Asunción Morán

Characterization of prejunctional 5‐HT1 receptors that mediate the inhibition of pressor effects elicited by sympathetic stimulation in the pithed rat

1 A study was made of the effects of 5‐carboxamidotryptamine (5‐CT) on pressor responses induced in vivo by electrical stimulation of the sympathetic outflow from the spinal cord of pithed rats. All animals had been pretreated with atropine. Sympathetic stimulation (0.1, 0.5, 1 and 5 Hz) resulted in frequency‐dependent increases in blood pressure. Intravenous infusion of 5‐CT at doses of 0.01, 0.1 and 1 μg kg−1 min−1 reduced the pressor effects obtained by electrical stimulation. The inhibitory effect of 5‐CT was significantly more pronounced at lower frequencies of stimulation. In the present study we characterized the pharmacological profile of the receptors mediating the above inhibitory effect of 5‐CT. 2 The inhibition induced by 0.01 μg kg−1 min−1 of 5‐CT on sympathetically‐induced pressor responses was partially blocked after i.v. treatment with methiothepin (10  μg kg−1), WAY‐100,635 (100 μg kg−1) or GR127935T (250 μg kg−1), but was not affected by cyanopindolol (100 μg kg−1). 3 The selective 5‐HT1A receptor agonist 8‐OH‐DPAT and the selective 5‐HT1B/1D receptor agonists sumatriptan and L‐694,247 inhibited the pressor response, whereas the 5‐HT1B receptor agonists CGS‐12066B and CP‐93,129 and the 5‐HT2C receptor agonist m‐CPP did not modify the pressor symapthetic responses. 4 The selective 5‐HT1A receptor antagonist WAY‐100,635 (100 μg kg−1) blocked the inhibition induced by 8‐OH‐DPAT and the selective 5‐HT1B/1D receptor antagonist GR127935T (250 μg kg−1) abolished the inhibition induced either by L‐694,247 or sumatriptan. 5 None of the 5‐HT receptor agonists used in our experiments modified the pressor responses induced by exogenous noradrenaline (NA). 6 These results suggest that the presynaptic inhibitory action of 5‐CT on the electrically‐induced pressor response is mediated by both r‐5‐HT1D and 5‐HT1A receptors.

Inhibitory 5‐hydroxytryptamine receptors involved in pressor effects obtained by stimulation of sympathetic outflow from spinal cord in pithed rats

1 A study was made of the effects of 5‐hydroxytryptamine (5‐HT) on pressor response induced in vivo by electrical stimulation of the sympathetic outflow from the spinal cord of pithed rats. All animals had been pretreated with atropine. Intravenous infusion of 5‐hydroxytryptamine at doses of 10 and 20 μg kg−1 min−1 reduced the pressor effects obtained by electrical stimulation at intervals of 10 min over the 1 h of infusion. 2 This inhibitory action of 5‐HT was depressed by cyproheptadine and methiothepin but was not modified by ketanserin or MDL‐72222. By contrast, the inhibitory action of 5‐HT was lost in pithed rats that had been pretreated with exogenous noradrenaline. 3 The 5‐HT1 receptor agonist 5‐carboxamidotryptamine (5‐CT) caused an inhibition of the pressor response, whereas the 5‐HT3 receptor agonist, 1‐phenylbiguanide, produced a variable but significant increase in the pressor response. The 5‐HT2 receptor agonist, m‐CPP, did not modify the pressor sympathetic response. 4 Our results suggest that 5‐hydroxytryptamine interferes with sympathetic neurotransmission by inhibiting pressor effects as a result of stimulation of the complete sympathetic outflow, and that this inhibition is mainly through a presynaptic 5‐HT1 mechanism.

5-Hydroxytryptamine inhibits the tachycardia induced by selective preganglionic sympathetic stimulation in pithed rats.

It has been shown in several species that serotonin (5-hydroxytryptamine; 5-HT) is able to inhibit the responses produced by sympathetic stimulation in a wide variety of blood vessels and other organs, including the heart. However, in pithed rats, the analysis of potential sympatho-inhibitory actions of 5-HT is hampered by the fact that 5-HT (given as i.v. bolus injections) produces tachycardia per se. Moreover, most studies have investigated 5-HT-induced sympatho-inhibition at only one frequency of stimulation. Thus, the present study set out to find the experimental conditions to overcome these problems. In this regard, we analyzed the potential ability of 5-HT, administered as i.v. continuous infusions, to inhibit the tachycardia caused by stimulation of the preganglionic (C7-T1) sympathetic outflow in pithed rats. Sympathetic cardiostimulation (0.01-3 Hz) resulted in frequency-dependent increases in heart rate; these responses were potentiated after desipramine (50 microg/kg, i.v.). During continuous infusions of 5-HT (3.1-10 microg/kg.min, i.v.), but not saline, the sympathetically-induced tachycardia was dose-dependently inhibited in both control and desipramine-pretreated rats. This inhibitory effect of 5-HT was significantly more pronounced at lower frequencies of stimulation. In contrast, the above infusions of 5-HT did not inhibit the tachycardia induced by i.v. bolus injections of noradrenaline in both control and desipramine-pretreated rats. Taken together, the above findings confirm that 5-HT induces inhibition of the sympathetic chronotropic outflow in the rat by acting at receptors located prejunctionally, without evoking tachycardia, over a wide range of stimulation frequencies.

