Cardiac and carotid vascular effects of 5-hydroxyttyptamine-related drugs in the pig

There exists now an extensive literature dealing with the nature of the 5-HT receptors involved in 5-Hf-induced cardiovascular effects. For example, 5-Hf-induced tachycardia is notoriously species-dependent and is mediated, directly or indirectly, either by 5-Hf,-like (cat), 5-Hf2 (rat, dog) or 5-Hf, (rabbit, dog) receptors, or by tyramine-like (guinea-pig) or unidentified mechanisms (pig, Helix aspersa) (see Saxena, 1986; Saxena and Villalon, 1990a; 1991). In marked contrast, little is known about the nature of the myocardial receptors involved in 5-Hf-induced positive inotropic effects (Kaumann et al., 1990a,b ). Therefore, Chapters 7 and 8 of the present thesis deal with the mechanism(s) and characteriaation of the 5-Hf receptor type involved in the positive chronotropic effects induced by 5-Hf and some indole- and benzamide derivatives in the pentobarbitone anaesthetized pig, whereas in Chapter 9 an attempt was made to delioeate the receptor involved in the positive inotropic effect by 5-Hf in the same species. On the other hand, it is has been demonstrated that 5-Hf,-like receptors mediate hoth the constriction of porcine cephalic arteriovenous anastomoses and the dilatation of arterioles induced by 5-Hf and some 5-Hf,-like receptor agonists, including the antimigraine drug sumatriptan (Saxena et al., 1989; Saxena and Villalon, 1990a; Den Boer et al., 1991); however, it has not yet been fully identified which specific 5-Hf, receptor subtype (5-HflA, 5-Hf16, 5-Hf1c or 5-Hf10) is involved in such effects (Born et al., 1989a,b; Saxena and Villalon, 1990a). For this reason in Chapter 10 of this dissertation we have further attempted to study the possible involvement of 5-Hf lA• 5-Hf,., 5-Hf1c and/or 5-Hf10 receptors in the distribution of common carotid artery blood flow into arteriolar (nutrient) and arteriovenous anastomotic (non-nutrient) parts in the pig by using indorenate~ a tryptamine derivative with antihypenensive properties (Hong et al., 1978; Hong, 1981) as well as a high affinity for the 5-Hf 1A binding site (Dompert et al., 1985; Hoyer et al., 1985). Ketanserin. methiothepin and metergolioe were used as potential antagonists. Finally, in view of the involvement of cranial arteriovenous anastomoses constriction as a possible mechaoism for antirnigraine action (see Saxena and Ferrari, 1989). the last part of the present dissertation is devoted to the analysis of the effects of dihydroergotamine (an established antimigraine drug). and S9977 (a potential antimigraine drug) on the distribution of the porcine total common carotid artery blood flow (Chapter 11), and accordingly, highligbts the possible mechanisms that migbt explain the action of the antimigraine drug

The Current Landscape of Pitfalls in Ontologies

A growing number of ontologies are already available thanks to development initiatives in many different fields. In such ontology developments, developers must tackle a wide range of difficulties and handicaps, which can result in the appearance of anomalies in the resulting ontologies. Therefore, ontology evaluation plays a key role in ontology development projects. OOPS! is an on-line tool that automatically detects pitfalls, considered as potential errors or problems, and thus may help ontology developers to improve their ontologies. To gain insight in the existence of pitfalls and to assess whether there are differences among ontologies developed by novices, a random set of already scanned ontologies, and existing well-known ones, data of 406 OWL ontologies were analysed on OOPS!’s 21 pitfalls, of which 24 ontologies were also examined manually on the detected pitfalls. The various analyses performed show only minor differences between the three sets of ontologies, therewith providing a general landscape of pitfalls in ontologies

Serotonin receptors as cardiovascular targets

Serotonin exerts complex effects in the cardiovascular system, including hypotension or hypertension, vasodilatation or vasoconstriction, and/or bradycardia or tachycardia; the eventual response depends primarily on the nature of the 5-HT receptors involved. In the light of current 5-HT receptor classification, the authors reanalyse the cardiovascular responses mediated by 5-HT receptors and discuss the established and potential therapeutic applications of 5-HT ligands in the treatment of some cardiovascular pathologie

Is selective 5-HT1F receptor agonism an entity apart from that of the triptans in antimigraine therapy?

