Cationic amphiphilic drugs are potent inhibitors of yeast sporulation.

Meiosis is a highly regulated developmental process that occurs in all eukaryotes that engage in sexual reproduction. Previous epidemiological work shows that male and female infertility is rising and environmental factors, including pollutants such as organic solvents, are thought to play a role in this phenomenon. To better understand how organic compounds interfere with meiotic development, the model organism Saccharomyces cerevisiae was exposed to 446 bioactive molecules while undergoing meiotic development, and sporulation efficiency was quantified employing two different high-throughput assays. 12 chemicals were identified that strongly inhibited spore formation but did not interfere with vegetative growth. Many of these chemicals are known to bind to monoamine-receptors in higher eukaryotes and are cationic amphiphilic drugs. A detailed analysis of one of these drugs, tripelennamine, revealed that it induces sporulation-specific cytotoxicity and a strong inhibition of meiotic M phase. The drug, however, only mildly interfered with pre-meiotic DNA synthesis and the early meiotic transcriptional program. Chemical-genomic screening identified genes involved in autophagy as hypersensitive to tripelennamine. In addition, we found that growing and sporulating yeast cells heterozygous for the aminophospholipid translocase, NEO1, are haploinsufficient in the presence of the drug.

Involvement of histamine H1 and H2 receptors in the regulation of STAT-1 phosphorylation: inverse agonism exhibited by the receptor antagonists.

Signal transducer and activator of transcription-1 (STAT1) is a latent signal transducer protein which, on phosphorylation, is translocated from the cytoplasm to the nucleus and is subsequently activated. This study was designed to determine the involvement of histamine receptors in histamine-mediated effect on STAT1 phosphorylation. It is known that the actions of histamine mediated through H1 and H2 receptors are dependent on their respective downstream pathways, Ca(2+)-PKC and cAMP-PKA. In this study, we investigated the significance of PKA in STAT1 phosphorylation. C57BL/6 mouse splenocytes were isolated and treated with histamine (10(-7)-10(-4) M) and then activated with PMA (phorbol 12 myristate 13-acetate) plus ionomycin. The phosphorylated STAT1 levels were analyzed by immunoblotting. Histamine receptor agonists amthamine and betahistine, histamine receptor antagonists pyrilamine maleate, tripelennamine, ranitidine, cimetidine and thioperamide, cAMP agonists N(6), 2'-0-dibutyryladenosine-3',5'-cyclic monophosphate sodium salt (db-cAMP) and forskolin, protein kinase A inhibitors N-(2-[p-bromocinnamylamino]ethyl)-5-isoquinoline-sulfonamide (H89) and Rp diastereomer of adenosine cyclic 3',5'-phosphorothioate (RpcAMPs) and tyrosine kinase inhibitor tyrphostin were used to identify the upstream signal transduction pathways. We observed that histamine augmented the phosphorylation of STAT1 through both H1 and H2 receptors. Furthermore, H1 and H2 receptor antagonists displayed inverse agonism. Ca(2+)-PKC-induced phosphorylation of STAT1 was completely inhibited by H89 and significantly inhibited by RpcAMPs. DbcAMP and forskolin augmented the Ca(2+)-PKC-induced STAT1 phosphorylation thus suggesting a convergent crosstalk between the two histamine receptor signaling pathways, PKA and PKC.

Role of N-methyl-D-aspartate receptors in gastric mucosal blood flow induced by histamine.

