Pharmacological Evidence That Dopamine Inhibits the Cardioaccelerator Sympathetic Outflow via D2-Like Receptors in Pithed Rats (original) (raw)
Related papers
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.
Naunyn-Schmiedeberg's Archives of Pharmacology, 2013
We have recently reported that quinpirole (a D 2like receptor agonist) inhibits the vasopressor sympathetic outflow in pithed rats via sympatho-inhibitory D 2 -like receptors. Since D 2 -like receptors consist of D 2 , D 3 and D 4 receptor subtypes, this study investigated whether these subtypes are involved in the above quinpirole-induced sympathoinhibition by using antagonists of these receptor subtypes. One hundred fifty-six male Wistar rats were pithed and prepared for preganglionic spinal (T 7 -T 9 ) stimulation of the vasopressor sympathetic outflow. This approach resulted in frequency-dependent vasopressor responses which were analysed before and during i.v. continuous infusions of either saline (0.02 ml/min) or quinpirole (1 μg/kg.min) in animals receiving i.v. bolus injections of vehicle [saline or dimethyl sulfoxide (DMSO)] or the antagonists L-741,626 (D 2 ), nafadotride or SB-277011-A (both D 3 ) as well as L-745,870 (D 4 ). Quinpirole inhibited the sympathetically-induced vasopressor responses. This sympatho-inhibition was (a) unaltered after 1 ml/kg saline, DMSO or 100 and 300 μg/kg L-741,626; (b) markedly blocked and abolished by, respectively, 30 and 100 μg/kg nafadotride or 100 and 300 μg/kg SB-277011-A and (c) slightly blocked after 30 and 100 μg/kg L-745,870, but 300 μg/kg L-745,870 produced no blockade whatsoever.
Cardiovascular Functions and Dopamine: Mechanism of Action in Adult Male Anesthetized Balady Rabbits
Bulletin of Egyptian Society for Physiological Sciences
This study aimed to elucidate mechanism(s) that mediate dopamine regulation of cardiovascular system (CVS) functions. Forty eight adult male anesthetized Balady rabbits (4 experiments, 8 groups, 6 animals each) were included. Experiment I assessed the effect of intravenous (iv) dopamine infusion (0.1, 1, 4 and 12 µg/kg/min) on diastolic (DBP), systolic (SBP), mean blood pressure (MBP), heart rate (HR), cardiac contractility (CC) and renal sympathetic nerve activity (RSNA). Experiment II assessed the effect of dopamine infusion on ventricular sarcomere length. Experiment III confirmed the contribution of dopamine receptor subtype(s). Experiment IV evaluated adrenergic receptors involved in dopamine's action. Mean BP, CC, HR and RSNA were recorded by physiograph. At low dopamine infusion rate DBP, MBP, CC and RSNA were decreased; while sarcomere length and A:I ratio were increased. At high dopamine infusion rate DBP, SBP, MBP, HR and CC were increased while; sarcomere length and A:I ratio were decreased. D 1-like receptor activation decreased MBP; while D 2-like receptor activation decreased MBP, CC, and RSNA. Both D 1-and D 2-like receptors blockade attenuated hypotensive response, whereas CC was abolished by D 2 receptor blockade. Mean BP, HR and CC were not changed after D 1-and D 2-like receptors blockade, but decreased after D 1-and D 2 like receptors activation. Low dopamine infusion into animals pre-treated with αadrenoceptor blockade (reserpine) or β-adrenoceptor blockade (propranolol) decreased MBP and CC whereas, with high dopamine infusion, the HR and CC were increased after α-adrenoceptor blockade and MBP was increased after βadrenoceptor blockade. From this study, we can conclude that dopamine elicits biphasic effect on CVS. Low dopamine doses acts via stimulation of D 1-and D 2-like receptors. With increasing dose, actions occur via stimulation of α-and β-adrenergic receptors. Normal endogenous dopamine may not alter basal cardiovascular functions.
In Vivo Evidence That Endogenous Dopamine Modulates Sympathetic Activity in Man
Hypertension, 1999
Dopamine receptors type 2 (D2)-like receptor blockers cause an increase in the norepinephrine response to intense physical exercise. However, during intense physical exercise, D2-like antagonists also cause an increase in the epinephrine response, which itself might cause an increase in plasma norepinephrine through the activation of 2 presynaptic receptors. Therefore, we evaluated the effect of domperidone, a D2-like antagonist, on the norepinephrine response to physical exercise in 6 Addison patients (3 were adrenalectomized and 3 had adrenal tuberculosis). In these patients, the norepinephrine increase observed during exercise was significantly higher after the administration of domperidone than a placebo (Fϭ4,328; PϽ0.001). Because peripheral plasma norepinephrine does not reflect the sympathetic tone to the heart accurately, we evaluated the effect of domperidone administration (20 mg orally) on the sympathovagal balance, which was measured by the ratio between the high-and low-frequency components of heart rate variability, in 9 normal volunteers in the supine and sitting positions. When compared with placebo, domperidone caused a significant increase in the low/high frequency ratio (PϽ0.05) in the sitting position without modifying basal and stimulated norepinephrine plasma levels or blood pressure. These data support a role for endogenous dopamine in modulating norepinephrine release by human sympathetic nerves in vivo. (Hypertension. 1999;34:398-402.)
