Evidence that the novel antihypertensive agent, flesinoxan, causes differential sympathoinhibition and also increases vagal tone by a central action

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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...

Section: Resultsmentioning

confidence: 99%

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

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“…It is now well established that 5-HTIA receptor agonists lower blood pressure via a reduction in sympathetic output (Ramage & Fozard, 1987;Ramage et al, 1988;Saxena & Villalon, 1990). Activation of central 5-HT1A receptors causes inhibition (Colino & Halliwell, 1987;Sprouse & Aghajanian, 1987) of neuronal activity, which in the dorsal raphe is thought to be mediated via a somatodendritic autoreceptor (Verge et al, 1985;Sprouse & Aghajanian, 1987).…”

Section: Discussionmentioning

confidence: 99%

“…The 5-hydroxytryptaminelA (5-HT1,J receptor agonists, flesinoxan and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), have been shown to lower arterial blood pressure in rats (Gradin et al, 1985;Martin & Lis, 1985;Fozard et al, 1987;, cats (McCall et al, 1987;Ramage & Fozard, 1987;Ramage et al, 1988;Wouters et al, 1988b) and dogs (Laubie et al, 1989) by a central action. In the rat, brain areas that contain 5-HTlA binding sites are the hypothalamus, midbrain raphe nuclei, the nucleus tractus solitarius and medullary raphe nuclei (Pazos & Palacios, 1985;Verge et al, 1986;Thor et al, 1990).…”

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

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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.

“…Data are illustrated only for single experiments with 8-OH-DPAT and DP-5-CT, (Figures 2 and 3) and the mean changes on gastric motility were + 16 ± 6 mm min' and + 2 ± 4 mm min-', respectively. (0) (Ramage & Fozard, 1987;Ramage et al, 1988;Ramage & Wilkinson, 1989). It has also been demonstrated that the sympathoinhibitory action of i.v.…”

Section: Analysis Of Datamentioning

confidence: 99%

Comparison of the effects of IVth ventricular administration of some tryptamine analogues with those of 8‐OH‐DPAT on autonomic outflow in the anaesthetized cat

Shepheard

Jordan

Ramage

1994

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1 The present study compares the effects on representative autonomic outflows of IVth ventricular application of tryptamine analogues which act at 5-HT, receptors with 8-hydroxy-2-(di-npropylamino)tetralin (8-OH-DPAT). 2 Cumulative doses of 8-OH-DPAT, N,N-di-n-propyl-5-carboxamidotryptamine (DP-5-CT) and 5-carboxamidotryptamine (5-CT, 2.5-40 nmol kg-'), sumatriptan (10-160 nmol kg-'), indorenate (100-800nmolkg-'), 5-hydroxytryptamine (5-HT, 20-640nmolkg-') both alone and in the presence of cinanserin (0.1 mg kg-') were given into the IVth ventricle of cats which were anaesthetized with a mixture of a-chloralose and pentobarbitone sodium, neuromuscularly blocked and artificially ventilated. Recordings were made of arterial blood pressure, heart rate, renal, cardiac, splanchnic and phrenic nerve activities, femoral arterial flow, tracheal and intragastric pressures. 3 Central application of each of the agonists evoked significant falls in arterial blood pressure. In addition 8-OH-DPAT, DP-5-CT, 5-CT and 5-HT all evoked a differential inhibition of sympathetic nerve activities, with renal nerve activity being the most sensitive and cardiac nerve activity the least sensitive. In the dose-ranges used, administration of sumatriptan evoked reductions only in renal and splanchnic nerve activities whilst indorenate reduced activity in all three sympathetic nerves to a similar extent.4 The effect of the agonists on heart rate was more inconsistent than the effects on sympathetic outflow. IVth ventricular application of 5-CT and sumatriptan were without effect on heart rate whilst 8-OH-DPAT, DP-5-CT, indorenate and 5-HT alone and in the presence of cinanserin all evoked significant bradycardias. However, whilst atropine partially reversed the bradycardias evoked by 8-OH-DPAT and only slightly reversed those caused by indorenate, atropine was without effect on those evoked by DP-5-CT or 5-HT. 5 None of the analogues tested had significant effects on gut motility, phrenic nerve discharge or tracheal pressure. 8-OH-DPAT, DP-5-CT, indorenate and 5-HT were without effect on femoral arterial conductance. However, following pretreatment with cinanserin, 5-HT evoked a significant reduction in femoral arterial conductance. At its highest dose, sumatriptan evoked a significant increase in femoral arterial conductance as did 5-CT at the 20nmolkg-' dose. 6 It is concluded that the present data support the view that 5-HTIA receptors at the level of the brainstem are involved in the central sympathoinhibitory effects caused by intravenous administration of 5-HTA agonists. Further, brainstem 5-HTIA receptors play an important role in the control of renal sympathetic outflow while brainstem 5-HT2 receptors are involved in the control of skeletal muscle and/or skin blood flow. Selective tryptamine agonists for 5-HTIA receptors differ from non-tryptamine agonists in that they do not cause an increase in central cardiac vagal tone.