Ionotropic N-methyl-D-aspartate (NMDA) receptor agonists, L-aspartic acid (L-Asp) and NMDA, have been shown to inhibit histamine-stimulated acid secretion, but their effect on gastric mucosal blood flow (GMBF) is largely unknown. The aim of this study was to investigate whether L-Asp and NMDA inhibit histamine-stimulated GMBF and to examine the expression patterns of NMDA receptor subunits NR1, NR2A, and NR2B in rat stomach. Laser Doppler flowmetry was used to measure gastric blood flow in anesthetized rats. The GMBF was assessed during an intravenous infusion of histamine in the presence of tripelennamine. The effects of L-Asp and NMDA on histamine-induced gastric blood flow were examined. In addition, the distribution patterns of NR1-, NR2A-, and NR2B-contaning NMDA receptors in rat stomach were determined immunohistochemically by using specific antibodies against NR1, NR2A, and NR2B. Histamine-induced enhancement of GMBF depended on acid secretion and the activation of H(2)-receptors. Neither L-Asp nor NMDA had an effect on the spontaneous GMBF. However, L-Asp and NMDA reduced the histamine-induced increase in GMBF. DL-2-amino-5-phosphonopentanoic acid (AP-5), an NMDA receptor antagonist; and prazosin, an alpha(1)-receptor antagonist; but not propanolol, a beta(2)-receptor antagonist; or yohimbine, a alpha(2)-receptor antagonist; reversed the inhibitory effect of L-Asp and NMDA on the histamine-induced increase in GMBF. Therefore, L-Asp and NMDA inhibit histamine-induced GMBF via a mechanism involving the activation of NMDA receptors and alpha(1)- adrenoceptors. The fact that NMDA receptor subunits NR1, NR2A, and NR2B were found to be localized in the rat stomach as visualized immunohistochemically with specific antibodies against NR1, NR2A, and NR2B is consistent with this hypothesis.

Mast cell--pituitary interaction: modulation by serine phospholipids.

The influence of mast cell activation on the secretion of prolactin has been studied in rats receiving lysophosphatidylserine, a natural occurring phospholipid with secretagogue activity in these cells. After the i.v. injection of lysophosphatidylserine (10 mg/kg) a plasma prolactin peak correlates with an increased blood histamine level. Following the secretory event, which is inhibited by the H1 anti-histamine tripelenamine, plasma prolactin level drops below the basal line. Repeated lysophosphatidylserine administrations induce mast cell desensitisation, thus reducing also the pituitary response. Under these conditions a decrease in prolactin basal level is still observed, although the pituitary stores of this hormone are preserved. Control tests in vitro with lysophosphatidylserine, show that the diacyl lysophosphatidylserine derivative amplifies the inhibitory effect of dopamine on prolactin secretion from isolated pituitaries. The data suggests that lysophosphatidylserine induces prolactin secretion through mast cell activation. After this event, the reacylation of this phospholipid into lysophosphatidylserine in the pituitary membrane may enhance the inhibitory control by dopamine.

Does the neurotransmitter transporter underlie adaptation at a histaminergic photoreceptor synapse?

Using autoradiographic and biochemical techniques, we studied the sodium-dependent forward and reverse transport of the neurotransmitter histamine in an arthropod photoreceptor in order to test whether the transporter plays a central role in visual signal transfer at this synapse. In particular, we asked whether the histamine transporter might be the important factor in synaptic adaptation, the process by which the operating range of the synapse adapts to increasing depolarizations of the photoreceptor in increasing background light. Drugs known from electrophysiological observations to interfere with synaptic adaptation blocked the uptake of [3H]histamine into photoreceptors. These drugs also blocked the sodium (Na)-triggered efflux of [3H]histamine, previously loaded into photoreceptors, via the histamine transporter. Several lines of evidence showed that efflux of [3H]histamine did not occur via calcium-dependent exocytosis. First, efflux occurred when the preparation was bathed in calcium (Ca)-free/EGTA salines or in cobalt (Co)-containing salines. Even more importantly, efflux could be elicited from axons, whose membranes must contain the transporter protein since they take up [3H]histamine independently from the presynaptic terminals. Since both adaptation and the histamine transporter are blocked by the same agents, the transporter may underlie adaptation by maintaining the cleft histamine concentration in a particular range independent of light intensity. We also characterized the transporter further and found that it is partially dependent on chloride ions, and that neither [3H]norepinephrine nor [3H]dopamine are transported (at 20 microM), adding to evidence that the transporter is highly selective for histamine.

