Repeated short periods of regional myocardial ischemia: effect on local function and high energy phosphate levels

Summary The effect of recurrent periods of ischemia on the myocardium was investigated in 15 open-chest dogs. Ischemia was produced by 3 minutes of proximal occlusion of the left anterior descending coronary artery. Each occlusion was followed by reperfusion of 3 minutes duration. Forty occlusions with a total of 120 minutes of ischemia were performed, and regional function (sonomicrometry) as well as high energy phosphates (needle biopsies) were determined at the end of the 5th, 20th, and 40th period of ischemia and reperfusion. The first periods of ischemia had a cumulative effect both on regional postischemic function (44% and 59% respectively of preischemic control after 20 occlusions) and on the ATP content, but with increasing number of occlusions the additive effects became smaller (ATP reduction/mol/gww/per occlusion). The ATP breakdown per occlusion was diminished with increasing number of periods of ischemia, and no significant adenosine was measured in the ischemic myocardium. Higher than normal postischemic creatine phosphate levels (9.1 mol/g w w at the 40th reperfusion vs. 6.7 mol/gw w control) indicated a functioning oxidative phosphorylation in the presence of an ATP utilization problem at the sarcomere level, because indicators of the cellular energy level (energy charge, free energy change of ATP hydrolysis) quickly normalized during reperfusion. Stunned myocardium is therefore not a problem of energy supply but rather of energy utilization. Reduced ATP utilization and regional dysfunction are the expressions of the same cellular defect which resides either in the ATP-splitting contractile apparatus or in the electromechanical coupling. Contractile dysfunction during reperfusion protects the heart against subsequent periods of ischemia because ATP turnover is reduced.Parts of the results were presented at the 57th Sessions of the American Heart Association, Miami, Florida/U.S.A. 1984     

Left ventricular function before and after kidney transplantation. A prospective study in patients with juvenile-onset diabetes mellitus

The aim of the present investigation was to discover whetherdisturbed left ventricular (LV) function limits renal replacementtherapy in patients with juvenile onset diabetes mellitus. Seventeenpatients given functioning kidney grafts were studied non-invasively(M-mode echocardiography, apexcardiography, phonocardiography)before renal transplant and an average of six, 13 and 44 monthsafter transplant. The main pretransplant findings were pronouncedLV hypertrophy with impaired diastolic LV function (prolongedrelaxation time + signs of decreased LV distensibility) anda hyperdynamic circulation. Most of these abnormalities were significantly less severe aftersuccessful kidney transplantation. LV mass decreased by 37%44 months after transplant (p<0.01) and LV diastolic andsystolic volumes decreased with a subsequent increase in ejectionfraction from 0.65 to 0.78 (p<0.01). The LV distensibilityand filling pattern improved significantly while the prolongedrelaxation time was unchanged. These findings imply that pretransplant disturbances in LV functionare related more to factors such as hypertension, volume overloadand uraemia than to diabetes per se because no pronounced improvementin the metabolic disorder resulting from diabetes can be expected,even after the most successful transplant. Disturbed LV functionshould not, therefore, exclude uraemic diabetics from renalreplacement.     

Bilateral brain abscesses complicating the use of crutchfield tongs

The case of a 4-year-old girl who developed bilateral brain abscesses complicating skull traction is reported. Crutchfield tongs were used to reduce a fracture dislocation at C2–3. Presenting symptoms consisted of headaches and focal seizures. Surgical treatment and antibiotics using serial CT led to a satisfactory outcome. This is the first reported case of this complication in a child. The current literature is reviewed.To whom offprint requests should be addressed at Avda. Pio Baroja 4, 30011 Murcia, Spain     

CCK and other peptides modulate hypothalamic norepinephrine release in the rat: Dependence on hunger or satiety

The purpose of this investigation was to determine the functional relationship between putative satiety peptides and endogenous norepinephrine (NE) activity in the hypothalamus. Permanent guide cannulae for push-pull perfusion were implanted stereotaxically in Sprague-Dawley rats so as to rest above the medial or lateral hypothalamus (LH). Post-operatively, the animals were either satiated with food and water, both available ad lib, or fasted for 18-22 hr prior to an experiment. To perfuse a site in the LH, paraventricular (PVN) or ventromedial nucleus (VMN), a concentric 29-23 ga push-pull cannula system was lowered to a pre-determined site, in most cases after catecholamine stores had been pre-labeled with [3H]-NE. During control tests, an artificial CSF was perfused at a rate of 20-25 microliter/min for 5-8 min with a 5 min interval between each sample. The addition of cholecystokinin (CCK) in a concentration of 2.0-6.0 ng/microliter to the CSF perfused in PVN or VMN of the satiated rat enhanced the efflux of NE; however, in the fasted animal CCK often suppressed the catecholamine's release. Perfused in the LH, CCK exerted opposite effects, typically augmenting NE output when the rat was fasted but not affecting the amine's activity during the sated condition. Proglumide (1.2 micrograms/microliter) attenuated CCK's effect in releasing NE when the antagonist was perfused in the PVN of the satiated rat. Similar experiments in which neurotensin (NT) was perfused in the LH, PVN and VMN revealed virtually the same inverse effects on NE release in the fasted and satiated rat, which again were anatomically specific. Finally, insulin and 2-deoxy-D-glucose (2-DG) exerted similar state-dependent effects on the release of NE within LH and PVN. Overall, the results suggest that CCK or other neuroactive peptide could serve as a "neuromodulator" of the pre-synaptic release of NE within classical hypothalamic structures which are thought to underlie both hunger and satiety. The state-dependent nature of the peptides' activity on the noradrenergic feeding mechanism implies that these substances constitute a pivotal portion of the profile of factors which impinge functionally upon the hypothalamic neurons responsible for the feeding response and its cessation.     

