Mustafa Ilhan

Tracheal epithelium releases a vascular smooth muscle relaxant factor: demonstration by bioassay

Acetylcholine caused no relaxation of a rubbed strip from rabbit aorta (RASR) which was precontracted with phenylephrine. When the same strip was taken into epithelium-intact guinea-pig trachea, acetylcholine produced a slow-developing relaxation which was antagonized by atropine but not by propranolol, indomethacin, theophylline or hydroquinone. RASR was not relaxed by acetylcholine when it was taken from epithelium-rubbed trachea. The results indicate that acetylcholine releases vascular smooth muscle relaxant factor from tracheal epithelium.

The rat anococcygeus muscle is a convenient bioassay organ for the airway epithelium-derived relaxant factor.

The response to epithelium-derived relaxant factor (EpDRF) released from guinea-pig trachea by acetylcholine was studied in the precontracted rat anococcygeus muscle in a coaxial bioassay system. Acetylcholine caused no relaxation of rat anococcygeus muscle which was precontracted with phenylephrine. When the same muscle was placed into a guinea-pig trachea with intact epithelium, acetylcholine produced a slowly developing relaxation which was potentiated by neostigmine and antagonized by atropine but was not altered by indomethacin, propranolol, hydroquinone nor methylene blue. The rat anococcygeus muscle was not relaxed by acetylcholine when it was placed in an epithelium-free trachea. The results indicate that acetylcholine releases EpDRF from guinea-pig trachea and that rat anococcygeus muscle is a convenient organ for the bioassay of EpDRF.

Antinociceptive activity of coniine in mice

ETHNOPHARMACOLOGICAL RELEVANCE Hemlock was used as an analgesic in certain ethnopharmacological traditions and there has been no record about the antinociceptive effect of coniine which is the major alkaloid compound of Hemlock. AIM OF THIS STUDY The present study was undertaken to evaluate the possible antinociceptive activity of coniine. MATERIAL AND METHODS Antinociceptive activity of coniine was tested dose in Hotplate test (thermal pain model) and in Writhing test (chemical pain model) in different nociception models. RESULTS Coniine caused a prolongation in reaction time in Hotplate test at 20mg/kg dose. In addition, it was observed that coniine decreased the number of writhes in Writhing test. Both data indicated an antinociceptive effect of coniine. A rotarod test was also conducted in order to clarify, whether this activity was related with a loss of locomotion or with an analgesic activity. None of the chemical agents at those doses used in experiments caused a loss of locomotor activity. It was also shown that antinociceptive effect of morphine was potentialized by coniine which was inhibited by nicotinic receptor blocker mecamylamine (1mg/kg). CONCLUSION Coniine has antinociceptive effect via the nicotinic receptors. A pharmacological assessment about the painless death of Socrates due to Hemlock (coniine) toxicity has also been presented by using this data.

Potentiation of the morphine-induced respiratory rate depression by captopril.

The effects of morphine and captopril, an angiotensin-converting enzyme inhibitor, on respiratory frequency have been investigated in non-anesthetized mice. Morphine (10.0 mg/kg) reduced the respiratory frequency which gradually returned to the control level 2 h after the injection. The same dose of morphine when given together with captopril (0.1 and 1.0 mg/kg), caused a similar reduction in respiratory rate. This respiratory depression however, persisted until the end of the observation period. Similar results were obtained with the same dose of morphine in mice pretreated with captopril. The minimal dose of morphine reducing respiratory frequency (3.0 mg/kg), when given to the mice pretreated with captopril (0.1 mg/kg) caused a significant reduction in respiratory frequency and this effect was equal to that obtained with 10.0 mg/kg morphine alone. The results are discussed from the point of the possible inhibitory effect of captopril on the enkephalin degrading enzyme(s).

ARRHYTHMOGENIC ACTION OF ENDOTHELIN PEPTIDES IN ISOLATED PERFUSED WHOLE HEARTS FROM GUINEA PIGS AND RATS

The arrhythmogenic actions of endothelin peptides were studied in isolated perfused hearts from guinea pigs and rats. Digoxin-induced ectopic ventricular complexes were partially antagonized by phosphoramidon, an endothelin-converting enzyme inhibitor. On the contrary, these rhythm disturbances were potentiated by big endothelin-1 in isolated perfused whole hearts from guinea pigs. Endothelin-1, when infused through the coronary circulation at a concentration of 10(-10) mol/l, produced an increase in coronary perfusion pressure without altering the heart rate and contractility in the isolated perfused hearts of rats. However, ventricular ectopic complexes occurred when the rise in coronary perfusion pressure reached the peak value. BQ 485, an endothelin-A receptor antagonist, at a concentration of 10(-6) mol/l, completely blocked the vasoconstrictor and arrhythmogenic effects of endothelin-1. In BQ 485-pretreated rat hearts, endothelin-1 produced a fall in coronary perfusion pressure and a slight positive inotropic response which could be blocked by NG-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor. BQ 485 at the same concentration also caused a significant reduction in the duration but not the onset of ventricular ectopic complexes in the guinea pig isolated perfused heart induced by digoxin. These results were taken as evidence of the arrhythmogenic action of endothelin peptides and their possible participation in the ventricular dysrhythmia induced by digoxin.

