Analysis of new imidazoline derivative-induced increase in the maximum response to norepinephrine in the rat vas deferens

The effects of newly synthesized 5-imidazoline derivatives on the dose-response relationship to norepinephrine were investigated in the normal and denervated vasa deferentia of the rat. Three derivatives (K-3827, K-4011 and K-4300) exerted alpha-antagonistic action, the potency of which was similar to that of tolazoline. The pA2 values of these derivatives and currently known alpha-antagonists (tolazoline, phentolamine and prazosin, but not yohimbine) in the denervated tissue were slightly but significantly larger than those in the normal tissue. All imidazoline derivatives and alpha-antagonists produced an increase in the maximum response to norepinephrine in the normal vas deferens. In the denervated tissue, however, K-3827, K-4011 and alpha-antagonists caused only a rightward shift of the dose-response curve to norepinephrine, but not an increase in the maximum response, i.e., relatively pure alpha-antagonism. In contrast, the other 3 imidazoline derivatives, K-4299 and K-6342 which exhibited neither alpha-agonistic nor antagonistic action and K-4300, increased the maximum response to norepinephrine even after denervation. Their effects were nonspecific in that they also potentiated acetylcholine-induced contractions in both normal and denervated tissues. These 3 imidazoline derivatives antagonized the action of diltiazem. The effects of imidazoline derivatives and alpha-antagonists were discussed in relation to those of denervation, and the drug enhancement by 3 imidazoline derivatives was analyzed from the viewpoint of calcium movement.     

A method for evaluating antianginal drugs in experimental animals: assessment of myocardial ischemia by myocardial pH

This paper describes a method by which antianginal drugs can be evaluated in the dog heart in situ. Myocardial pH was measured continuously by a micro glass pH electrode inserted in the left ventricular endocardial layers of the dog anesthetized with pentobarbital. Occlusion of the left anterior descending coronary artery (LAD) decreased myocardial pH, and release of the LAD restored the pH. The myocardial acidosis induced by ischemia was metabolic in nature and accompanied by a decrease in the levels of adenosine triphosphate and creatine phosphate and an increase in the levels of lactate in the myocardium. Drugs were injected intravenously 30 min after incomplete (partial) occlusion ot the LAD, lasting until 60 min after drug injection. Propranolol, atenolol, and sotalol markedly attenuated the myocardial pH that had been decreased by LAD occlusion. Nitroglycerin, diltiazem, and nicorandil also attenuated the pH, but these drugs were less active in attenuating myocardial acidosis. Dipyridamole, nifedipine, and beta-2 adrenoceptor antagonists were least active in this regard. It is concluded that myocardial pH can be used as an indicator of myocardial regional ischemia and utilized for evaluation of antianginal drugs.     

Effects of antimalarial drugs on interleukin 1-induced cartilage proteoglycan degradation in-vitro

Previous studies having shown that chloroquine and hydroxychloroquine could reduce interleukin 1 (IL-1)-induced cartilage degradation in-vitro, the effects of a range of antimalarial drugs on the cartilage proteoglycan degrading actions of porcine leucocyte (pI 4.8) alpha-interleukin 1 (syn. catabolin) have been examined using the standard bovine nasal cartilage culture system. The anti-IL-1 effects in this system were specific to several aminoquinoline and aminoacridine analogues having a side chain with a tertiary amino group similar to that of chloroquine. Aminoquinoline compounds devoid of this side chain and the tertiary amino, as well as pyrimidines or biguanides with antimalarial activity were without effect. Mefloquine, the most potent of the compounds active against porcine alpha-IL-1, was only equipotent with chloroquine and its hydroxyanalogue against human recombinant alpha-IL-1. This suggests that there may be subtle differences in the receptors for these drugs and interleukins in bovine cartilage. The results provide further evidence for the specificity and utility of antimalarial drugs in the treatment of chronic inflammatory conditions, especially in relation to actions on IL-1.     

Various problems in the diagnosis and treatment of the broncho-obstructive syndrome

Clinico-x-ray-laboratory investigation, bronchoscopy were performed, respiratory function and ECG were studied in 212 patients with different forms of chronic bronchitis. Six groups of patients were defined with relation to the presence or absence of obstruction, its nature (permanent, transient), prevalence (small, medium and large bronchi), genesis of disease (inflammatory, allergic). The characteristics of the groups and their clinico-x-ray, functional and immunological features were presented. Treatment including methods of climatotherapy, exercise therapy, pharmacological agents (antibacterial, broncholithic and antihistaminic), physiotherapy and administered with relation to the defined groups, proved to be effective. The improvement of bronchial permeability was noted in 49.5% (ranging from 40.0 to 68.7% in different groups).     

Immunological mechanisms giving rise to latency of herpes simplex virus in the spinal ganglia of the mouse

In the model of genital herpes simplex virus (HSV)-infection of mice, early latency could be induced by passive immunization with HSV-specific antibodies and, to a lesser degree, by adoptive transfer of immune lymphocytes prepared from spleen and draining lymph nodes of genitally infected syngeneic mice. Conversely, spontaneously occurring latency was inhibited by treatment of the animals with cyclophosphamide (Cph) and, to a lesser degree, with cyclosporin A (CyA). Whereas the effect of CyA could be compensated by passively administered HSV-specific antibodies, that of Cph could not. Apparently specific antibodies cooperate with a non-specific proliferating cell type, probably macrophages and/or NK-cells, as could be demonstrated by significantly reduced antibody effect in silica-treated mice. Moreover, F(ab)₂ fragments, in contrast to complete antibody molecules, were inactive. HSV-specific antibodies and also immune lymphocytes had little effect on virus production in the mucous membranes, immune lymphocytes being at least as active as antibodies. It is therefore not probable that latency is induced by attenuation of the peripheral disease. It can rather be concluded that the neuron itself is the target for the action of specific antibodies, cooperating in turn with macrophages and/or NK cells.With support of the Deutsche Forschungsgemeinschaft, Schn 174/6-3     

Intrapartum fetal heart rate patterns and neonatal intraventricular hemorrhage

A goal for the obstetrician and neonatologist is to screen for risk factors associated with intraventricular hemorrhage (IVH) in the low-birthweight infant. Perinatal events that lead to neonatal metabolic and cardiovascular derangements seem to provoke IVH, and conflicting reports have implicated labor as being contributory. A fetal heart rate (FHR) abnormality during premature labor may be a predictor of subsequent neonatal IVH. For this reason, 5 years of FHR tracings at two university medical centers were reviewed for inborn infants who were delivered after premature labor and weighed less than or equal to 2000 gm. Sixty-four infants developed IVH, but pre-existing labor with a discernible FHR pattern was recorded in only 38 (59%) cases. Interpretations were reassuring in 17 (45%) cases, suspicious in 7 (18%) cases, and ominous in 14 (37%) cases. This proportion of FHR patterns was not significantly different from a matched group of premature infants without IVH during the same period. Interpretations of intrapartum FHR patterns of low-birthweight infants are limited, especially before 30 weeks gestation, and not useful in predicting neonatal IVH.