Effects of Dopaminergic Drugs on the Sympathoadrenal System (original) (raw)
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Journal of Pharmacological Sciences, 2013
It has been suggested that N,N-di-n-propyl-dopamine (dopamine analogue) decreased heart rate in rats through stimulation of dopamine receptors. Nevertheless, the role of prejunctional dopamine D 1/2 -like receptors or even a 2 -adrenoceptors to mediate cardiac sympatho-inhibition induced by dopamine remains unclear. Hence, this study identified the pharmacological profile of the cardiac sympatho-inhibition to dopamine in pithed rats. Male Wistar rats were pithed and prepared to stimulate the cardiac sympathetic outflow or to receive i.v. bolus of exogenous noradrenaline. I.v. continuous infusions of dopamine (endogenous ligand) or quinpirole (D 2 -like agonist) dose-dependently inhibited the tachycardic responses to sympathetic stimulation, but not those to exogenous noradrenaline. In contrast, SKF-38393 (100 mg/kg•min, D 1 -like agonist) failed to modify both of these responses. The sympatho-inhibition to dopamine (1.8 mg/kg•min) or quinpirole (100 mg/kg•min): i) remained unaltered after saline or the antagonists SCH-23390 (D 1 -like, 300 mg/kg) and rauwolscine (a 2 -adrenoceptors, 300 mg/kg); and ii) was significantly antagonized by raclopride (D 2 -like, 300 mg/kg). These antagonists, at the above doses, failed to modify the sympatheticallyinduced tachycardic responses. The above results suggest that the inhibition of the cardiac sympathetic outflow to dopamine and quinpirole is primarily mediated by prejunctional D 2 -like receptors but not D 1 -like receptors or a 2 -adrenoceptors.
British Journal of Pharmacology, 1987
The effect of local administration of the dopamine2 (DA2)-receptor agonist quinpirole and of the DA,-receptor agonist fenoldopam was studied in the in situ, constant flow autoperfused, superior mesenteric vascular bed of the rat. 2 Local infusion of quinpirole (30 pg kg-'min-' for 5min) had no effect on baseline perfusion pressure; it reduced the pressor responses to electrical stimulation (4 Hz, 1 ms, supramaximal voltage) of the periarterial sympathetic nerves to 45.6 ± 2.1% of its original value but did not modify similar pressor responses produced by locally administered noradrenaline. 3 The inhibitory effect of quinpirole was antagonized by the selective DA2-receptor antagonist domperidone (10 pg kg-') but not by the selective DA,-receptor antagonist SCH 23390 (50 pg kg-'). 4 Local infusion of fenoldopam (30 pg kg-' min-' for 5 min) reduced baseline perfusion pressure to 89.9 ± 1.9%, increased the pressor response to electrical stimulation (4Hz, 1 ms, supramaximal voltage) of the periarterial nerves to 134.7 ± 14.0%, but reduced the pressor response to locally administered noradrenaline to 37.2 ± 8.2%. Similar pressor responses induced by the selective a,adrenoceptor agonist phenylephrine were also reduced by fenoldopam (to 38.4 ± 6.4%), but responses to locally administered angiotensin II were not modified. 5 Pretreatment with SCH 23390 (50 pg kg-') antagonized the effect of fenoldopam on baseline perfusion pressure, but had no influence on the effect of fenoldopam on responses to electrical stimulation or to noradrenaline. 6 Pretreatment with the selective az-adrenoceptor antagonist rauwolscine (100 pg kg-') had no effect on the reduction in baseline perfusion pressure induced by fenoldopam nor on its inhibitory effect on the response to noradrenaline, but it antagonized the stimulatory effect of fenoldopam on the response to electrical stimulation. 7 The results show that quinpirole inhibits neurogenic vasoconstriction in the rat superior mesenteric vascular bed through stimulation of presynaptic DA2-receptors while fenoldopam stimulates postsynaptic vasodilatory DA,-receptors. In addition, our results suggest that the inhibitory effect of fenoldopam on the vasoconstrictor response to noradrenaline may be due to an antagonistic action at postsynaptic a,-adrenoceptors, while its potentiating effect on neurogenic vasoconstriction is due to blockade of presynaptic oi2-adrenoceptors.