H1-receptor antagonist, tripelennamine, does not affect arterial hypoxemia in exercising Thoroughbreds.

It has been suggested that pulmonary injury and inflammation-induced histamine release from airway mast cells may contribute to exercise-induced arterial hypoxemia (EIAH). Because stress failure of pulmonary capillaries and EIAH are routinely observed in exercising horses, we examined whether preexercise administration of an H1-receptor antagonist may mitigate EIAH. Two sets of experiments, placebo (saline) and antihistaminic (tripelennamine HCl at 1.10 mg/kg iv, 15 min preexercise) studies, were carried out on seven healthy, exercise-trained Thoroughbred horses in random order 7 days apart. Arterial and mixed venous blood-gas and pH measurements were made at rest before and after saline or drug administration and during incremental exercise leading to maximal exertion at 14 m/s on 3.5% uphill grade for 120 s. Galloping at this workload elicited maximal heart rate and induced exercise-induced pulmonary hemorrhage in all horses in both treatments, thereby indicating that capillary stress failure-related pulmonary injury had occurred. In both treatments, EIAH, desaturation of hemoglobin, hypercapnia, and acidosis of a similar magnitude developed during maximal exertion, and statistically significant differences between the placebo and antihistaminic studies could not be demonstrated. The failure of the H1-receptor antagonist to modify EIAH significantly suggests that pulmonary injury-induced histamine release may not play a major role in bringing about EIAH in Thoroughbred horses.

Inhibition of Na(+) current by diphenhydramine and other diphenyl compounds: molecular determinants of selective binding to the inactivated channels.

Diphenhydramine is an H1 histamine receptor antagonist, yet it also has a clinically useful local anesthetic effect. We found that diphenhydramine inhibits the neuronal Na(+) current, and the inhibition is stronger with more positive holding potentials. The dissociation constant between diphenhydramine and the inactivated Na(+) channel is approximately 10 microM, whereas the dissociation constant between diphenhydramine and the resting channel is more than 300 microM. The local anesthetic effect of diphenhydramine thus is ascribable to inhibition of Na(+) current by selective binding of the drug to the inactivated channels. Most interestingly, many other compounds, such as the anti-inflammatory drug diclofenac, the anticonvulsant drug phenytoin, the antidepressant drug imipramine, and the anticholinergic drug benztropine, have similar effects on neuronal Na(+) current. There is no apparent common motif in the chemical structure of these compounds, except that they all contain two phenyl groups. Molecular modeling further shows that the two benzene rings in all these drugs have very similar spatial orientations (stem bond angle, approximately 110 degrees; center-center distance, approximately 5 A). In contrast, the two phenyl groups in phenylbutazone, a drug that has only a slight effect on Na(+) current, are oriented in quite a different way. These findings strongly suggest that the two phenyl groups are the key ligands interacting with the channel. Because the binding counterpart of a benzene ring usually is also a benzene ring, some aromatic side chain groups of the Na(+) channel presumably are realigned during the gating process to make the very different affinity to the aforementioned drugs between the inactivated and the resting channels.

Does histamine stimulate trigeminal nasal afferents?

The response to histamine of nasal afferents has been studied in guinea pigs by recording the electrical activity of the whole ethmoidal nerve (EN) or that of single units. Guinea pigs were anaesthetized with urethane and breathed through a tracheostomy. Prior to intranasal instillation of histamine (1 x 10(-4)-10(-1) M), the nasal mucosa was treated with 20 microl of saline (0.9% NaCl) or HCl (pH = 2), and in some cases, H2SO4 (pH = 2). In other experiments, following HCl instillation animals were pretreated by tripelennamine (1 x 10(-2) M) and/or cimetidine (1 x 10(-2) M) in order to determine the histamine receptor type of sensory nerve endings. Whole EN activity was not stimulated even by the highest dose (1 x 10(-1) M) of histamine when the nose was pretreated with saline, but was substantially stimulated by histamine in a dose-response fashion (1 x 10(-2) M) after pretreatment with HCI or H2SO4. Pretreatment with tripelennamine and HCl prevented the effect of histamine on the afferent EN activity; but after cimetidine and HCl pretreatment histamine still had a marked stimulant effect. In the case of single unit activities, histamine with HCl pretreatment had a long-lasting stimulatory effect (110.2 +/- 26.6 sec). It is concluded that the EN in guinea pigs include histamine-sensitive fibers whose sensitivity is mediated by H1 receptors and can respond to histamine only under abnormal conditions of the nasal mucosa.

