AN INVESTIGATION INTO THE MECHANISMS OF THE CARDIOVASCULAR EFFECTS OF 5‐HYDROXYTRYPTAMINE IN CONSCIOUS NORMOTENSIVE AND DOCA‐SALT HYPERTENSIVE RATS

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Abstract
1 The actions of intravenously administered 5-hydroxytryptamine (5-HT) have been analyzed in conscious DOCA-salt hypertensive rats using selective 5-HT receptor agonists and antagonists to determine the receptor mechanisms involved and to compare them with those in conscious normotensive rats. 2 In both normotensive and hypertensive rats 5-HT, 3 and 10 .mu.g i.v., produced a complex triphasic effect on blood pressure consisting of an initial short lasting depressor response, which was followed by a pressor response and then, finally, a hypotensive phase. Marked decreases in heart rate were observed immediately after dosing, which were followed by small increases in rate. 3 The selective 5-HT3-receptor agonist, 2-methyl 5-HT, 3-30 .mu.g i.v., produced immediate and marked dose-related decreases in blood pressure and heart rate in both normotensive and DOCA-salt hypertensive rats. The 5-HT3-receptor antagonist, MDL 72222, 0.03 and 0.1 mg/kg i.v., antagonised these effects in both normotensive and DOCA-salt hypertensive rats. Treatment with MDL 72222, 0.3 mg/kg i.v., abolished the initial depressor response and bradycardia produced by 5-HT. 4 The 5-HT2 receptor agonist, .alpha.-methyl 5-HT, 3-30 .mu.g i.v., produced dose-related increases in blood pressure which were significantly greater in magnitude in DOCA-salt hypertensive than normotensive rats. Bradycardia were observed consistently at 30 .mu.g only. The 5-HT2 receptor atagonist, ketanserin, 0.03-0.3 mg/kg i.v., caused a dose-dependent antagonism of the pressor responses produced by .alpha.-methyl 5-HT, but had no effect on the increases in blood pressure produced by angiotensin. Ketanserin also antagonized the pressor responses produced by 5-HT in rats pretreated with MDL 72222. 5 5-Carboxamidotryptamine (5-CT), the selective ''5-HT1-like'' receptor agonist, at doses of 0.1-3 .mu.g i.v. produced dose-related decreases in blood pressure which were more pronounced in the DOCA-salt hypertensive rats than in normotensive rats. These depressor responses were dose-dependently antagonised by methiothepin, 0.3 and 1 mg/kg, i.v. which did not antagonize the depressor responses produced by isoprenaline 0.1 .mu.g/kg i.v. In rats pretreated with MDL 72222 and ketanserin, 5-HT produced dose-related depressor responses which were also antagonised by methiothepin 1 mg/kg i.v. and presumably mediated by 5-HT1-like receptors. 6 In this study, selective 5-HT receptor agonists and antagonists have been used to mimic and block, respectively, the various phases of the 5-HT response. It is concluded that in the conscious rat, the complex cardiovascular effects of 5-HT involve stimulation of at least three different 5-HT receptors (for nomenclature see Bradley, Engel, Feniuk, Fozard, Humphrey, Middlemiss, Mylecharane, Richardson and Saxena, 1986). The initial depressor response and bradycardia involves activation of 5-HT3-receptors, the secondary vasopressor effect, which is significantly greater in DOCA-salt than normotensive rats results from stimulation of 5-HT2 receptors and the late vasodepressor response is due to vasodilatation via ''5-HT1-like'' receptors.