Basic & Clinical Pharmacology & Toxicology, 2011
This study investigated in pithed rats whether dopamine can inhibit the sympathetic vasopressor outflow and analysed the pharmacological profile of the receptors involved. Male Wistar pithed rats were pre-treated with intravenous (i.v.) bolus injections of gallamine (25 mg ⁄ kg) and desipramine (50 lg ⁄ kg). The vasopressor responses to electrical stimulation of the sympathetic vasopressor outflow (0.03-3 Hz; 50 V and 2 msec.) were analysed before and during i.v. continuous infusions of the agonists dopamine (endogenous ligand), SKF-38393 (D 1 -like) or quinpirole (D 2 -like). If inhibition was produced by any agonist, then its capability to inhibit the vasopressor responses to i.v. bolus injections of exogenous noradrenaline (0.03-3 lg ⁄ kg) was also investigated. Dopamine (3-100 lg ⁄ kg min.) inhibited the vasopressor responses to both electrical stimulation and noradrenaline. In contrast, SKF-38393 (10-100 lg ⁄ kg min.) failed to inhibit the vasopressor responses to electrical stimulation; whereas quinpirole (0.1-30 lg ⁄ kg min.) inhibited the vasopressor responses to electrical stimulation but not those to noradrenaline. The sympatho-inhibition by quinpirole (1 lg ⁄ kg min.) remained unaltered after i.v. SCH 23390 (300 and 1000 lg ⁄ kg; D 1 -like receptor antagonist), but was abolished after i.v. raclopride (1000 lg ⁄ kg; D 2 -like receptor antagonist). These doses of antagonists did not modify per se the sympathetically-induced vasopressor responses. In conclusion, quinpiroleinduced inhibition of the sympathetic vasopressor outflow is primarily mediated by activation of dopamine D 2 -like receptors.
Journal of Pharmacology and Experimental Therapeutics
In the isolated superior cervical ganglion of the rat, activation of either DA1 or DA2 receptors leads to inhibition of ganglionic transmission. Using dopamine as well as relatively selective dopamine receptor agonists and antagonists we have performed electrophysiological as well as biochemical experiments to study the nature of dopamine receptors in this sympathetic ganglion. Fenoldopam, a selective DA1 receptor agonist caused marked inhibition of the compound postganglionic action potential evoked by stimulation of preganglionic nerve. The inhibitory effect of fenoldopam was antagonized by the DA1 receptor antagonist R-sulpiride but not by the DA2 receptor antagonist S-sulpiride. However, the more potent and selective DA1 receptor antagonist SCH-23390 failed to antagonize ganglion blocking effect of fenoldopam indicating that DA1 receptor in sympathetic ganglia is different from that in blood vessels. The superior cervical ganglion also contains DA2 receptors inasmuch as quinpiro...
British Journal of Pharmacology, 1977
I The effects of noradrenaline upon the cardiovascular system of the rat, anaesthetized with pentobarbitone, have been investigated. 2 Noradrenaline produces a dose-dependent increase in mean arterial blood pressure (MABP) which is due entirely to an increase in cardiac output; total peripheral vascular resistance (TPR) remains unchanged. 3 Following P-adrenoceptor blockade the pressor response to infused noradrenaline is enhanced and is now due mainly to an increase in TPR; the increment in cardiac output is reduced. 4 After a-adrenoceptor blockade the pressor response is greatly reduced; the residual increase in MABP is due solely to an increase in cardiac output. 5 After ganglion blockade resting cardiac output and TPR both fall, resulting in a reduction in MABP. The pressor response to noradrenaline is enhanced and is now due to increases in both TPR and in cardiac output. 6 The cardiovascular response of the anaesthetized rat to noradrenaline can be explained in terms of classical a-and /J-adrenoceptor stimulation by the amine; the unusual form of the response may be due to an effective predominance of/-adrenoceptor-mediated effects in this species. 7 It is suggested that the failure of exogenous noradrenaline to produce a rise in TPR results from a balance between the a-adrenoceptor-mediated increase and fl-adrenoceptor-mediated decrease in this variable. However, this proposed balance is lost if resting vasoconstrictor tone is reduced by ganglion blockade.
Effects of 6-hydroxydopamine on dopamine and noradrenaline content in dog blood vessels and heart
Naunyn-Schmiedeberg's Archives of Pharmacology, 1985
I. The noradrenaline and dopamine depletion induced by 6-hydroxydopamine (6-OHDA) and pargyline plus 6-OHDA was investigated in the heart, mesenteric, renal, splenic and femoral arteries and saphenous vein of the dog. Catecholamine concentrations in plasma were also analyzed in these two experimental conditions. 2. 6-OHDA and pargyline plus 6-OHDA induced a parallel decrease of the noradrenaline and dopamine content in the main trunk of the mesenteric artery, femoral artery and heart. In the proximal branches of the mesenteric artery, renal and splenic arteries 6-OHDA selectively reduced noradrenaline (by 50%) without changes in dopamine levels. Previous treatment with pargyline abolished this selectivity and depleted the tissue levels of both noradrenaline and dopamine by 75%. 3. The noradrenaline and dopamine levels in the saphenous vein were not significantly reduced by 6-OHDA (15%) and pargyline plus 6-OHDA (40%). 4. 6-OHDA and pargyline plus 6-OHDA increased both noradrenaline and adrenaline concentrations in plasma, without significant changes in dopamine concentrations. 5. The present findings suggest: an independent dopamine presence in the proximal branches of the mesenteric artery, renal artery and splenic artery; that noradrenaline and dopamine are in one and the same structure in the heart, femoral artery and the main trunk of the mesenteric artery; the saphenous vein is more resistant to chemical sympathectomy than arterial blood vessels; the changes in plasma catecholamine concentrations are probably related to a compensatory mechanism initiated at the adrenal medulla.
