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One-month serotonin infusion results in a prolonged fall in blood pressure in the deoxycorticosterone acetate (DOCA) salt hypertensive rat.

ABSTRACT: A 7-day infusion of serotonin (5-hydroxytryptamine, 5-HT) causes a sustained fall in elevated blood pressure in the male deoxycorticosterone acetate (DOCA)-salt rat. As hypertension is a long-term disease, we presently test the hypothesis that a longer (30 day) 5-HT infusion could cause a sustained fall in blood pressure in the established hypertensive DOCA-salt rat. This time period (∼4 weeks) was also sufficient to test whether 5-HT could attenuate the development of DOCA-salt hypertension. 5-HT (25 μg/kg/min; sc) or vehicle (Veh) was delivered via osmotic pump to (1) established DOCA-salt rats for one month, (2) Sprague-Dawley rats prior to DOCA-salt administration for one month, and blood pressure and heart rate measured telemetrically. On the final day of 5-HT infusion, free platelet poor plasma 5-HT concentrations were significantly higher in 5-HT versus Veh-infused rats, and mean arterial pressure was significantly lower in 5-HT-infused (135 ± 4 mmHg vs Veh-infused 151 ± 7 mmHg) established DOCA-salt rats. By contrast, 5-HT-infusion did not prevent the development of DOCA-salt hypertension (144 ± 7 mmHg vs Veh = 156 ± 6 mmHg). Isometric contraction of aortic strips was measured, and neither the potency nor maximum contraction to the alpha adrenergic receptor agonist phenylephrine (PE) or 5-HT were modified by infusion of 5-HT (established or preventative infusion), and maximum aortic relaxation to acetylcholine (ACh) was modestly but not significantly enhanced (∼15% improvement). This study demonstrates 5-HT is capable of lowering blood pressure in established DOCA-salt hypertensive rats over the course of one month in a mechanism that does not significantly modify or is dependent on modified vascular responsiveness. This finding opens the possibility that elevation of 5-HT levels could be useful in the treatment of hypertension.

SUBMITTER: Davis RP

PROVIDER: S-EPMC3547487 | biostudies-other | 2013 Jan

REPOSITORIES: biostudies-other

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Project description:1. The roles of nitric oxide (NO), superoxide anion (O(2)(-)), and hydrogen peroxide (H(2)O(2)) in the modulation of spontaneous tone were investigated in isolated aorta from deoxycorticosterone acetate (DOCA)-salt hypertensive rats. 2. Increases in preload from 1 to 5 g were accompanied by increases in spontaneous tone in aortic rings from DOCA-salt hypertensive rats but not from SHAM-normotensive rats. 3. Tone was higher in endothelium-denuded aortic rings than in endothelium-intact vessels. Inhibition of nitric oxide synthase (NOS) with 300 microM N(G)-nitro-L-arginine methyl ester (l-NAME) increased spontaneous tone. 4. Basal O(2)(-) generation was higher in aortic rings from DOCA-salt hypertensive rats than in those from SHAM-normotensive rats. Stretch increased O(2)(-) levels even further in the DOCA-salt group. In rings isolated from DOCA-salt hypertensive rats, administration of the O(2)(-) scavenger, superoxide dismutase (SOD, 150 U ml(-1)), or the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase inhibitor, apocynin (100 microM), completely abolished the development of spontaneous tone in endothelium-intact aortic rings but not in endothelium-denuded or in L-NAME-treated rings. SOD and apocynin decreased the generation of O(2)(-) in endothelium-intact, endothelium-denuded, and L-NAME-treated aortic rings. 5. Oral treatment of DOCA-salt hypertensive rats with the O(2)(-) scavengers, tempol or tiron, or with apocynin for 3 weeks prevented the development of hypertension and abolished the increases in O(2)(-) generation and spontaneous tone. 6. Administration of catalase (1000 U ml(-1)) to aortic rings increased spontaneous tone in vessels from DOCA-salt hypertensive rats. 7. Administration of the cyclooxygenase (COX) inhibitor, valeroyl salicylate, or the thromboxane/prostaglandin antagonist, SQ 29548, to aortic rings abolished tone. 8. The results suggest that NO plays a major role in preventing the generation of spontaneous tone in isolated aortic rings from DOCA-salt hypertensive rats. NADPH-oxidase-derived O(2)(-) enhanced spontaneous tone by inactivating NO. Endogenous H(2)O(2) appears to mitigate the increase in tone. In addition, a COX component may also contribute to spontaneous tone.

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One-month serotonin infusion results in a prolonged fall in blood pressure in the deoxycorticosterone acetate (DOCA) salt hypertensive rat.

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