Knowles, Ian David; (1999) The role of 5-HT2 receptors in central cardiovascular regulation in anaesthetized rats. Doctoral thesis (Ph.D.), University College London.

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Abstract

Previous studies have demonstrated that activation of central 5-HT2 receptors in anaesthetized and unanaesthetized rats causes the release of vasopressin and a rise in arterial blood pressure (Anderson et al., 1992, Pérgola et al., 1993). However, studies in cats have also demonstrated that activation of central 5-HT2 receptors causes sympathoexcitation. The present study was carried out to determine if, in the rat, 5-HT2 receptors also mediated sympathoexcitation. In addition, experiments were also carried out to determine which particular subtype/s of 5-HT2 receptor (A, B & C) may be involved in the above effects. Experiments were performed in α-chloralose (80 mg kg-1) anaesthetized, artificially ventilated and neuromuscular blocked rats, in which simultaneous recordings were made of mean arterial blood pressure (MAP), heart rate (HR), renal nerve (RNA) and phrenic nerve activities (PNA) while test ligands were administered intracerebroventricularly (i.c.v.). Administration of the 5-HT2 receptor agonists quipazine and DOI (2 μmol kg-1) evoked increases in MAP of 18 ± 4 and 13 + 4 mmHg respectively and HR of 40 ± 8 and 45 ± 10 bpm, respectively, but decreases in RNA-26 ±12 and -24 ± 5%. However, injection i.v. of a vasopressin Vi-receptor antagonist after 3 min immediately reversed the rise in MAP. Pretreatment with either a 5-HT2 or a 5-HT2A receptor antagonist (i.c.v.) significantly attenuated the quipazine evoked response, while pretreatment with a 5-HT2B receptor antagonist (i.c.v.) or a vasopressin V1-receptor antagonist (i.v.) reversed the renal sympathoinhibitory response to sympathoexcitation (+67 ± 24 and +53 ± 24% respectively). Administration of the putative 5-HT2B receptor agonist BW723C86 (0.2 μmol kg-1, i.c.v.) evoked a renal sympathoexcitation (+39 ± 7%) which was associated with no change in MAP or HR and the sympathoexcitation was only attenuated by pretreatment, centrally, with a 5-HT2B receptor antagonist SB 204741. Vasopressin release has been demonstrated to involve an angiotensinergic pathway (Saydorff et al., 1996) and in this respect pretreatment with an angiotensin II AT1-receptor antagonist (i.c.v.) was found also to attenuate this rise in MAP evoked by quipazine and reverse the renal sympathoinhibition to sympathoexcitation, the quipazine induced tachycardia was unaffected. Pretreatment centrally with an AT2-receptor antagonist failed to affect the quipazine evoked pressor effect or tachycardia but reversed the sympathoinhibition to an excitation. In conclusion these data show that the rise in blood pressure evoked by quipazine in anaesthetized rats is due to the release of vasopressin. This rise is mediated by the activation of central 5-HT2A receptors and involves a central angiotensinergic pathway. However, by interfering with the effects of released vasopressin a centrally mediated sympathoexcitation can be demonstrated due to activation of 5-HT2 receptors. Further, these studies suggest that 5-HT2B receptors play a role in the control of renal sympathetic outflow. Interestingly these results have lead to the suggestion that central 5-HT2B receptors, might by involved in blood volume regulation.

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