Contribution of Hacettepe University Faculty of Medicine to the world's biomedical literature (1988-1997)

The contribution of Turkish researchers to sciences is increasing. Turkish scientists published more than 6.000 articles in 1999 in scientific journals indexed by the Institute for Scientific Informations Science Citation Index, which puts Turkey to the 25th place in the world rankings in terms of total contribution to science. The number of biomedical publications authored by Turkish scientists is increasing faster than that of engineering and other non-medical sciences, which might be one of the main causes of the steep rise in Turkeys rankings that we have been witnessing in recent years. More specifically, researchers affiliated with Hacettepe University produce almost a quarter of all the biomedical publications of Turkey that appear in international biomedical literature. In this paper, we report the findings of the bibliometric characteristics (authors and affiliations, medical journals and their impact factors, among others) of a total of 1.434 articles published between 1988 and 1997 by scientists affiliated with Hacettepe University Faculty of Medicine and indexed in MEDLINE, a well-known biomedical bibliographic database.

L-canavanine and dexamethasone attenuate endotoxin-induced suppression of ischaemia-reperfusion arrhythmias.

The role of inducible nitric oxide synthase in the antiarrhythmic effects of Escherichia coli endotoxin was examined in an anaesthetised rat model of myocardial ischaemia (7 min occlusion) and reperfusion (7 min) arrhythmias by using its specific blocker L-canavanine (100 mg/kg) and dexamethasone (5 mg/kg), which inhibits its expression. Endotoxin (1 mg/kg) or its solvent saline was administered intraperitoneally 4 h before the occlusion of the left coronary artery and L-canavanine or dexamethasone was administered 1 h before endotoxin or saline injection. The mean arterial blood pressure of rats receiving endotoxin was significantly lower than that of saline-treated controls, and neither L-canavanine nor dexamethasone prevented the hypotension exerted by endotoxin. However, during both the occlusion and reperfusion periods, endotoxin significantly reduced the total number of ectopic beats (e.g., during reperfusion, saline: 1177 +/- 183, n = 11; endotoxin: 248 +/- 91, n = 9; P < 0.005) and the duration of ventricular tachycardia (e.g., during occlusion, saline: 30.9 +/- 5.7 s; endotoxin: 1.8 +/- 0.9 s; P < 0.0001) while L-canavanine or dexamethasone treatment abolished the reduction exerted by endotoxin. Therefore we conclude that endotoxin possesses significant antiarrhythmic (protectant) effects in this rat model of ischaemia-reperfusion arrhythmias, and that its mechanism appears to involve the inducible nitric oxide synthase since both L-canavanine and dexamethasone inhibited this phenomenon.

Inhibitory Muscarinic Cholinoceptors on Postganglionic Sympathetic Nerves in the Guinea Pig Isolated Atrium Are of the M3 Subtype

Pre- and postjunctional effects of four muscarinic (m)-cholinoceptor antagonists were investigated against carbachol in isolated spontaneously beating guinea pig atria which were also exposed to brief periods of electrical field stimulation. The cholinoceptor agonist carbachol concentration-dependently inhibited the contraction rate of the atria with an EC50 value of 92.3 +/- 20.6 nmol/l. The m-cholinoceptor antagonists atropine, 4-DAMP (M1- and M3-selective), AF-DX 116 (M2-selective) and pirenzepine (M1-selective) shifted the concentration-response curves of carbachol to the right without modifying the maximal responses yielding pA2 values of 8.98, 8.37, 7.44 and 6.79, respectively. Electrical field stimulation increased the concentration rate of the atria which was potentiated by atropine or 4-DAMP while AF-DX 116 or pirenzepine had no significant effect. Therefore, on the basis of the findings with 4-DAMP, it is concluded that prejunctional m-cholinoceptors on the sympathetic nerve endings in guinea pig atria are inhibitory and are of the M3 subtype.

Superoxide dismutase and allopurinol prevent the pressor effects of angiotensin II and histamine in the guinea-pig isolated perfused lung exposed to hypoxia.

1. In the guinea-pig isolated perfused lung exposed to hypoxia by infusing N2-gassed Krebs solution, angiotensin II and histamine produced a reduced vasoconstrictor response when compared with the responses obtained in nonhypoxic lung. 2. These reduced vasoconstrictor responses were prevented by prior addition of superoxide dismutase or allopurinol to the medium. 3. These results were taken as evidence for the initiation of the cascade free radical formation in the guinea-pig lung during hypoxia and the primary role of the released intracellular xanthine oxidase. 4. Possible mechanisms of the reduced responses to angiotensin II and histamine and tissue protective activities of allopurinol and superoxide dismutase are discussed.

Effect of naloxone on physostigmine-induced pressor response in adrenalectomized rats.

Physostigmine-induced pressor response was studied in adrenalectomized rats. The increase in mean arterial blood pressure elicited by intravenous administration of physostigmine was not altered by adrenalectomy or sham-operation. The pressor response to intracerebroventricular administration of physostigmine was found to be partially inhibited in both acutely adrenalectomized and sham-operated rats, but not in those adrenalectomized 24 h earlier. This inhibition was completely prevented by naloxone pretreatment. The results suggest that endogenous opioid peptide release induced by surgical stress may be responsible for inhibition of the pressor effect of centrally administered physostigmine in rats.