Effects of single oral doses of bisoprolol and atenolol on airway function in nonasthmatic chronic obstructive lung disease and angina pectoris

Summary A randomized, placebo-controlled, double-blind crossover investigation in 12 patients with non-asthmatic chronic obstructive lung disease and co-existing stable angina pectoris was done to compare two ₁-selective adrenoceptor blocking agents, atenolol 100 mg and bisoprolol 20 mg. Systolic and diastolic blood pressures (SBP, DBP), heart rate (HR) as well as airway resistance (AWR, and less frequently forced expiratory volume in 1 s (FEV₁) and intrathoracic gas volume (ITGV) were measured in the sitting position before and at various times up to 24 h after drug intake.During the first 4 h both beta-blockers produced a significant reduction in HR in comparison to placebo (p<0.01). Atenolol 100 mg significantly increased AWR relative to placebo and bisoprolol (p<0.05). After 24 h, a significant reduction in HR (p<0.01) could only be demonstrated after bisoprolol, whereas atenolol alone led to a significant elevation in AWR relative to placebo and bisoprolol (p<0.05) at that time.It is concluded that bisoprolol appears to have a high degree of beta₁-selectivity, thus providing a wide split between beta₁- and beta₂-adrenoceptor blockade. Bisoprolol in its therapeutic dose range is expected to be relatively safe as regards bronchoconstriction in patients suffering both from hypertension and/or angina pectoris and chronic obstructive lung disease.     

Evidence for a displaceable non-specific [3H]neurotensin binding site in rat brain

Summary Levocabastine is a potent antihistamine drug, structurally unrelated to neurotensin. In rat and mouse brain but not in other animal species, it inhibited 60% of the [³H]neurotensin binding displaced by unlabelled neurotensin or neurotensin (8–13).The levocabastine-sensitive site or site 1 displayed high affinity properties for levocabastine (IC₅₀=25 nM) and was highly stereospecific (IC₅₀-value higher than 10 M for one of the isomers). Binding to the site 1 in rat brain corresponded to the [³H]neurotensin binding displaceable by 1 M levocabastine, whereas binding to the site 2 corresponded to the binding displaced by 1 M neurotensin when the site 1 was occluded by 1 M levocabastine.Both site 1 and site 2 appeared to be saturable. Scatchard plots obtained in rat bulbus olfactorius allowed to calculate a K _D-values of 7.1 nM and a B _max-values of 37.2 fmol/mg original tissue for site 1, while site 2 displayed a K _D-value of 0.7 nM and a B _max-value of 16.3 fmol/mg original tissue. The regional distributions of both sites showed marked differences. The site 1 was homogeneously distributed throughout all rat brain areas, whereas the amount of site 2 binding was markedly different in separate brain areas: bulbus olfactorius and substantia nigra had the highest amounts (8.9 and 7.8 fmol/mg tissue) while cerebellum had the lowest (0.4 fmol/mg tissue).In spite of its high affinity and stereospecificity, site 1 has to be considered as an acceptor or recognition site for [³H]neurotensin because of its species-link, low saturability and homogeneous distribution in all rat brain areas.On the other hand, site 2 had the characteristics of a physiological receptor: high affinity, saturability in the low nanomolar range and marked regional distribution in rat brain. Site 2 corresponds therefore most probably to the physiological neurotensin receptor. The foregoing experiments provide evidence for the presence of a drug displaceable, non-specific (=unrelated to a physiological receptor) neurotensin binding site in rat brain; levocabastine should be an important tool to occlude this site in order to reveal, by means of in vitro binding assays, the specific neurotensin binding site in rat brain.     

Effect of dihydroergosine (DHESN) on the serotoninergic system and behaviour: Is DHESN a new antidepressive agent?