Analgesic, antipyretic and anti-inflammatory activity of the essential oil of Artemisia caerulescens subsp. gallica

The essential oil of Artemisia caerulescens subsp. gallica was observed to have analgesic, antipyretic and anti-inflammatory actions when administered intraperitoneally to rats and mice at doses one-fourth to one-third that of its LD50 of 1.35 ml/kg. Lysine acetylsalicylate was used as a reference compound.

Renal vasoconstrictor response to 5-hydroxytryptamine in the in situ autoperfused rat kidney: involvement of angiotensin II and the 5-HT2 receptor activation

Using a number of agonist and antagonist compounds, we attempted to characterize the responses and receptors involved in the effects of 5-hydroxytryptamine (5-HT) in the in situ autoperfused rat kidney. An intra-arterial (i.a.) bolus injection of 5-HT (0.0125 to 0.1 microg/kg) increased renal perfusion pressure in a dose-dependent way but did not change the systemic blood pressure. The 5-HT2 receptor agonist, (1-(3-chlorophenyl) piperazine), m-CPP, caused a local vasoconstrictor effect in the autoperfused rat kidney. An intra-arterial injection of 5-carboxamidotryptamine, 5-CT and 1-(m-chlorophenyl)-biguanide (m-CPBG) did not modify the renal perfusion pressure. The vasoconstrictor effect elicited by 5-HT and m-CPP was significantly decreased by ritanserin, enalapril and losartan but was not modified by prazosin, propranolol or indomethacin pretreatment. Our data suggest that the vasoconstrictor serotonergic response induced in the in situ autoperfused rat kidney is mediated through angiotensin II activation by a local 5-HT2 receptor mechanism.

Sedating and antipyretic activity of the essential oil of Calamintha sylvatica subsp. ascendens

The essential oil of Calamintha sylvatica subsp. ascendens exerts significant sedating and antipyretic activities in the rat. The components responsible for these activities appear to be the major monoterpenes present: pulegone, menthone and eucalyptol (1,8-cineol).

Antihypertensive effect of some oxazolo[3,2-a]pyridines, thiazolo[3,2-a]pyridines and pyrido[2,1-b]oxazines in conscious spontaneously hypertensive rats

The antihypertensive activity of eighteen oxazolo[3,2‐a]pyridine, fhiazolo[3,2‐a]pyridine and pyrido[2,1‐b]oxazine derivatives has been evaluated in conscious spontaneously hypertensive rats (SHRs), and compared with that of nifedipine, used as reference.

Peripheral 5-HT1D and 5-HT7 serotonergic receptors modulate sympathetic neurotransmission in chronic sarpogrelate treated rats

5-HT₂ receptor activation induces vasoconstriction, hypertension and platelet aggregation; therefore, its blocking may be useful in cardiovascular diseases, probably due to alterations in the modulation of serotonergic system. The aim of this study was to evaluate whether 5-HT₂ receptor blockade changes serotonergic modulation of sympathetic neurotransmission in pithed rats. Serotonergic modulation of sympathetic neurotransmission was investigated in Wistar rats treated with sarpogrelate, a 5-HT₂ receptor antagonist, during 14 days (30 mg/kg/day). After central nervous system destruction, we conducted electrical stimulation throughout the spinal cord flow to study the 5-HT-related products action on adrenergic system. 5-Hydroxytryptamine exerted inhibition of sympathetic outflow in sarpogrelate-treated pithed rats. This effect was mimicked and enhanced by 5-CT (5-HT₁/₇ receptor agonist). L-694,247 and AS-19, 5-HT₁D and 5-HT₇ receptor agonists respectively, reproduced this action. Pretreatment with LY310762+SB258719 (5-HT₁D and 5-HT₇ receptor antagonists, respectively) completely abolished 5-CT inhibitory action. The nature of this action was prejunctional since these agonists did not modify the pressor responses induced by exogenous noradrenaline. Western Blot analysis confirmed a higher expression of 5-HT₁D receptors in sarpogrelate-treated rats. Experimental 5-HT₂ receptor blockade induces changes in the 5-HT receptors involved in the serotonergic inhibition of sympathetic-induced pressor responses. Prejunctional activation of 5-HT₁D and 5-HT₇ receptors induces a significantly higher serotonergic inhibition on adrenergic neurotransmission in sarpogrelate-treated pithed rats. The antagonism of 5-HT₂ receptors produces an enhancement of serotonergic sympathoinhibitory effect, which may explain the beneficial effects of this blockade in cardiovascular disorders where 5-hydroxytryptamine plays a crucial role.