Migraine is a neurovascular disorder that involves activation of the trigeminovascular system and cranial vasodilation mediated by release of calcitonin gene-related peptide (CGRP).The gold standard for acute migraine treatment are the triptans, 5-HT1B/1D/(1F) receptor agonists. Their actions are thought to be mediated through activation of: (i) 5-HT1B receptors in cranial blood vessels with subsequent cranial vasoconstriction; (ii) prejunctional 5-HT1D receptors on trigeminal fibers that inhibit trigeminal CGRP release; and (iii) 5-HT1B/1D/1F receptors in central nervous system involved in (anti)nociceptive modulation. Unfortunately, coronary arteries also express 5-HT1B receptors whose activation would produce coronary vasoconstriction; hence, triptans are contraindicated in patients with cardiovascular disease. In addition, since migraineurs have an increased cardiovascular risk, it is important to develop antimigraine drugs devoid of vascular (side) effects.Ditans, here defined as selective 5-HT1F receptor agonists, were developed on the basis that most of the triptans activate trigeminal 5-HT1F receptors, which may explain part of the triptans' antimigraine action. Amongst the ditans, lasmiditan: (i) fails to constrict human coronary arteries; and (ii) is effective for the acute treatment of migraine in preliminary Phase III clinical trials. Admittedly, the exact site of action is still unknown, but lasmiditan possess a high lipophilicity, which suggests a direct action on the central descending antinociceptive pathways. Furthermore, since 5-HT1F receptors are located on trigeminal fibers, they could modulate CGRP release.This review will be particularly focussed on the similarities and differences between the triptans and the ditans, their proposed sites of action, side effects and their cardiovascular risk profile

Gender aspects of CGRP in migraine

Background: Migraine is two to three times more prevalent in women than in men, but the mechanisms involved in this gender disparity are still poorly understood. In this respect, calcitonin gene-related peptide (CGRP) plays a key role in migraine pathophysiology and, more recently, the functional interactions between ovarian steroid hormones, CGRP and the trigeminovascular system have been recognized and studied in more detail. Aims: To provide an overview of CGRP studies that have addressed gender differences utilizing animal and human migraine preclinical research models to highlight how the female trigeminovascular system responds differently in the presence of varying ovarian steroid hormones. Conclusions: Gender differences are evident in migraine. Several studies indicate that fluctuations of ovarian steroid hormone (mainly estrogen) levels modulate CGRP in the trigeminovascular system during different reproductive milestones. Such interactions need to be considered when conducting future animal and human experiments, since these differences may contribute to the development of gender-specific therapies

CGRP inhibitors for migraine prophylaxis: a safety review

Introduction: Since calcitonin gene-related peptide (CGRP) plays an important role in the pathophysiology of migraine via the activation of the trigeminovascular system, the newest prophylactic treatments directly block CGRP or its receptor. However, the safety of these novel antimigraine drugs is not yet sufficiently established. Areas covered: Based on the blockade of CGRP or its receptor, this review considers: (i) the effects of the novel prophylactic antimigraine drugs (i.e. gepants and monoclonal antibodies) in clinical trials; and (ii) the potentially negative effects of blocking CGRP or its receptor in terms of safety. Expert opinion: In the last decade, clinical trials have demonstrated the efficacy of new drugs for the preventive treatment of migraine which aim to (i) block CGRP or its receptor; (ii) increase tolerability as compared to the currently available prophylactics; and/or (iii) be more effective and safer than other treatments. However, these trials are limited to study the safety on the short term, and a cardiovascular risk with prolonged use cannot be excluded. Clearly, basic science experimental studies and long-term clinical trials (i.e. Phase IV) are required to delineate the safety of the newest prophylactic antimigraine drugs without causing unwanted side effects due to chronic CGRP (receptor) blockade

Pharmacological evidence that α1- and α2-adrenoceptors mediate vasoconstriction of carotid arteriovenous anastomoses in anaesthetized pigs

1. Vasoconstriction of carotid arteriovenous anastomoses may be involved in the therapeutic action of acutely acting antimigraine agents, including the triptans and ergot alkaloids. While 5-HT(1B/1D) receptors mediate the effect of triptans, ergotamine and dihydroergotamine also interact with α-adrenoceptors. In the present study, we investigated the potential role of α1- and α2-adrenoceptors in mediating vasoconstriction of carotid arteriovenous anastomoses in anaesthetized pigs. 2. Ten minute intracarotid infusions of phenylephrine (1, 3 and 10 μg kg-1 min-1) or BHT 933 (3, 10 and 30 μg kg-1 min-1) produced dose-dependent decreases in total carotid and arteriovenous anastomotic conductances; no changes were observed in the capillary fraction. 3. The carotid vascular effects of phenylephrine and BHT 933 were selectively abolished by prazosin (100 μg kg-1, i.v.) and rauwolscine (300 μg kg-1, i.v.), respectively. The responses to phenylephrine and BHT 933 were not affected by the selective 5-HT(1B/1D) receptor antagonist GR127935 (500 μg kg-1, i.v.). 4. These results show that both α1- and α2-adrenoceptors can mediate vasoconstriction of carotid arteriovenous anastomoses in anaesthetized pigs. Since vasoconstrictor activity in this in vivo model is predictive of anti-migraine activity, an agonist activity at particularly the α2-adrenoceptor subtypes, in view of their less ubiquitous nature, could provide migraine abortive potential. Thus, the present results may aid further understanding of the mode of action of some current antimigraine agents and may eventually be helpful in the development of future treatment in migraine