Both α- and β-adrenoceptors contribute to the central depressor effect of catecholamines
Brain Research, 1988
We compared the effects of a 2-and fl-adrenoreceptor blockade on the central actions of catecholamines and metabolites of a-methyldihydroxyphenylalanine, epinephrine, a-methylnorepinephrine, and a-methylepinephrine were studied. I.c.v. and nucleus tractus solitarii (NTS) injections were carried out under anesthesia. Following i.c.v, injection, both epinephrine and methylepinephrine rapidly reduced blood pressure and heart rate, but the effects of methylnorepinephrine occurred somewhat later. Following microinjection into the nucleus of the solitary tract, epinephrine, methylepinephrine, and methylnorepinephrine all caused hypotension and bradycardia. The hypotensive effects of all 3 amines in the NTS were attenuated in additive fashion by yohimbine, an a 2 adrenoreceptor antagonist, and timolol, a fl-adrenoreceptor antagonist, whereas only yohimbine attenuated the bradycardia. The combination of yohimbine and timolol abolished the effects of the amines. These data suggest that in the NTS both a 2 and fl adrenoreceptor stimulation contribute to the hypotensive effects of these amines, but that only a 2 adrenoreceptors are principally involved in the heart rate response.
Cardiac alpha-1 adrenoceptors are not involved in heart rate control of the anaesthetized dog
Pfl�gers Archiv European Journal of Physiology, 1987
To study the possible role of cardiac postsynaptic alpha-I adrenoceptors in heart rate control of the anaesthetized open-chest dog we injected a specific alpha-1 agonist (amidephrine) into the right coronary artery or stimulated electrically the right stellate ganglion. Reflex influences were minimized by bilateral cervical vagotomy and de-afferentiation of both stellate ganglia. Activation of alpha-2, beta-and muscarinic receptors was prevented by intravenous administration of yohimbine, propranolol and atropine, respectively. Since alpha-1 receptor stimulation could affect heart rate indirectly via coronary constriction, a continuous intracoronary infusion of adenosine (0.25 mg/ kg/h) was given. Amidephrine did not affect heart rate at the lower dose (1-10 gg). After the highest dose (100 gg) the maximum variation in heart rate was an increase of 2.2_+ 1.1 bpm at 3 min after injection (mean _+ SEM; P < 0.05). This slight cardioacceleration was simultaneous with an aortic pressure rise of 13.8 ___ 3.4 mmHg and it was abolished by alpha-t blockade with prazosin (1 mg/kg i.v.). After propranolol (1 mg/kg +0.5 mg/kg/h) the residual positive chronotropic effect of sympathetic stimulation (12.2 ___ 4.0 bpm) was not significantly altered (13.8 _+ 5.7 bpm) by prazosin administration. Similar results were recorded without adenosine infusion. We conclude that in the anaesthetized dog chronotropic effects directly mediated by alpha-1 adrenoceptors either do not exist or lack physiological significance.
Journal of Clinical Investigation, 1986
We studied the effects of clonidine, an a2-adrenoreceptor agonist, and yohimbine, an a2-adrenoreceptor antagonist, on blood pressure, heart rate, and plasma catecholamines in 12 patients with autonomic dysfunction. Clonidine (0.1 mg, orally) lowered blood pressure 18±3 torr in six subjects and raised it 5±1 torr in six. The change in blood pressure in response to this dose of clonidine was inversely proportional to the supine level of norepinephrine (P < 0.05). Yohimbine (4-64 ,ug/kg) raised plasma norepinephrine and blood pressure in six patients with degenerative autonomic dysfunction. Yohimbine also attenuated by 50% (P < 0.05) the hypotensive response to head-up tilt of patients with degenerative autonomic dysfunction. Clonidine depends upon postjunctional hypersensitivity and the degree ofautonomic insufficiency to elicit its pressor response. In contrast, the pressor response to yohimbine is related to the capacity of the sympathetic nervous system to be activated and release norepinephrine. If plasma norepinephrine levels following yohimbine administration are monitored, the biochemical and hemodynamic response to the drug may provide a sensitive indication of the capacity of the sympathetic nervous system to be activated in patients with autonomic dysfunction.