The American Journal of Cardiology, 1988
Studies in our laboratory have confirmed that dopexamine hydrochloride is a potent #2-adrenoceptor and DAs-dopamine receptor agonist. We examined the effects of dopexamine hydrochloride on both cardiac contractile force, determined by use of a Walton-Brodie strain-gauge arch sutured to the right ventricle, and heart rate in anesthetized dogs. Dopexamine hydrochloride increased cardiac contractile force and heart rate and decreased blood pressure. After administration of the ganglionic blocking agents, hexamethonium and atropine, or the selective #t-adreneceptor antagonist, atenolol, the positive inotropic and chronotropic effects of dopexamine hydrochloride were reduced or eliminated, demonstrating that the drug had little or no direct Bt-adreneceptor action and that a myocardial ~2-adreneceptor action was not involved in its cardiac effects. During these investigations, dopexamine hydrochloride was found to be an inhibitor of norepinephrine uptake, potentiating the cardiac effects of both exogenously administered norepinephrine and norepinephrine released from sympathetic nerves.
European Journal of Pharmacology, 2007
It has been suggested that the α 2 -adrenoceptors mediating cardiac sympatho-inhibition in pithed rats closely resemble the pharmacological profile of the α 2A -adrenoceptor subtype. However, several lines of evidence suggest that more than one subtype may be involved. Thus, the present study has pharmacologically re-evaluated the receptor subtype(s) involved in the inhibitory effect of the α 2 -adrenoceptor agonist, B-HT 933, on the tachycardic responses elicited by selective cardiac sympathetic stimulation (0.03, 0.1, 0.3, 1 and 3 Hz) in desipramine-pretreated pithed rats. I.v. continuous infusions of B-HT 933 (30 μg/kg min), which failed to modify the tachycardic responses to exogenous noradrenaline, inhibited those induced by preganglionic (C 7 -T 1 ) stimulation of the cardiac sympathetic outflow at all frequencies of stimulation (0.03-3 Hz). This cardiac sympatho-inhibitory response to B-HT 933 was: (1) unaltered by saline (1 ml/kg) or the antagonists BRL44408 (100 μg/kg; α 2A ) or imiloxan (3000 and 10,000 μg/kg; α 2B ); (2) partially antagonized by BRL44408 (300 μg/kg) or MK912 (10 μg/kg; α 2C ) given separately; and (3) completely antagonized by rauwolscine (300 μg/kg; α 2 ), MK912 (30 μg/kg) or the combination of BRL44408 (300 μg/kg) plus MK912 (10 μg/kg). Moreover, the above doses of antagonists, which are high enough to block their respective receptors, failed to block per se the tachycardic responses to sympathetic stimulation. These results suggest that the cardiac sympatho-inhibition induced by B-HT 933 in pithed rats is mainly mediated by stimulation of α 2A -and α 2C -adrenoceptors.
Effects of prolonged infusion of dopexamine on β 1 - and β 2 -adrenoceptors in guinea-pig myocardium
Journal of Autonomic Pharmacology, 1990
The effects of 7-day infusion of dopexamine (50 and 200 pg kg-lh-l) were examined on P1and P,-adrenoceptors in guinea-pig left ventricular membranes. 2 Receptor binding performed using the high affinity radioligand (-)-[lZ51]cyanopindolol (CUP) and the P,-adrenoceptor antagonist CGP 207 12A showed that treatment with dopexamine 200 pg kg-lh-l caused a 45% reduction in Pzadrenoceptors and a small but not significant increase in P,-adrenoceptors. 3 Functional effects of dopexamine were examined in the guinea-pig isolated electrically driven left atria and K+-depolarized uterus.
European Journal of Pharmacology, 2009
The present study set out to analyse the pharmacological profile of the inhibitory responses induced by the antimigraine agents dihydroergotamine (DHE) and methysergide on the tachycardic responses to preganglionic sympathetic stimulation in pithed rats. For this purpose, 132 male Wistar normotensive rats were pithed and prepared to: (i) selectively stimulate the preganglionic (C 7 -T 1 ) cardiac sympathetic outflow; or (ii) receive intravenous (i.v.) bolus injections of exogenous noradrenaline. Electrical sympathetic stimulation or exogenous noradrenaline produced, respectively, frequency-dependent and dose-dependent tachycardic responses. Moreover, i.v. continuous infusions of DHE (1.8, 3.1 and 5.6 µg/kg.min) or methysergide (100, 300 and 1000 µg/kg.min) dose-dependently inhibited the tachycardic responses to sympathetic stimulation, but not those to exogenous noradrenaline. Using physiological saline or antagonists (given as i.v. bolus injections), the cardiac sympatho-inhibition induced by either DHE (3.1 µg/kg.min) or methysergide (300 µg/kg.min) was: (1) unaffected by saline (1 ml/kg); (2) partially blocked by the antagonists rauwolscine (300 µg/kg; α 2 ) or N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl) [1,1,-biphenyl]-4-carboxamide hydrochloride monohydrate (GR127935, 300 µg/kg; 5-HT 1B/1D ); and (3) completely antagonised by the combination rauwolscine plus GR127935. These antagonists, at doses high enough to completely block their respective receptors, failed to modify the sympathetically-induced tachycardic responses per se. The above results, taken together, suggest that the cardiac sympatho-inhibition induced by DHE (3.1 µg/kg.min) and methysergide (300 µg/kg.min) may be mainly mediated by stimulation of both α 2 -adrenoceptors and 5-HT 1B/1D receptors.