Potential Mechanisms Involved in Palmitoylethanolamide-Induced Vasodepressor Effects in Rats

Palmitoylethanolamide is an endogenous lipid that exerts complex vascular effects, enhances the effects of endocannabinoids and induces a direct hypotension, but the mechanisms involved have been poorly explored. Hence, this study investigated in Wistar pithed rats the role of CB1, CB2, TRPV1 and GPR55 receptors in the inhibition by palmitoylethanolamide of the vasopressor responses produced by sympathetic stimulation or exogenous noradrenaline. Frequency- and dose-dependent vasopressor responses were analysed before and during intravenous (i.v.) continuous infusions of palmitoyle

Pharmacological analysis of the increases in heart rate and diastolic blood pressure produced by (S)-isometheptene and (R)-isometheptene in pithed rats

Background: Isometheptene is a sympathomimetic drug effective in acute migraine treatment. It is composed of two enantiomers with diverse pharmacological properties. This study investigated in pithed rats the cardiovascular effects of (S)- isometheptene and (R)-isometheptene, and the pharmacological profile of the more potent enantiomer. Methods: The effects of i.v. bolus injections (0.03, 0.1, 0.3, 1 and 3 mg/kg) of isometheptene racemate, (S)-isometheptene or (R)-isometheptene on heart rate and blood pressure were analyzed in control experiments. The enantiomer producing more pronounced tachycardic and/or vasopressor responses was further analyzed in rats receiving i.v. injections of prazosin (0.1 mg/kg), rauwolscine (0.3 mg/kg), propranolol (1 mg/kg) or intraperitoneal reserpine (5 mg/kg, -24 h). Results: Compared to (R)-isometheptene, (S)-isometheptene produced greater vasopressor responses, whilst both compounds equipotently increased heart rate. The tachycardic responses to (S)-isometheptene were abolished after propranolol, but remained unaffected by the other antagonists. In contrast, the vasopressor responses to (S)-isometheptene were practically abolished after prazosin. Interestingly, after reserpine, the tachycardic responses to (S)-isometheptene were abolished, whereas its vasopressor responses were attenuated and subsequently abolished by prazosin. Conclusions: The different cardiovascular effects of the isometheptene enantiomers are probably due to differences in their mechanism of action, namely: (i) a mixed sympathomimetic action for (S)-isometheptene (a tyramine-like action and a direct stimulation of α1-adrenoceptors); and (ii) exclusively a tyramine like action for (R)-isometheptene. Thus, (R)-isometheptene may represent a superior therapeutic benefit as an antimigraine agent

Dihydroergotamine inhibits the vasodepressor sensory CGRPergic outflow by prejunctional activation of α2-adrenoceptors and 5-HT1 receptors

Background: Dihydroergotamine (DHE) is an antimigraine drug that produces cranial vasoconstriction and inhibits trigeminal CGRP release; furthermore, it inhibits the vasodepressor sensory CGRPergic outflow, but the receptors involved remain unknown. Prejunctional activation of α2A/2C-adrenergic, serotonin 5-HT1B/1F, or dopamine D2-like receptors results in inhibition of this CGRPergic outflow. Since DHE displays affinity for these receptors, this study investigated the pharmacological profile of DHE-induced inhibition of the vasodepressor sensory CGRPergic outflow. Methods: Pithed rats were pretreated i.v. with hexamethonium (2 mg/kg·min) followed by continuous infusions of methoxamine (20 μg/kg·min) and DHE (3.1 μg/kg·min). Then, stimulus-response curves (spinal electrical stimulation; T9-T12) or dose-response curves (i.v. injections of α-CGRP) resulted in frequency-dependent or dose-dependent decreases in diastolic blood pressure. Results: DHE inhibited the vasodepressor responses to electrical stimulation (0.56–5.6 Hz), without affecting those to i.v. α-CGRP (0.1–1 μg/kg). This inhibition by DHE (not produced by the methoxamine infusions): (i) was abolished by pretreatment with the combination of the antagonists rauwolscine (α2-adrenoceptor; 310 μg/kg) plus GR127935 (5-HT1B/1D; 31 μg/kg); and (ii) remained unaffected after rauwolscine (310 μg/kg), GR127935 (31 μg/kg) or haloperidol (D2-like; 310 μg/kg) given alone, or after the combination of rauwolscine plus haloperidol or GR127935 plus haloperidol at the aforementioned doses. Conclusion: DHE-induced inhibition of the vasodepressor sensory CGRPergic outflow is mainly mediated by prejunctional rauwolscine-sensitive α2-adrenoceptors and GR127935-sensitive 5-HT1B/1D receptors, which correlate with α2A/2C-adrenoceptors and 5-HT1B receptors, respectively. These findings suggest that DHE-induced inhibition of the perivascular sensory CGRPergic outflow may facilitate DHE’s vasoconstrictor properties resulting in an increased vascular resistance