Flesinoxan lowers blood pressure and heart rate in cats via 5-HT1A receptors

Self Cite

1 The effects of electrical stimulation and microinjections (90 nl) of the 5-HTlA receptor agonists, flesinoxan and 8-hydroxy-24di-n-propylamino) tetralin (8-OH-DPAT), and glutamate into the raphe obscurus on blood pressure, heart rate and phrenic nerve activity (central inspiratory drive) were investigated in rats anaesthetized with a-chloralose. 2 Electrical stimulation of the raphe obscurus caused a rise in blood pressure which was associated with bradycardia, while glutamate (2.7 nmol) caused only a rise in blood pressure. 3 Flesinoxan (1.3 nmol) and 8-OH-DPAT (0.7 nmol) increased blood pressure by 9 + 1 and 14 + 2 mmHg, respectively and did not affect heart rate. For both agonists the effect on blood pressure was shown to be dose-dependent; again no effect on the heart rate was observed over the dose-ranges chosen. 4 Microinjections of the non-selective 5-HT1A receptor antagonists, (± )pindolol (2.7 nmol) or methiothepin (5.2 nmol), into the raphe obscurus prevented the increase in blood pressure caused by microinjection of flesinoxan. However, (± )-pindolol caused a sustained rise in blood pressure of 15 + 1 mmHg while methiothepin caused a transient rise in blood pressure. Neither drugs affected heart rate. The ability of methiothepin to attenuate the pressor effect of flesinoxan was found to be partially reversed after 30 min. 5 It is suggested that activation of 5-HTlA receptors within the raphe obscurus can cause sympathoexcitation.

Section: Discussionsupporting

confidence: 48%

Section: Introductionmentioning

confidence: 99%

Pressor effects following microinjection of 5‐HT_1A receptor agonists into the raphe obscurus of the anaesthetized rat

Dreteler¹,

Wouters²,

Saxena³

et al. 1991

Self Cite

“…There is a large amount of evidence to suggest that 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and flesinoxan activate 5-HTlA receptors to cause their hypotensive action McCall et al, 1987;Ramage & Fozard, 1987;Doods et al, 1988;Wouters et al, 1988;Laubie et al, 1989) and that such an action is entirely within the central nervous system. However, only moderate thoracic preganglionic sympathoinhibition is observed in anaesthetized cats (Ramage & Fozard, 1987;Ramage et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

Evidence that different regional sympathetic outflows vary in their sensitivity to the sympathoinhibitory actions of putative 5‐HT_1A and α₂‐adrenoceptor agonists in anaesthetized cats

Ramage

Wilkinson

1989

1 An investigation was carried out to determine whether the centrally acting hypotensive drugs whose mechanisms of action are due either to activation of 5-HTIA receptors (flesinoxan, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and urapidil also an a,-adrenoceptor antagonist) or to activation of M2-adrenoceptors (clonidine and moxonidine) cause differential sympathoinhibition. 2 Cats were anaesthetized with a-chloralose and simultaneous recordings were made of whole cardiac, splanchnic and renal nerve activity, blood pressure and heart rate. Cumulative doseresponse (i.v.) curves were constructed in separate experiments for the above hypotensive agents on these parameters. 3 Renal nerve activity was found to be more sensitive to the sympathoinhibitory action of flesinoxan and 8-OH-DPAT when compared with cardiac nerve activity, whereas the reverse was observed for clonidine and moxonidine, cardiac being more sensitive than renal nerve activity. Splanchnic nerve activity was similarly affected by all drugs. Furthermore at the highest dose, all drugs tended to cause complete inhibition in all regional sympathetic nerve outflows. 4 Urapidil differed from all the above hypotensive drugs in that it caused a similar degree of sympathoinhibition in all sympathetic outflows at all doses. It is suggested that this may be due to the ability of urapidil to block central a,-adrenoceptors in addition to stimulation of 5-HTlA receptors. IntroductionThere is a large amount of evidence to suggest that 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and flesinoxan activate 5-HTlA receptors to cause their hypotensive action McCall et al., 1987;Ramage & Fozard, 1987;Doods et al., 1988;Wouters et al., 1988;Laubie et al., 1989) and that such an action is entirely within the central nervous system. However, only moderate thoracic preganglionic sympathoinhibition is observed in anaesthetized cats (Ramage & Fozard, 1987;Ramage et al., 1988). One explanation for this lack of correlation between the thoracic sympathoinhibitory action and the hypotensive action of 8-OH-DPAT and flesinoxan is that these drugs could be having a more potent sympathoinhibitory action at a different level or levels of sympathetic outflow. In this respect the sympathoinhibitory action of flesinoxan on renal ' Author for correspondence.outflow, when compared with other sympathetic outflows has been shown to be greater (Ramage et al., 1988). However a weakness of this latter investigation was that the recordings made from different sympathetic outflows were carried out in separate animals and further, that some of the outflows were recorded from preganglionic, while others were recorded from postganglionic nerves. In order to overcome these weaknesses the present experiments were carried out in which the sympathoinhibitory actions of flesinoxan and 8-OH-DPAT were studied on cardiac, splanchnic and renal nerve activity recorded simultaneously in the same animal. Further, the effects of other hypotensive agents, urapidil (which has also been shown to bind...

