Effect of age on the prejunctional α-adrenoceptor-mediated feedback in the heart of spontaneously hypertensive rats and normotensive Wistar Kyoto rats

Summary The prejunctional ₂-adrenoceptor-mediated feed-back in the heart of pithed young and adult spontaneously hypertensive rats (SHR) and corresponding normotensive Wistar Kyoto rats (WKY) was studied. After electrical stimulation of the sympathetic outflow from the spinal cord to the heart, B-HT 920 induced an inhibition of the cardiac response, which was significant at stimulation frequencies up to 1 Hz in young SHR and WKY and up to 2 Hz in the adult animals. Rauwolscine produced a potentiation of the cardiac response to electrical stimulation in SHR, which was significant from 0.2–10 Hz in young SHR and from 0.1–10 Hz in adult SHR. In young WKY, rauwolscine did not potentiate the increase in heart rate to sympathetic nerve stimulation, whereas in adult WKY ₂-adrenoceptor blockade by rauwolscine significantly potentiated the cardiac response to electrical stimulation at frequencies in the range of 0.2–10 Hz. In SHR the potentiation of the cardiac response to sympathetic nerve stimulation by rauwolscine was much stronger than in WKY.These results suggest that in adult animals the prejunctional ₂-adrenoceptor mediated feedback is more developed than in young rats. In contrast with young WKY, a significant endogenous feedback can be demonstrated in adult WKY. In SHR, however, the physiological role of prejunctional ₂-adrenoceptors is much more important.     

Tissue specific susceptibility of alpha-adrenoceptor mediated vasoconstriction to nifedipine

Summary The influence of the calcium antagonist nifedipine on ₁- and ₁-adrenoceptor vasoconstrictor effects was investigated in vitro. Changes in tension were monitored isometrically on helical strips of canine circumflex coronary and saphenous arteries suspended in 10 ml organ baths and of saphenous veins superfused with Krebs-Henseleit solution. Distinction between ₁- and ₂-adrenoceptor was made by using selective -adrenoceptor blocking drugs such as rauwolscine, yohimbine, corynanthine and prazosin, and the agonists noradrenaline, phenylephrine and guanfacine. In venous and both arterial vascular smooth muscles, the contractile process could be triggered by stimulation of both ₁- and ₂-like adrenoceptors. Nifedipine inhibited the venoconstrictor response to the ₂-agonist guanfacine, leaving that to the ₁-agonist phenylephrine unchanged. In saphenous arteries, nifedipine in addition to guanfacine also antagonized constrictor responses to phenylephrine, though to a significantly weaker extent. In circumflex coronary arteries, nifedipine was equally potent in antagonizing responses to both ₁- and ₂-adrenoceptor stimulation.It is suggested that the susceptibility of -adrenoceptormediated vasoconstrictor effects to blockade by calcium antagonists depends not only on the subtype of -adrenoceptor but, in addition, on the type and origin of vascular smooth muscle and may be a reflection of tissue variations in intracellular calcium stores.     

Neuropathological findings of an autopsy case of adult β-galactosidase and neuraminidase deficiency

Summary An autopsy case of a Japanese male with familial -galactosidase and neuraminidase deficiency is reported. The clinical picture was characterized by adult onset, a gargoyle-like face, cerebellar ataxia, myoclonus, convulsions, retinal degeneration and cortical blindness.Histopathologically, most neurons seemed to have become degenerated in the whole cerebral cortex. Moreover, the calcarine cortex appeared spongy with depopulation of nerve cells. Stuffed neurons or neuronal storage changes were found throughout the brain, especially in the motor nuclei of the spinal cord and brain stem.The inclusions in the stuffed neurons revealed various profiles on the electron microscope. They were composed of membranous lamellar and/or multilamellar structures, often accompanying vacuoles and reminiscent of lipofuscin-like profiles.     

Long-term treatment with Pilogel/β-blocker in glaucoma patients

In a multicentre clinical trial thirteen patients with primary open angle glaucoma or ocular hypertension were followed during at least six months while selfinstilling Pilogel (once daily) and topical -blocker (twice daily). After six months of combination therapy there was an average decrease in intra-ocular pressure (IOP) of 33.6% 9.5 hours after Pilogel administration and an IOP decrease of 23.4% 22.5 hours after Pilogel administration. With topical -blocker alone, an average IOP decrease of 15% was measured. Throughout the study we observed in six patients (46.1%) a superficial punctate keratitis which mostly spontaneously cleared. We did not see any serious side-effects after six months of combination therapy.     