Dirofilaria immitis: heartworm infection converts histamine-induced constriction to endothelium-dependent relaxation in canine pulmonary artery.

Heartworm (Dirofilaria immitis) infection alters the behavior of vascular endothelial cells in vivo and in vitro, with the potential, therefore, to influence vascular function. Histamine, an autocoid implicated in the pathogenesis of parasitic and inflammatory diseases, is vasoactive, and causes endothelium-dependent relaxation in some vascular beds. Experiments were designed to determine if histamine is an endothelium-dependent vasodilator in in vitro rings of canine pulmonary artery from heartworm and control dogs; to elucidate the mechanisms involved in histamine vasoactivity; and to measure circulating levels of histamine. Dose-response relationships to histamine were done in rings of canine pulmonary artery from heartworm and control dogs, in the presence and absence of endothelial cells, the H1 receptor blocker tripelennamine, or the H2 receptor blocker cimetidine. Histamine caused a dose-dependent constriction in control, that was not influenced by endothelial cell removal. However, histamine caused an endothelium-dependent relaxation in heartworm pulmonary artery that was converted to constriction by endothelial cell removal. In heartworm, histamine relaxation was mediated by H2 receptors, but did not appear to involve nitric oxide or cyclooxygenase products. While diseases cause depression of endothelium-dependent relaxation, this is the first report of a disease that changes a constriction response to an endothelium-dependent relaxation.

Interactions between H1-antagonists and opioids: a drug discrimination study.

We previously demonstrated that combination of opioids, pentazocine and dihydrocodeine, with the histamine H1-receptor antagonists tripelennamine and chlorpheniramine could enhance their rewarding effects in rats. In the present study, the effects of combined treatment with opioids and H1-antagonists on discriminative stimulus effects were examined in rats trained to discriminate between cocaine (10 mg/kg) or morphine (3.0 mg/kg) and saline, since it is believed that discriminative stimulus effects of abused drugs are related to their rewarding effects. Tripelennamine and chlorpheniramine, but not pentazocine or dihydrocodeine, generalized to the discriminative stimulus effects of cocaine. Pentazocine (3.0 mg/kg) and dihydrocodeine (5.6 mg/kg) significantly potentiated the cocaine-like discriminative stimulus effects of low doses of tripelennamine and chlorpheniramine, respectively. On the other hand, pentazocine and dihydrocodeine, but not tripelennamine or chlorpheniramine, generalized to the discriminative stimulus effects of morphine. Neither 1.0 or 3.0 mg/kg tripelennamine nor chlorpheniramine affected the morphine-like discriminative stimulus effects of pentazocine and dihydrocodeine, respectively. These results suggest that the potentiation of the cocaine-like discriminative stimulus effects of H1-antagonists by opioids may be involved in the enhanced rewarding effects of combinations of opioids and H1-antagonists.

Stimulation of formation of adenosine 3',5'-phosphate by histamine in myenteric ganglia isolated from guinea-pig small intestine.

Effects of histamine and related agonists and antagonists on formation of cAMP were determined for enzymatically dissociated ganglia from the myenteric plexus of the guinea-pig small intestine. Formation of cAMP was stimulated by histamine in both dose- and time-dependent manners. The stimulatory action of histamine was suppressed by the histamine H2 receptor antagonist, cimetidine. The histamine H1 receptor antagonists, tripelennamine or pyrilamine also suppressed the stimulatory action of histamine, but only at concentrations 3-4 orders higher than required for cimetidine. Formation of cAMP was stimulated dose-dependently by the histamine H2 receptor agonist, dimaprit. The histamine H1 receptor agonist, 2-methyl-histamine, also stimulated cAMP production, but required a threshold concentration 4-5 orders higher than dimaprit. We conclude that histamine acts at the histamine H2 receptor subtype to stimulate adenylate cyclase and the formation of cAMP in myenteric ganglia of the guinea-pig small bowel.

