Differential cardiac sympatho‐inhibitory responses produced by the agonists B‐HT 933, quinpirole and immepip in normoglycaemic and diabetic pithed rats

Abstract

This study compared the cardiac sympatho-inhibitory responses produced by agonists at α -adrenergic (B-HT 933), dopamine D -like (quinpirole) and histamine H /H (immepip) receptors between normoglycaemic and streptozotocin-pretreated (diabetic) pithed rats. Intravenous (i.v.) continuous infusions of B-HT 933, quinpirole or immepip were used in normoglycaemic and diabetic pithed rats to analyse their sympatho-inhibitory effects on the electrically-stimulated cardioaccelerator sympathetic outflow. Both in normoglycaemic and diabetic animals, B-HT 933 (until 100 μg/kg per minute) and quinpirole (until 10 μg/kg per minute) inhibited the tachycardic responses to electrical sympathetic stimulation, but not those to i.v. bolus of exogenous noradrenaline. These sympatho-inhibitory responses were more pronounced in diabetic than in normoglycaemic animals. Accordingly, the areas under the curve for 100 μg/kg per minute B-HT 933 and 10 μg/kg per minute quinpirole in diabetic rats (1065 ± 70 and 920 ± 35, respectively) were significantly smaller (P < .05) than those in normoglycaemic rats (1220 ± 45 and 1360 ± 42, respectively). In contrast, immepip infusions produced cardiac sympatho-inhibition in normoglycaemic (until 10 μg/kg per minute), but not in diabetic (until 100 μg/kg per minute) animals. Our results suggest that in diabetic pithed rats: (i) the more pronounced cardiac sympatho-inhibition to B-HT 933 and quinpirole may be probably due to up-regulation of α -adrenergic and dopamine D -like receptors, respectively; (ii) the histamine H /H receptors do not seem to play a sympatho-inhibitory role; and (iii) there is a differential participation of α -adrenergic and dopamine D -like receptors, which may certainly represent therapeutic targets for the treatment of diabetic complications such as cardiovascular autonomic neuropathy.

Exclusive Peripheral Overexpression of 5-HT5A Receptors is Involved in 5‑HT‑Induced Cardiac Sympatho-Inhibition in Type 1 Diabetic Rats

“…Considering the above, the baseline values of diastolic blood pressure in diabetic rats (48±1 mmHg) were not significantly different from those obtained in normoglycaemic rats (50±2 mmHg). This suggests that the systemic vascular tone and, therefore, the functionality of the systemic vasculature in diabetic rats (in the early stage of T1D) appears to be unaffected by 28-day T1D, as previously described [28,29]. In contrast, baseline heart rate values in diabetic rats were significantly lower (219±7 beats/min) than those determined in normoglycaemic rats (249±7 beats/min).…”

“…injection of streptozotocin (STZ, 50 mg/kg) which was dissolved in citrate buffer (pH=4.5); whereas set 2 received an i.p. injection of vehicle (citrate buffer, 1 ml/kg) as previously reported [28,29]. Both J.A.…”

“…After cannulation of the trachea, the rats were pithed by inserting a stainless-steel rod through the ocular orbit and foramen magnum into the vertebral foramen. Immediately afterwards, the animals were artificially ventilated with room air using an Ugo Basile pump (56 strokes/min and a stroke volume of 20 ml/kg; Ugo Basile Srl, Comerio, VA, Italy) [22,29]. After cervical bilateral vagotomy, catheters were placed in: (i) the left and right femoral veins for the continuous infusions of agonists (or vehicle), and bolus injections of gallamine/desipramine or antagonists, respectively; and (ii) the left carotid artery, connected to a Grass pressure transducer (P23XL, Grass Instrument Co., Quincy, MA, U.S.A.) for the recording of blood pressure.…”

“…Certainly, at the very beginning of the experiments, we used two different body weights for the administration of vehicle or STZ because the tachycardic responses induced by electrical stimulation are optimally produced in animals weighing around 290 g [28,29]. Thereupon, as the i.p.…”

In Silico Study of Metoclopramide as A Small Molecule of Dopamine D2 Receptor: a Quantum-Mechanical (QM) Based Molecular Docking Treatment

“…The D2R structure has been known using a radiolabeled antipsychotic compound [2]. The main agonists for dopamine D2 receptor are bromocriptine [3], cabergoline [4], dihydrexidine [5], piribedil [6], pramipexole [7], quinelorane [8], quinpirole [9], ropinirole [10], sumanirole [11] and talipexole [12]. Some drugs like aplindore [13], aripiprazole [14], armodafinil [15], brexpiprazole [16], cariprazine [17], ketamine [18], GSK-789 [19], 2-phenethylamine [20], LSD [21], OSU-6162 [22], roxindole [23], RP5063 [24] and salvinorin A [25] show the partial agonistic activity in interaction with D2R binding sites.…”