AN INVESTIGATION INTO THE MECHANISMS OF THE CARDIOVASCULAR EFFECTS OF 5‐HYDROXYTRYPTAMINE IN CONSCIOUS NORMOTENSIVE AND DOCA‐SALT HYPERTENSIVE RATS
Authors: DALTON D. W. , FENIUK W. , HUMPHREY P. P. A. 
Published: September 2010

The actions of intravenously administered 5‐hydroxytryptamine (5‐HT) have been analysed 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.

In both normotensive and hypertensive rats 5‐HT, 3 and 10 μg 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.

The selective 5‐HT3‐receptor agonist, 2‐methyl 5‐HT, 3–30 μg 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.

The 5‐HT2receptor agonist, α‐methyl 5‐HT, 3–30 μg i.v., produced dose‐related increases in blood pressure which were significantly greater in magnitude in DOCA‐salt hypertensive than normotensive rats. Bradycardia was observed consistently at 30 μg only. The 5‐HT2receptor antagonist, ketanserin, 0.03‐0.3 mg/kg i.v., caused a dose‐dependent antagonism of the pressor responses produced by α‐methyl 5‐HT, but had no effect on the increases in blood pressure produced by angiotensin. Ketanserin also antagonised the pressor responses produced by 5‐HT in rats pretreated with MDL 72222.

5‐Carboxamidotryptamine (5‐CT), the selective ‘5‐HT1‐like’ receptor agonist, at doses of 0.1–3 μg 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 antagonise the depressor responses produced by isoprenaline 0.1 μg/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.

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 & Saxena, 1986). The initial depressor response and bradycardia involves activation of 5‐HT3‐receptors, the secondary vasopressor effect, which is significandy greater in DOCA‐salt than normotensive rats results from stimulation of 5‐HT2receptors and the late vasodepressor response is due to vasodilatation via ‘5‐HT1‐like’ receptors.