Direct evidence of parasympathetic vasodilatation in cat periodontal ligament.

Sympathetic regulation of periodontal ligament blood flow (PLBF) is well-attested; however, vasodilator responses mediated by parasympathetic nerve fibers have yet to be conclusively demonstrated in the periodontal ligament (PL). The present study was designed to determine whether parasympathetic vasodilator mechanisms do or do not exist in the cat PL. In our cats, the cervical sympathetic trunks were sectioned bilaterally prior to any stimulation in order to eliminate sympathetic effects on the vascular beds under study. Dynamic changes in PLBF, with mandibular lip blood flow (LBF) recorded for comparison, were investigated in cat mandibular canine teeth using laser Doppler flowmetry. The peripheral cut ends of the facial and glossopharyngeal nerve roots, which have been reported to contain parasympathetic nerve fibers to the oral tissues, were electrically stimulated intracranially. Such stimulation caused blood flow to increase in the ipsilateral PL and lip, without an increase in systemic blood pressure. These vasodilator responses in the PL and lip were sensitive to ganglion blockade (with hexamethonium), indicating vasodilation via activation of parasympathetic vasodilator fibers. In contrast, although intracranial stimulation of the trigeminal nerve root also induced increases in both PLBF and LBF, these were unaffected by hexamethonium, but reduced by tripelennamine, indicating antidromic vasodilatation via the trigeminal sensory nerve. These results suggest that parasympathetic vasodilator mechanisms do exist in feline PL.

The discriminative stimulus effects of tripelennamine in humans.

Twenty volunteers were trained to discriminate between 75 mg tripelennamine (TP) and placebo. During the first four sessions, the drugs were identified prior to ingestion by letter code. During the next six sessions, the procedure was the same except the capsules were not identified. At the end of the 3-h session, participants indicated which capsule they believed they received using the letter codes. When correct, they received a monetary bonus. If they were correct on five sessions, they entered the third phase which had ten additional training and 12 test sessions. During tests, participants received capsules that contained other drugs, including diphenhydramine (50 and 75 mg), chlorpheniramine (4 and 6 mg), diazepam (5 and 10 mg), d-amphetamine (5 and 10 mg), as well as tripelennamine (25, 50 and 75 mg) and placebo. Thirteen participants learned the discrimination and nine entered the third phase. Except for placebo, most participants identified the test compounds as TP and labeled them as sedatives. TP produced significant changes on several subjective and physiological measures. The test compounds produced varied effects which were neither clearly dose-related nor related to the identification as TP or placebo. These results indicate that tripelennamine can function as a discriminative stimulus, but with little evidence of pharmacological specificity.

Potentiation of L-dopa-induced behavioral excitement by histamine H1-receptor antagonists in mice.

Effects of histamine H1-receptor antagonists on L-dopa-induced behavioral excitement were examined in mice to confirm behaviorally the inhibition of dopamine uptake by these compounds. L-Dopa (100-300 mg/kg, s.c.) combined with pargyline hydrochloride (80 mg/kg, i.p.) caused a dose-dependent behavioral excitement. The marked excitement induced by L-dopa (300 mg/kg) plus pargyline was significantly inhibited by pimozide (0.1 - 1 mg/kg, s.c.), a selective dopamine antagonist. Tripelennamine (10 mg/kg, s.c.), d-chlorpheniramine (1 and 2 mg/kg, s.c.), homochlorcyclizine (2 and 5 mg/kg, s.c.), diphenhydramine (2 and 5 mg/kg, s.c.) and mepyramine (2 and 5 mg/kg, s.c.) each markedly enhanced the moderate behavioral excitement induced by L-dopa (150 mg/kg) plus pargyline. These findings are behavioral evidence for inhibition of dopamine uptake by H1 antagonists, which has been suggested by neurochemical studies.

