bemesetron and Hypoxia

The aim of this study was to investigate the potential role of 5-hydroxytryptamine (5-HT) on development of pulmonary hypertension during chronic exposure to mild (15% O2) and severe (10% O2) hypoxia. In isolated lungs from normoxic rats preconstricted with U-46619, 5-HT (10(-12)-10(-8) M) induced dose-dependent vasodilation (n = 6), which was suppressed by the NO synthesis inhibitor nitro-L-arginine methyl ester (L-NAME, 10(-4) M, n = 5) and reduced by the 5-HT3-receptor antagonist MDL-7222 (10(-5) M, n = 6). The vasoconstriction that was observed with higher concentrations of 5-HT (10(-7)-10(-4) M) was inhibited by ketanserin (10(-5) M) and methiothepin (10(-5) M, n = 6 each). The vasodilator response to 5-HT was suppressed in lungs from rats exposed to 10% O2 but not 15% O2 (n = 6 each). In conscious rats, intravenous administration of 5-HT potentiated the pulmonary pressor response to acute hypoxia (10% O2, n = 5), an effect that remained unchanged after pretreatment with a 5-HT1 and a 5-HT2 antagonist (n = 4) but was attenuated after treatment with the cyclooxygenase inhibitor meclofenamate (n = 4). Treatment with 5-HT (5 nmol/h i.v. by osmotic pumps) for 2 wk in rats simultaneously exposed to 10% O2 increased pulmonary arterial pressure, right ventricular hypertrophy, and muscularization of pulmonary vessels in comparison with their hypoxic controls (n = 12 each). No changes occurred in 15% O2 hypoxic rats (n = 12 each). The present findings show that 5-HT potentiates development of pulmonary hypertension in rats exposed to chronic hypoxia.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Cyclooxygenase Inhibitors; Hypertension, Pulmonary; Hypoxia; In Vitro Techniques; Infusions, Intravenous; Lung; Male; Meclofenamic Acid; NG-Nitroarginine Methyl Ester; Prostaglandin Endoperoxides, Synthetic; Pulmonary Circulation; Rats; Rats, Wistar; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin; Serotonin Antagonists; Thromboxane A2; Tropanes; Vasoconstriction; Vasodilation

Previous studies from our laboratory indicate that acute but not chronic hypoxia decreases the hemorrhage volume required to elicit reflex hypotension. Furthermore, chronically hypoxic animals exhibit an elevated hypotensive threshold during both normoxia and hypoxia compared with control animals. Because reports suggest that opioid and serotonergic mechanisms may be involved in mediating the sympathoinhibition that occurs with hemorrhage, we hypothesized that opioid and/or serotonergic systems are stimulated during hemorrhage under conditions of acute hypoxia and suppressed after chronic exposure to hypoxia and are thus responsible for the altered cardiovascular responses to hemorrhage under each condition. Control and chronically hypoxi rats were administered either the opioid receptor antagonist naltrexone (1 mg/kg), the selective 5-hydroxytryptamine receptor subtype 3 (5-HT3) serotonergic receptor antagonist MDL-72222 (0.5 mg/kg), or their respective vehicles intravenously before hemorrhage was initiated during normoxia or hypoxia (FIO2 = 0.12). In control animals, pretreatment with naltrexone increased the hemorrhage was initiated volume required to achieve hypotension in hypoxic but not normoxic conditions. Naltrexone had no effect on hypotensive threshold in chronically hypoxic animals under conditions of either normoxia or hypoxia. In addition, MDL-72222 had no effect on hypotensive threshold in either control or chronically hypoxic animals in either normoxic or hypoxic conditions. We conclude that endogenous opioids may contribute to the reflex hypotension that occurs during hypoxic hemorrhage in control rats, while no such involvement is evident in chronically hypoxic animals. Furthermore, peripheral 5-HT3 receptors are not likely involved in this response during either normoxic or hypoxic hemorrhage in control or chronically hypoxic rats.

Topics: Animals; Endorphins; Hemodynamics; Hemorrhage; Hypoxia; Male; Naltrexone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Serotonin; Serotonin Antagonists; Tropanes

The effects of intracarotid (i.c.) injections of 5-hydroxytryptamine (5-HT; 1-50 micrograms) on carotid chemoreceptor activity recorded from the carotid sinus nerve have been studied in anaesthetized cats. Three separate components in the complex response of the chemoreceptors to injected 5-HT were identified. Firstly, a transient burst of activity was obtained during the injection period in 56% of the recordings. Secondly, in all the recordings a period of chemodepression commenced a few seconds after completing the injection and was usually dose-related. Thirdly, a delayed longer-lasting chemoexcitation occurred in many experiments, concomitant with a fall in systemic blood pressure. The neuronal 5-HT receptor antagonist MDL 72222 (10-100 micrograms kg-1, i.c.) virtually abolished the transient chemoexcitation evoked during 5-HT injections and also significantly increased the mean ID50 for 5-HT-induced chemodepression; in 37% of recordings 5-HT caused a dose-related chemoexcitation after the high dose of MDL 72222. Neither the delayed chemoexcitation nor the hypotension caused by 5-HT were much affected by the antagonist. MDL 72222 itself had a biphasic effect on chemosensory discharge, causing depression followed by a delayed excitation. The 5-HT2-receptor antagonist ketanserin (100 micrograms kg-1, i.c.) had no appreciable effect on the transient chemoexcitation evoked during 5-HT injections and caused a slight but significant increase in the mean ID50 for 5-HT-induced chemodepression. The delayed chemoexcitation and accompanying hypotension associated with 5-HT were both substantially reduced or abolished by the antagonist. Ketanserin itself caused a short-lasting period of chemoexcitation. All the effects of injected 5-HT on chemosensory discharge could be abolished by the combination of MDL 72222 and ketanserin (100 micrograms kg-1, i.c.). Neither MDL 72222 nor ketanserin had any significant effect upon the response of the carotid chemoreceptors to hypoxia. The rate at which discharge increased, and also the steady-state discharge before and during hypoxia, were unaffected by the antagonists, alone or in combination. At least two types of 5-HT receptor appeared to be involved in the response of carotid body chemoreceptors to 5-HT. Transient excitation and chemodepression were mediated via MDL 72222-sensitive (peripheral neuronal) receptors whereas the delayed chemoexcitation and associated hypotension involved a ketanserin-sensitive, presumably 5-H

Topics: Action Potentials; Animals; Carotid Body; Cats; Chemoreceptor Cells; Domperidone; Dopamine; Electrophysiology; Female; Hypoxia; Ketanserin; Male; Piperidines; Serotonin; Serotonin Antagonists; Tropanes