1. Intravenous injection of five Goldblatt units (Gbl.U) of renin, or intravenous infusion of 2.5 mug of angiotensin into nephrectomized rats decreased plasma volume by 22 +/- 2% (calculated from the increase of the haematocrit) or by 14 +/- 2% (calculated from the increase in protein concentration) within 2 minutes. Fifteen minutes and 60 min after injection or infusion, the plasma volume (calculated from both parameters) was still 10% lower than initially.2. The initial discrepancy between haematocrit values and plasma protein concentration was neither due to mobilization of red blood cells (r.b.c.) from the spleen, nor to an increase in r.b.c. volume.3. The observed decrease in plasma volume was large enough to explain the drinking response to renin and angiotensin. Renin may thus induce or aggravate hypovolaemia rather than signalling its occurrence to hypothalamic receptors.