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At least 163 records · Page 9Linked to original sources
PubMed2005

Peripheral sympatholytic actions of four AT1 antagonists: are they relevant for long-term antihypertensive efficacy?

BACKGROUND: Angiotensin II causes hypertension not only by direct constriction of vascular smooth muscle, but also by facilitating the release of noradrenaline from sympathetic terminals and by enhancing vascular noradrenaline sensitivity. AT1 receptor antagonists attenuate all these actions, but display some evidence of substance-related selectivities. OBJECTIVE: The contribution of pre- or postsynaptic impairment of sympathetic transmission to long-term antihypertensive efficacy should be determined for four structurally different, clinically approved AT1 antagonists. DESIGN: Spontaneously hypertensive rats were treated with candesartan, eprosartan, irbesartan, or losartan via osmotic minipumps for 4 weeks at doses yielding identical reductions of blood pressure. Maximum efficacy was obtained with a tripled dose of candesartan. METHODS: In the pithed rat model, stimulus/response dependencies were determined for vasopressor effectivity of preganglionic electrical stimulation, and of intravenous bolus applications of noradrenaline and angiotensin II. RESULTS: Losartan, irbesartan, eprosartan, and candesartan at doses of 5, 40, 20, and 0.05 mg/kg per day, were equally effective in reducing basal systolic blood pressure (-42 mmHg), and the vasopressor potency of angiotensin II (approximately 10-fold). The efficacies of preganglionic stimulation and exogenous noradrenaline were unaltered, with the exception of irbesartan, which reduced vascular noradrenaline sensitivity. The tripled dose of candesartan further reduced basal and angiotensin II-stimulated blood pressures, and significantly attenuated vascular noradrenaline sensitivity. CONCLUSION: AT1 antagonists at doses that effectively reduce blood pressure in chronic therapy do not generally suppress peripheral sympathetic function. A potential interaction consists in a reduction of vascular noradrenaline sensitivity, which can be considered as a class effect of AT1 antagonists at high dosage.

Acrylates↗
PubMed1963

THE EFFECTS OF GANGLION-BLOCKING AND POSTGANGLIONIC SYMPATHOLYTIC DRUGS ON PREPARATIONS OF THE GUINEA-PIG VAS DEFERENS.

The contractions of the guinea-pig isolated vas deferens elicited by electrical stimulation of the hypogastric nerve were completely blocked by the following drugs: guanethidine, bretylium, dimethylphenylpiperazinium hydrochloride, nicotine, pempidine, hexamethonium, hemicholinium, D-tubocurarine and procaine. However, when the vas deferens was stimulated through an electrode in its lumen, the contractions in response to frequent, short stimuli (50 shocks/sec, 1 msec duration) were blocked by guanethidine, bretylium and dimethylphenylpiperazinium, but were not affected by the remaining drugs, except that procaine and hemicholinium each caused some reduction in the responses. When the preparation was stimulated transmurally with shocks of 200 msec duration at 1 shock/sec, the contractions were unaffected by any of the above drugs, except hemicholinium which again caused a slow reduction of up to 50% of the original response. It is concluded that nicotine, pempidine, hexamethonium, D-tubocurarine and hemicholinium probably block the response to stimulation of the hypogastric nerve by acting on peripheral ganglia in its pathway. Hemicholinium appears to have an additional effect in depressing the responses of the smooth muscle of the vas deferens to direct electrical stimulation, and procaine may act both on the ganglia and at the nerve terminals.

Animals↗
PubMed1974

Lowering of kininogen in rat blood by adrenaline and its inhibition by sympatholytic agents, heparin and aspirin.

1 (-)-Adrenaline lowered the kininogen content and transitorily elevated the fibrinolytic activity of plasma following intravenous injection into the rat. Its effect on kininogen increased when administered by intravenous infusion.2 Although less effective, (-)-noradrenaline had a similar action to adrenaline; (+/-)-isoprenaline was inactive and failed to inhibit the effect of adrenaline.3 The effect of adrenaline on kininogen could be reproduced in vitro by incubation of whole blood, but not cell-free plasma, with the catecholamine for 5 min at 37 degrees C.4 Propranolol or phenoxybenzamine, as well as heparin or acetylsalicylic acid (aspirin), blocked the reduction of rat blood kininogen by adrenaline in vivo and in vitro.

Animals↗
PubMed1984

Evidence for a peripheral component in the sympatholytic effect of clonidine in rats.

