Pharmacological Nature of the Purinergic P2Y Receptor Subtypes That Participate in the Blood Pressure Changes Produced by ADPβS in Rats

Figures

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  Figure 1. Prototypical experimental recordings of the responses to either the vehicle (left panel) or ADPβS (right panel). Responses produced by the i.v. bolus of the vehicle (bidistilled water; 1 mL/kg given seven times) or ADPβS (0.3, 0.56, 1, 1.8, 3, 5.6, and 10 µg/kg) on blood pressure in male Wistar rats under different experimental conditions, namely: (i) anaesthetised rats without bilateral vagotomy (Group 1); (ii) anaesthetised rats with bilateral vagotomy (Group 2); (iii) pithed rats (Group 3); and (iv) pithed rats continuously infused (i.v.) with 20 µg/kg·min of methoxamine (Group 4).

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  Figure 2. Reproducibility of the responses induced by the vehicle or ADPβS on diastolic blood pressure (percent change). Effects produced by consecutive i.v. bolus of either the vehicle (bidistilled water, 1 mL/kg given seven times; black empty symbols) or ADPβS (0.3, 0.56, 1, 1.8, 3, 5.6, and 10 µg/kg; coloured symbols) on diastolic blood pressure (D–R curves were repeated three times for each compound) in anaesthetised rats without bilateral vagotomy (Group 1), anaesthetised rats with bilateral vagotomy (Group 2), pithed rats (Group 3), and pithed rats continuously infused (i.v.) with methoxamine (Group 4) (n = 6 for each group). Unfilled symbols represent vehicle responses (◯, ⎔, △), whereas filled symbols (●, ◆, ■) denote a significant difference (p < 0.05) in ADPβS responses compared with the corresponding vehicle responses. There were no significant differences (p > 0.05) amongst the three D–R curves produced by either the vehicle or ADPβS. Values represent means ± SEM (n = 6 for each group).

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  Figure 3. Effect of the P2Y1 receptor antagonist on the decreases in diastolic blood pressure (% change) elicited by ADPβS Effect of i.v. administration of MRS2500 (100 and 300 μg/kg) on the vasodepressor responses (determined as peak changes) elicited by ADPβS (0.3, 0.56, 1, 1.8, 3, 5.6, and 10 µg/kg, i.v.) in anaesthetised rats without bilateral vagotomy (Group 1), anaesthetised rats with bilateral vagotomy (Group 2), pithed rats (Group 3), and pithed rats continuously infused (i.v.) with methoxamine (Group 4). Unfilled symbols denote either control responses (O) or a nonsignificant response (◇) compared to the corresponding control response (p > 0.05). Filled symbols (◆, ■) exemplify significant differences (p < 0.05) against the corresponding control responses (O). (*) Indicates significant differences (p < 0.05) between the vasodepressor responses produced by 100 and 300 μg/kg MRS2500. Values represent means ± SEM (n = 6 for each group).

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  Figure 4. Effect of the P2Y12 receptor antagonist on the decreases in diastolic blood pressure (% change) elicited by ADPβS. The effect of i.v. administration of PSB0739 (100 and 300 μg/kg) on the vasodepressor responses (determined as peak changes) elicited by ADPβS (0.3, 0.56, 1, 1.8, 3, 5.6, and 10 µg/kg, i.v.) in anaesthetised rats without bilateral vagotomy (Group 1), anaesthetised rats with bilateral vagotomy (Group 2), pithed rats (Group 3), and pithed rats continuously infused (i.v.) with methoxamine (Group 4). Unfilled symbols denote either control responses (O) or nonsignificant responses (◇, ☐) compared to the corresponding control responses (p > 0.05). Values represent means ± SEM (n = 6 for each group).

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  Figure 5. Effect of the P2Y13 receptor antagonist on the decreases in diastolic blood pressure (% change) elicited by ADPβS. Effect of i.v. administration of MRS2211 (1000 and 3000 μg/kg) on the vasodepressor responses (determined as peak changes) elicited by ADPβS (0.3, 0.56, 1, 1.8, 3, 5.6, and 10 µg/kg, i.v.) in anaesthetised rats without bilateral vagotomy (Group 1), anaesthetised rats with bilateral vagotomy (Group 2), pithed rats (Group 3), and pithed rats continuously infused (i.v.) with methoxamine (Group 4) (n = 6 for each group). Unfilled symbols denote either control responses (O) or nonsignificant responses (◇, ☐)) compared to the corresponding control responses (p > 0.05). Values represent means ± SEM (n = 6 for each group).

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  Figure 6. The systolic (left panel) and diastolic (right panel) blood pressure changes in pithed rats continuously infused (i.v.) with methoxamine (Group 4). The effects elicited by an i.v. bolus of the vehicle (1 mL/kg given seven times; n = 6) or ADPβS (0.3, 0.56, 1, 1.8, 3.1, 5.6, and 10 µg/kg; n = 6) on systolic and diastolic blood pressure in pithed rats continuously infused (i.v.) with 20 μg/kg.min of methoxamine (Group 4). Filled symbols denote a significant difference (p < 0.05) compared to the corresponding i.v. bolus of the vehicle (1 mL/kg). (*) The third D–R curve of the vasopressor responses to ADPβS (left panel) was significantly attenuated (p < 0.05) when contrasted with the first (control) D–R curve.

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  Figure 7. Effects of the antagonists MRS2500 (P2Y1), PSB0739 (P2Y12), or MRS2211 (P2Y13) on the systolic vasopressor responses elicited by ADPβS in Group 4. The effects produced by MRS2500 (100 and 300 µg/kg; left panel), PSB0739 (100 and 300 µg/kg; middle panel) or MRS2211 (1000 and 3000 μg/kg; right panel) given i.v. on the increases in systolic blood pressure elicited by an i.v. bolus of ADPβS (0.3, 0.56, 1, 1.8, 3, 5.6, and 10 µg/kg) in pithed rats continuously infused (i.v.) with methoxamine (Group 4). Unfilled symbols represent control responses (O). Filled symbols (◆, ■) denote significant differences (p < 0.05) compared to the corresponding control responses (O). (*) Indicates significant differences (p < 0.05) in the vasopressor responses to ADPβS between i.v. administration of 100 and 300 μg/kg PSB0739 (middle panel) or 1000 and 3000 μg/kg MRS2211 (right panel). Values represent means ± SEM (n = 6 for each group).

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  Figure 8. Experimental Design. Distribution of the animals (n = 120) in the different protocols indicating the specific number of animals utilised in the two experimental models (i.e., anaesthetised and pithed; n = 60 each) and, subsequently, their division into: Group 1 (anaesthetised rats without vagotomy; Group 2 (anaesthetised rats with bilateral vagotomy); Group 3 (pithed rats); and Group 4 (pithed rats continuously infused [i.v.] with 20 µg/kg.min of methoxamine. Note that each group (n = 30) was further subdivided into five subgroups (n = 6 for each) that underwent the same pharmacological treatments.