Polyamine involvement in the secretion and action of TGF-α in hormone sensitive human breast cancer cells in culture

These experiments were designed to test polyamine (PA)* involvement in the secretion and action of transforming growth factor (TGF-) in hormone responsive MCF-7 breast cancer cells in liquid culture. At the same time, we evaluated the influence of culture conditions (with serum vs. serum depleted) and subclonality of MCF-7 cells on PA involvement in estrogen (E₂) and TGF- stimulated cell proliferation. Despite inducing a profound suppression of cellular PA levels and inhibiting basal and E₂-stimulated growth, administration of the PA synthesis inhibitor -difluoromethylornithine (DFMO) did not influence either basal or E₂-induced TGF- secretion. In the same experiments, on the other hand, addition of DFMO completely blocked the growth stimulatory effect of exogenous TGF-. However, when the culture conditions were changed to serum-free medium, TGF- and E₂-induced cell proliferation was affected modestly or not at all by DFMO administration, despite similar suppression of cellular ornithine decarboxylase (ODC) activity and PA levels. In addition, different clones of MCF-7 cells differed in their sensitivity to the antiproliferative effect of DFMO as well as in basal levels of ODC activity and PA. We conclude that PAs are not involved in basal or E₂-stimulated TGF- secretion in MCF-7 breast cancer cells. On the other hand, PAs do seem to be important mediators of TGF- and E₂-induced breast cancer cell proliferation, though the degree of such involvement appears to be influenced by serum factors and clonal variability of MCF-7 cells.     

Effects of gamma-vinyl GABA (vigabatrin) on blood pressure and body weight of hypertensive and normotensive rats

Summary Inactivation of GABA was inhibited by -vinyl GABA (GVG) and the effects of the increased GABA level in the brain on blood pressure and body weight of spontaneously hypertensive rats (SHR) and normotensive rats (WKY) were investigated.When started at the age of 8 weeks or 5 weeks, treatment of SHR and WKY with GVG (150 mg/kg, s.c.) for several weeks did not influence systolic blood pressure. In 1-week old SHR, treatment with GVG (up to 150 mg/kg, s.c.) abolished the rise in blood pressure until animals were 8 weeks old. Thereafter, arterial blood pressure started to increase but it remained distinctly lower than that in untreated animals. When started at the age of 1 week, treatment with GVG for 7 weeks did not influence arterial blood pressure in WKY. GVG delayed increase in body weight in SHR and WKY, irrespective of their age. GVG greatly increased GABA levels in the hypothalamus, frontal cortex, brainstem and rest of the brain in both WKY and SHR.It is concluded that an increase in the GABA level in the brain leads to a delay in the development of hypertension in young SHR. Hence, development of genetic hypertension seems to be susceptible to activation of the GABAergic system in a very early critical phase only. Send offprint requests to N. Singewald at the above addressThis work was supported by the Fonds zur Förderung der wissenschaftlichen Forschung     

Effects of drugs of abuse on acquisition of behavioral chains in squirrel monkeys

The acute effects of various drugs of abuse on the acquisition of chains of behavior were assessed in squirrel monkeys trained to respond on three keys for food. Each new session the monkeys acquired a different four-response chain by responding sequentially on three keys in the presence of four different stimuli. Incorrect responses inactivated the keys and darkened the chamber for 10 s (time-out). Dose-effect curves were obtained by administering the drugs intramuscularly before the session and recording their effects on the rate and accuracy of responding. Cocaine,d-amphetamine, and ⁹-tetrahydrocannabinol all decreased the accuracy and rate of responding within the dose range of 0.56–3 mg/kg. The highest dose of morphine tested (3 mg/kg) produced parallel decreases in the accuracy and rate of responding in some monkeys but had no effect at lower doses. These drugs decreased within-session accuracy though clearly acquisition did occur, but high doses of caffeine (30 and 56 mg/kg) prevented acquisition and recovery of performance and, furthermore, at 30 mg/kg these effects were observed in the absence of decreases in the rate of responding. The drugs of abuse tested all produced dose-related decreases in both the accuracy and rate of responding, and the decreases in accuracy were primarily observed only at doses that also decreased response rates. Therefore, based on these results from nonhuman primates each of these drugs has the potential to alter learning particularly when doses that disrupt other behaviors are administered.     