In an attempt to assess separately the peripheral and central effects of clonidine on cardiovascular parameters and plasma catecholamine levels, the selective alpha 2-adrenoceptor antagonist idazoxan (RX 781094) was given either intravenously (i.v.) or intracerebroventricularly (i.c.v.) to anaesthetized rats before administration of intravenous clonidine. Plasma noradrenaline and plasma growth hormone concentrations were used as indices of peripheral sympathetic nervous activity and central alpha-adrenoceptor stimulation, respectively. Peripheral and central administration of idazoxan antagonized the cardiovascular responses to i.v. clonidine, 5 micrograms kg-1. However, idazoxan was more effective against the hypotension than the bradycardia induced by clonidine. Idazoxan 300 micrograms kg-1 i.v. and 50 micrograms i.c.v. prevented clonidine-induced falls in plasma noradrenaline and adrenaline. The results suggest that 50 micrograms idazoxan i.c.v. caused some blockade of peripheral as well as central alpha 2-adrenoceptors. Idazoxan, 10 micrograms i.c.v., caused similar inhibition of the hypotensive response to clonidine as 300 micrograms kg-1 i.v. and 50 micrograms i.c.v. but did not significantly inhibit the clonidine-induced fall in plasma noradrenaline concentration. Animals pretreated with i.v. or i.c.v. idazoxan had significantly lower levels of plasma growth hormone than vehicle-treated rats. Idazoxan 10 micrograms and 50 micrograms i.c.v. suppressed growth hormone secretion to the same extent. These results suggest that stimulation of peripheral, prejunctional alpha 2-adrenoceptors in anaesthetized rats may contribute to the fall in plasma catecholamines produced by i.v. clonidine, and confirm that the hypotensive effect is centrally mediated.

Adrenergic alpha-Antagonists↗
PubMed1995

Sympatholytic effect of tricyclic antidepressants: site and mechanism of action in anesthetized rats.

Intravenous desipramine (DMI) and amitriptyline, but not fluoxetine, dose dependently inhibited splanchnic sympathetic nerve discharge (sSND; -64 +/- 3% after 4 mg/kg iv DMI, 172 ng/ml plasma) in urethan-anesthetized debuffered rats. Inhibition was reversed or prevented by microinjection of the alpha 2-adrenergic receptor (alpha 2-AR) antagonist 2-methoxyidazoxan (MOI) into the rostral ventrolateral medulla (RVLM, 1 nmol/side). sSND inhibition (-58 +/- 12%) by baclofen (8 mg/kg iv, a gamma-aminobutyric acid-B receptor agonist) was unaffected by MOI. MOI alone raised sSND 46 +/- 9%. Microinjection of 6-hydroxydopamine into the RVLM (2 micrograms/side, 10-13 days, to destroy noradrenergic terminals) did not change the effect of intravenous DMI or MOI on sSND. Slow-firing presympathetic neurons of the RVLM were activated by iontophoretic MOI (26 +/- 4%) and inhibited by 4 mg/kg iv DMI (-44 +/- 12%, effect reversed by alpha 2-AR antagonists iv). We interpret these findings as follows: 1) alpha 2-ARs in the RVLM are activated at rest, probably by catecholamines released by C1 adrenergic cells, 2) this activation reduces sSND, 3) DMI and amitriptyline reduce sSND by increasing alpha 2-AR activation in the RVLM, and 4) these effects are due to neither serotonin uptake inhibition nor blockade of norepinephrine uptake by noradrenergic fibers.

Adrenergic alpha-Antagonists↗
PubMed1988

Mechanism of action of the anti-shock effect of CCK-8: influence of CCK antagonists and of sympatholytic drugs.

In an experimental model of haemorrhagic shock that causes 100% mortality in rats within 30 min, the intravenous bolus injection (20 micrograms/kg) of sulfated cholecystokinin octapeptide (CCK-8) induces a prompt and sustained rise in blood pressure and pulse amplitude, all treated animals still surviving at the end of the experiment (2 h). This effect of CCK-8 is completely blocked by reserpine (5 mg/kg i.p.), significantly antagonized by prazosin (0.1 mg/kg i.v.) and yohimbine (1 mg/kg i.v.), and unaffected by practolol (15 mg/kg i.v.) and proglumide (0.2 mg/kg i.v.); it is completely antagonized by the intravenous (0.01-0.05 mg/kg), but not by the intracerebroventricular (0.002 mg/kg) injection of the 'peripheral' CCK antagonist, L-364,718. The present data indicate that the cardiovascular effects of CCK-8 in haemorrhagic shock involve peripheral CCK receptors, and require the functional integrity of the sympathetic nervous system.

Animals↗
PubMed1976

Effect of catecholamines and sympatholytics on survival and circulatory parameters in protracted anaphylactic shock of guinea pigs.

Protracted anaphylactic shock of guinea pigs led to death in over 90% of the animals, and good protection was obtained with an infusion of adrenaline after dibenamine pretreatment. Adrenaline alone, in doses which prevented the anaphylactic fall of arterial blood pressure, had no beneficial effect. Practolol abolished the therapeutic action of the combination of dibenamine/adrenaline. Stimulation of beta-receptors by isoproterenol did not increase the survival rate. With dopamine, however, a significant prolongation of the survival times was obtained.

Anaphylaxis↗