Effects of trepelennamine on brain monoamine turnover in morphine dependent and abstinent mice.

Previous studies have reported that the histamine H1 receptor blocker tripelennamine potentiates morphine withdrawal. In this paper, the in vivo effects produced by tripelennamine on the turnover of serotonin (5-HT), dopamine (DA) and noradrenaline (NA) in the whole brain, excluding the cerebellum, were studied in control, morphine-dependent (by SC implantation of a 75 mg morphine pellet) and morphine-dependent male CD1 mice just before naloxone-precipitated withdrawal. Tripelennamine (1-10 mg/kg) was administered SC 45 min. before the animals were killed. Serotonin, 5-hydroxyindole-3-acetic acid (5-HIAA), dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and noradrenaline were measured by high performance liquid chromatography coupled with electrochemical detection (HPLC-ECD) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) was measured by HPLC coupled with fluorimetric detection. Ratios 5-HIAA/ 5-HT, DOPAC + HVA/DA and MHPG/NA were taken as an index of serotonin, dopamine and noradrenaline turnovers, respectively. Tripelennamine (1 and 10 mg/kg) significantly reduced serotonin turnover in control and morphine-dependent mice, and potentiated the serotonin turnover reduction when it was administered 30 min before naloxone injection. The dopamine turnover was diminished by tripelennamine (1 and 10 mg/kg) in the morphine-dependent group. Tripelennamine (10 mg/kg) reduced noradrenaline turnover during abstinence. These results suggest that the potentiation of opiate abstinence by tripelennamine could be related to its antiserotonergic profile.

Absence of parasympathetic vasodilatation in cat dental pulp.

The existence and nature of parasympathetic nerve fibers in the dental pulp have long been a subject for discussion; indeed, vasodilator responses mediated by such nerve fibers have yet to be conclusively demonstrated in the dental pulp. This study was designed to determine whether parasympathetic vasodilator mechanisms do or do not exist in the cat dental pulp. Dynamic changes in pulpal blood flow (PBF), with mandibular lip blood flow (LBF) recorded as a control, were investigated in cat mandibular canine teeth by means of laser Doppler velocimetry. Peripheral trigeminal afferents (see below) were stimulated electrically to confirm that somato-parasympathetic reflex vasodilatation could be induced. The peripheral cut ends of the facial and glossopharyngeal nerve roots, which have been reported to contain parasympathetic nerve fibers to the oral tissues, were then stimulated intracranially. Electrical stimulation of trigeminal afferents (in the infraorbital nerve or the maxillary buccal gingiva) caused no change in PBF but did increase ipsilateral LBF. Neither facial nor glossopharyngeal nerve root stimulation caused a PBF increase, though both elicited increases in ipsilateral LBF. The vasodilator responses in the lip were sensitive to ganglion blockade (with hexamethonium), indicating vasodilatation via activation of parasympathetic vasodilator fibers. In contrast, intracranial stimulation of the trigeminal nerve root induced increases in both PBF and LBF which were reduced by pre-treatment with tripelennamine, indicating antidromic vasodilatation via the trigeminal sensory nerve. These results suggest that a parasympathetic vasodilator mechanism is not present in feline dental pulp.

Role of histamine in the intestinal flow response following mesenteric ischemia.