Acute (50.0 mg/kg) and repeated (0.1–10.0 mg/kg) administration of dihydroergosine (DHESN) to rats over 5 days lowered the concentration of 5-HIAA in the brain. DHESN given acutely increased the brain 5-HT in p-CPA-treated animals and diminished the probenecid-induced increase in brain 5-HIAA. In pargyline-treated rats DHESN enhanced the 5-HT/5-HIAA ratio. DHESN administered to rats repeatedly over 5 days decreased the level of 5-HT in blood platelets, and in vitro at concentrations of 10^-4 M and 10^-3 M inhibited the uptake of [¹⁴C]-5-HT in platelets. DHESN (10.0–100.0 mg/kg) potentiated the 5-HT syndrome produced in rats by pargyline and 5-HTP. This potentiation was blocked with cyproheptadine but not with haloperidol. DHESN (1.0 and 10.0 mg/kg) lowered the locomotor activity of rats and 10.0 mg/kg DHESN also reduced the duration of immobility in rats forced to swim in a restricted space. The results indicate that DHESN, like antidepressants, decreases the turnover of serotonin in the brain and potentiates the 5-HT-mediated behaviour. This might suggest that the drug should be further investigated for its potential antidepressive properties.     

The effects of a 5-HT1 receptor ligand isapirone (TVX Q 7821) on 5-HT synthesis and the behavioural effects of 5-HT agonists in mice and rats

The effects of 2-(4-(4-(2-pyrimidinyl)-1-piperazinyl)-butyl)-1,2-benzoisothiazol-3(2H)one-1,1-dioxide hydrochloride (isapirone, TVX Q 7821), a putative 5-HT₁ receptor antagonist, has been studied on various models of 5-HT receptor sub-type function. In mice TVX Q 7821 produced a dose-dependent inhibition of the hypothermia induced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) with an ED₅₀ of 5.3 mg/kg suggesting that TVX Q 7821 was an antagonist of the presynaptic (possibly somato-dendritic) 5-HT_1A receptor. TVX Q 7821 did not alter the locomotor response to the suggested 5-HT_1B agonist RU 24969. The rate of mouse brain 5-HT synthesis was accelerated by TVX Q 7821 (10 mg/kg). 5-HT₂ receptor-mediated head twitch behaviour induced by precursor loading with 5-HTP was unaffected by TVX Q 7821 (10 mg/kg) pretreatment 75 min earlier, but the head-twitch induced by the agonist 5-methoxy-N,N-dimethyltryptamine was enhanced by prior treatment with TVX Q 7821.In rats the hypothermia induced by 8-OH-DPAT was partially antagonised by TVX Q 7821 while the behavioural serotonin syndrome induced by 8-OH-DPAT (a possible post-synaptic 5-HT_1B-mediated effect) was unaffected by TVX Q 7821 as was the locomotion induced by RU 24969.The data suggest that TVX Q 7821 is a good presynaptic 5-HT_1A antagonist in mice, as indicated by the 8-OH-DPAT-induced hypothermia and 5-HT synthesis rate studies. It did not antagonise 5-HT_1B-mediated behaviour in mice or rats and appeared to have an antagonist action at pre- but not post-synaptic 5-HT_1A receptors in rats. Offprint requests to: G.M. Goodwin     

Acute renal dysfunction by cadmium injected with cysteine in relation to renal critical concentration of cadmium

In order to study the critical concentration of cadmium (Cd) in acute renal dysfunction following Cd, male mice were injected IV with Cd complexed with cysteine. The critical concentration was 10 g Cd/g wet weight in whole kidney and it was the same as that for Cdthionein (Cd-Th), which may suggest that the toxicity of Cd-Th is due to Cd ions liberated from Cd-Th in the kidneys. Renal Cd concentration was at first higher than the critical concentration, but decreased to the critical concentration by 24 h after administration. As an index for renal dysfunction, the uptake of p-aminohippurate (PAH) by renal cortical slices in vitro was sensitive, and showed the different time-course from those of urinary protein and glucose levels. The results suggest the usefulness of PAH uptake as an index. Incidental to the renal dysfunction, renal calcium levels exhibited a marked increase.     

The protective effect of vitamin E on cerebral ischemia

Using the "canine model of the completely ischemic brain regulated with a perfusion method," the effects on cerebral ischemia of vitamin E, which is known to act as an antioxidant, were investigated. After pretreatment with vitamin E by oral or intravenous administration, cerebral blood flow was reduced to 1/10th the normal state and, 1 hour later, allowed to return to normal. Subsequent changes in electrical activity were observed, and the effects of vitamin E were evaluated. In the control group, no recovery of electrical activity was seen. In the groups given vitamin E, the recovery time was significantly shortened in the dogs given 30 mg/kg of vitamin E intravenously. Furthermore, in the groups treated with vitamin E, distinct recovery of electroencephalographic potentials at 3 hours after recirculation was apparent. These effects were more favorable in the case of intravenous administration than in the case of oral administration. These experimental results indicate that the administration of vitamin E is effective in protecting the brain from cerebral ischemia.