“…This is in good agreement with the rank order of affinities of these compounds for 5-HTIAreceptors obtained from radioligland binding studies. The reported pICmo or Ki values are 8.8, 8.4 and 8.0, respectively (Gross et al, 1987;Wouters et al, 1988). In addition, radioligand binding experiments have demonstrated that with the exception of 5-methyl-urapidil, which has high affinity for al-adrenoceptors, the 4 synthetic agonists under study are relatively selective for 5-HTlA-receptors (Gross et al, 1987;Wouters et al, 1988;Hoyer, 1991).…”

Section: Discussionmentioning

confidence: 99%

“…Two other compounds have been identified that appear to act in such a novel manner, urapidil (Sanders & Jurna, 1985;Ramage, 1986;Sanders et al, 1990) and flesinoxan (Wouters et al, 1988). Whilst urapidil itself had a relatively low affinity for 5-HTIA receptors (Fozard & Mir, 1987), 5-methyl-urapidil and flesinoxan have affinities in the low nanomolar range and are potent hypotensive agents in animals (Gross et al, 1987;Mandal et al, 1990;Wouters et al, 1988). More recently, it has been reported that flesinoxan also has anxiolytic and perhaps even anti-depressant activity Schipper et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

Differential effects of centrally‐active antihypertensives on 5‐HT_1A receptors in rat dorso‐lateral septum, rat hippocampus and guinea‐pig hippocampus

Leishman

Boeijinga²,

Galvan³

1994

1 The electrophysiological responses elicited by 5-hydroxytryptaminelA-(5-HTIA) receptor agonists in rat and guinea-pig CAl pyramidal neurones and rat dorso-lateral septal neurones were compared in vitro by use of conventional intracellular recording techniques. 2 In the presence of 1 jtM tetrodotoxin (TTX), to prevent indirect effects, 5-HT, N,N-dipropyl-5-carboxamidotryptamine (DP-5-CT) and 8-hydroxy-2(di-n-propylamino) tetralin (8-OH-DPAT) hyperpolarized the neurones from rat and guinea-pig brain. 3 The hypotensive drug flesinoxan, a selective 5-HTA receptor agonist, hyperpolarized neurones in all three areas tested; however, another hypotensive agent with high affinity at 5-HTlA-receptors, 5-methylurapidil, hyperpolarized only the neurones in rat hippocampus and septum. 4 In guinea-pig hippocampal neurones, 5-methyl-urapidil behaved as a 5-HTlA-receptor antagonist. 5 The relative efficacies (5-HT = 1) of DP-5-CT, 8-OH-DPAT, flesinoxan and 5-methyl-urapidil at the three sites were: rat hippocampus, 1.09, 0.7, 0.5 and 0.24; rat septum, 0.88, 0.69, 0.82 and 0.7; guinea-pig hippocampus, 1.0, 0.69, 0.89 and 0, respectively. 6 It is concluded that the hypotensive agents flesinoxan and 5-methyl-urapidil appear to have different efficacies at 5-HTIA receptors located in different regions of the rodent brain. Whether these regional and species differences arise from receptor plurality or variability in intracellular transduction mechanisms remains to be elucidated.