Sudden reperfusion of the gut following prolonged ischemia can itself have more deleterious consequences than the ischemia alone. Studies of vasodilator factors influencing the increased flow on reperfusion are therefore of importance. In the present study, a possible role of histamine in the postischemic flow response was examined after a period of total segmental ischemia. The artery supplying the terminal ileum was occluded in anesthetized dogs. Ischemia of 30 min duration was followed by a 30 min reperfusion period (control postischemic flow response), and the arterial blood flow to the segment was measured. After the control postischemic flow response, one of the following drugs was administered intravenously: histamine H1-or H2-blockers (tripelennamine, .5 mg/kg, cimetidine, 10 mg/kg, ranitidine, 2 mg/kg), cromolyn (a mast cell stabilizer, 25 mg/kg), and aminoguanidine (a diamine oxidase blocker, 50 mg/kg). The 30 min ischemia-30 min reperfusion cycle was then repeated (test postischemic flow response). A 30 min mesenteric ischemia-reperfusion period is reproducible once without a significant change in its hemodynamic parameters. The duration and volume of the postischemic flow response were significantly decreased by cimetidine, ranitidine, or cromolyn, and were increased by aminoguanidine. Tripelennamine did not affect the postischemic vasodilator response. At the onset of reperfusion, a release of endogenous histamine occurs from the gut, originating mainly from mast cells. It is proposed that histamine participates in the postischemic flow response through the H2-receptors.

The role of histamine in the increased cardiac output in hyperdynamic endotoxemia.

The role of histamine in the hyperdynamic circulatory response to endotoxin (ETX) was investigated in 32 anesthetized dogs by means of histamine H1- and H2-receptor blockade. A hyperdynamic circulation was elicited with a prolonged, slow infusion of a low dose of ETX, and hemodynamic parameters were examined in control and histamine receptor-blocked groups. The following groups were studied: Group ETX received a 2 h infusion of Escherichia coli 055:B5 endotoxin in a total dose of 13.75 micrograms/kg at a rate of 10 micrograms/kg for 45 min and then 5 micrograms/kg for 75 min. In addition to the same dose of ETX, Groups ETX+TPA and ETX+RAN received 0.5 mg/kg of the H1-blocker tripelennamine (TPA) or 2 mg/kg of the H2-blocker ranitidine (RAN), respectively. Infusion of ETX caused a moderate decrease in arterial pressure in Group ETX, whereas TPA but not RAN inhibited this pressure fall. The cardiac output (CO) increased by 41% above the baseline level in Group ETX. Both TPA and RAN prevented this rise in CO. The total peripheral resistance was considerably lowered by ETX, but this decrease was significantly attenuated in the TPA or RAN-treated groups. The heart rate rose significantly after ETX infusion and was unaffected by TPA or RAN. The stroke volume remained unchanged following ETX but was decreased both by TPA and by RAN. TPA or RAN, when given alone, did not affect any of the measured hemodynamic parameters. These experiments provide evidence of the participation of histamine in the hyperdynamic circulatory response in endotoxemia.

Mechanism by which histamine increases gastric mucosal blood flow in the rat. Role of luminal H+.

The mechanism by which histamine increases gastric mucosal blood flow (GMBF) was investigated in the anesthetized rat. The experiment was performed in the presence of tripelennamine, an H1 antagonist, to focus on the relationship between acid secretion (H2-receptor-mediated response) and GMBF. The stomach was mounted on a Lucite chamber, perfused with saline, and GMBF was measured by laser Doppler flowmetry simultaneously with acid secretion. Under these conditions, histamine at the submaximal dose significantly increased GMBF as well as acid secretion, and this increase of GMBF was completely blocked when acid secretion was inhibited by cimetidine or omeprazole. The elevation of GMBF caused by histamine was also significantly attenuated when luminal H+ was removed by intraluminal perfusion with NaHCO3 or glycine. Glycine by itself did not affect the increase of acid secretion induced by histamine and the increase of GMBF caused by isoproterenol, yet significantly inhibited the GMBF response induced by pentagastrin. Intraluminal perfusion with HCl also produced an increase of GMBF in a concentration-related manner, even in the presence of omeprazole during histamine infusion. Pretreatment of the animals with indomethacin significantly blocked the GMBF responses induced by either histamine or luminal HCl. These results suggest that the increase of GMBF during acid secretion induced by histamine may be caused by luminal H+ and involve endogenous prostaglandins in its mechanism.