Serotonergic function and late luteal phase dysphoric disorder

Thirty-eight subjects who met criteria for the DSM-III-R diagnosis late luteal phase dysphoric disorder (LLPDD) were compared with 18 controls in 5-HT uptake kinetics of the platelets in the premenstrual (day 26) as well as in the postmenstrual phase (day 4) of the cycle. Furthermore, 5-hydroxytryptophan (5-HTP) was administered to LLPDD patients and controls in both phases of the cycle, to investigate pituitary sensitivity for serotonin. Plasma samples for the measurement of cortisol and -endorphin were taken before and after oral administration of 200 mg 5-HTP, and considered as an index of pituitary-adrenal function. LLPDD was not associated with a lower platelet 5-HT uptake and content in the premenstrual phase of the cycle, compared with the postmenstrual phase. Patients appeared not to be different from controls in 5-HT uptake kinetics of platelets in the premenstrual phase of the cycle. No main differences were observed between LLPDD patients and controls in their ability to respond with secretion of cortisol and -endorphin to 5-HTP stimulation, either in the premenstrual, or in the postmenstrual phase. This observation could not be attributed to differences in 5-HTP metabolism. The findings of the present study do not support a specific role for 5-HT in the pathophysiology LLPDD.     

Increase in ω3 (Peripheral-Type Benzodiazepine) binding site densities in different types of human brain tumours

Summary The density of ₃ (peripheral type benzodiazepine) binding sites, a marker of reactive and tumoural cells, has been measured in different types of human brain tumours; ₃ sites were quantified autoradiographically in sections from biopsy or autopsy specimens labelled with the specific radioligand³H-PK 11195. Compared to normal brain parenchyma, up to 12-fold increase in ₃ site densities were found in appparently viable areas of high grade astrocytoma and glioblastoma specimens, whereas more limited increases (2 to 3-fold) in this marker were observed in areas of necrosis. Low grade gliomas (astrocytomas) and meningiomas exhibited only moderate increases (2 to 3-fold) in this autoradiographic marker. Metastases of lung or kidney origin were characterized by greatly elevated (up to 20-fold) ₃ site densities as compared to normal brain parenchyma. In every case, there was a good spatial correspondence between the histopathological limits of the tumour and the anatomical location of the increase in ₃ site densities. These results suggest that ₃ site densities in human brain tumours reflect their proliferative activity and point to a possible future usefulness of positron or gamma-ray emitting ₃ site ligands for the clinical investigation and detection of human brain proliferative diseases.     

Evaluation of cellular viability by quantitative autoradiographic study of myocardial uptake of a fatty acid analogue in isoproterenol-induced focal rat heart necrosis

Previous studies led us to hypothesize that a fatty acid analogue, 15-p-iodophenyl--methyl pentadecanoic acid (IMPPA or BMIPP), which is taken up but not quickly metabolized by heart cells, would be a more suitable tracer of cellular viability than thallium-201. Biodistribution studies of 1-¹⁴C-IMPPA in conscious, freely moving rats showed that the concentration ratio of radioactivity in the heart with respect to the blood was about 8 for at least 60 min after intravenous administration, permitting its use as a putative tracer in these conscious, freely moving rats. Thereafter, the myocardial uptake of¹⁴C-IMPPA was studied in isoproterenol-treated rats (daily treatment for 10 days in order to induce cardiac hypertrophy and necrotic foci) with respect to control ones. Comparison of myocardial localizations by quantitative autoradiography of the uptake of²⁰¹Tl and¹⁴C-IMPPA with that of triphenyltetrazolium chloride (TTC) staining enabled comparative evaluation of nutritional blood flow, localization and uptake of¹⁴C-IMPPA and necrotic foci size. Distributions of¹⁴C-IMPPA and²⁰¹1 T1 in control rats' hearts were homogeneous, like TTC staining. In infarcted hearts, areas of decreased¹⁴C-IMPPA uptake were nearly the same (100%±5%) as those unstained by TTC. These areas were larger than those showing a decrease in thallium uptake (about 70%±5% of the total scar size). Therefore, IMPPA seems to be a more accurate and sensitive indicator of necrosis localization compared with thallium. It may be a useful agent for assessment of myocardial viability by single photon emission tomography (SPET) imaging.