Diabetes-induced changes in the 5-hydroxytryptamine inhibitory receptors involved in the pressor effect elicited by sympathetic stimulation in the pithed rat

1 We investigated the effect of alloxan‐induced diabetes on the inhibitory mechanisms of 5‐hydroxytryptamine (5‐HT) in the pressor responses induced by stimulation of sympathetic vasopressor outflow in pithed rats, and analysed the type and/or subtype of 5‐HT receptors involved. 2 Diabetes was induced in male Wistar rats by a single s.c. injection of alloxan, then 4 weeks later, they were anaesthetized, pretreated with atropine and pithed. Electrical stimulation of the sympathetic outflow from the spinal cord (0.1, 0.5, 1 and 5 Hz) resulted in frequency‐dependent increases in blood pressure. 3 Intravenous infusions of 5‐HT (1–80 μg kg−1 min−1) reduced the pressor effects obtained by electrical stimulation. The 5‐HT1 receptor agonist 5‐carboxamidotryptamine, 5‐CT (5 μg kg−1 min−1), caused an inhibition of the pressor response, whereas the selective 5‐HT2 receptor agonist, α‐methyl‐5‐HT (5 μg kg−1 min−1) and the selective 5‐HT3 receptor agonist, 1‐phenylbiguanide (40 μg kg−1 min−1), did not modify the sympathetic pressor responses. 5‐HT had no effect on exogenous noradrenaline (NA)‐induced pressor responses. 4 The inhibition of electrically induced pressor responses by 5‐HT (10 μg kg−1 min−1) was unable to be elicited after i.v. treatment with methiothepin (100 μg kg−1) because of the marked inhibition produced by methiothepin alone. The 5‐HT‐induced inhibition was blocked after i.v. administration of WAY‐100,635 (100 μg kg−1) and not affected by ritanserin (1 mg kg−1), MDL 72222 (2 mg kg−1). 5 The selective 5‐HT1A receptor agonist, 8‐hydroxydipropylaminotretalin hydrobromide (8‐OH‐DPAT) (5–20 μg kg−1 min−1) but neither the rodent 5‐HT1B receptor agonist, CGS‐12066B (5 μg kg−1 min−1), nor the selective nonrodent 5‐HT1B and 5‐HT1D receptor agonist, L‐694,247 (5 and 40 μg kg−1 min−1), inhibited the electrically induced pressor response. The selective 5‐HT1A receptor antagonist, WAY‐100,635 (100 μg kg−1), blocked the inhibition induced by 8‐OH‐DPAT (10 μg kg−1 min−1). 8‐OH‐DPAT had no effect on exogenous NA‐induced pressor responses. 6 Experimental diabetes produces changes in the inhibitory effect induced by 5‐HT on electrically induced sympathetic pressor responses, such that the inhibitory action induced by 5‐HT in diabetic pithed rats is mediated by prejunctional 5‐HT1A receptors.

Vasoconstrictor Responses to 5-Hydroxytryptamine in the Autoperfused Hindquarters of Spontaneously Hypertensive Rats

In this work we studied the responses and receptors involved in the effects of intra-arterial 5-hydroxytryptamine (5-HT) in the in situ autoperfused hindquarters of spontaneously hypertensive rats (SHR). Intra-arterial administration of the highest doses (50–1,000 ng/kg) produced a vasoconstrictor effect that was inhibited by ritanserin (a selective 5-HT2 receptor antagonist), SB 206553 (a selective 5-HT2B/2C receptor antagonist) and spiperone (a nonspecific 5-HT1/2A receptor antagonist), and was mimicked by α-methyl-5-HT (a selective 5-HT2 receptor agonist) and m-CPP (a selective 5-HT2C receptor agonist), but not by the intra-arterial administration of BW 723C86, a selective 5HT2B receptor agonist. SB 206553 and spiperone inhibited α-methyl-5HT-induced vasoconstriction in the hindquarters of SHR. Our data suggest that the vasoconstrictor response induced by 5-HT in the autoperfused hindquarters of SHR is mainly mediated by the activation of 5-HT2A and 5-HT2C receptors.