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(Hypertension. 2006;48:e115.)
© 2006 American Heart Association, Inc.

Letters to the Editor

Blood Pressure in Mutant Rats Lacking the 5-Hydroxytryptamine Transporter

Hubrecht Laboratory, Utrecht, The Netherlands

Branko Braam

Department of Nephrology and Immunology, University of Alberta, Alberta, Canada

Bart Ellenbroek

Department of Psychoneuropharmacology, Radboud University, Nijmegen, The Netherlands

Edwin Cuppen

Hubrecht Laboratory, Utrecht, The Netherlands

Jaap A. Joles

Department of Nephrology and Hypertension, University Medical Centre Utrecht, Utrecht, The Netherlands

To the Editor:

Although 5-HT uptake inhibitors are widely used as antidepressants, the role of 5-HT in the control of systemic blood pressure is far from clear.¹ In a recent issue of Hypertension, Ni et al reported that 5-hydroxytryptamine (5-HT) transporter (SERT) expression was increased, whereas SERT function was decreased in aorta of rats with DOCA salt and N-nitro-L-arginine (L-NNA)-induced hypertension.² We have observed that several 5-HT receptors are induced in leukocytes of hypertensive patients.³ These 2 observations could point at a functional response of the serotonin system to counter prohypertensive forces. We used the recently generated and unique SERT knockout rat to investigate whether the constitutive absence of SERT affected blood pressure and aggravated the development of hypertension and renal damage on NO synthesis inhibition.

A target-selected N-ethyl-N-nitrosourea–driven mutagenesis approach was used in Wistar rats to inactivate genes.⁴ High-throughput resequencing of genes of interest in a library of mutant rats resulted in the identification of a premature stop codon in the serotonin transporter. We have established that the homozygous SERT knockout (SERT^–/–) rat completely lacks functional SERT in the brain (data not shown). Furthermore, 5-HT in blood platelets, which plays a crucial role in vasoconstriction and has mitogenic activity in vascular smooth muscle, was almost completely lacking in SERT^–/– rats (Figure).

View larger version (12K): [in this window] [in a new window]   5-HT in blood platelets of SERT+/+, SERT+/–, and SERT–/– rats. 5-HT levels were determined by 5-HT enzyme immunoassay.

To characterize the SERT^–/– rat with respect to the cardiovascular system, we measured systolic blood pressure (SBP) in female SERT^–/–, SERT^+/–, and SERT^+/+ rats under control conditions and during chronic L-NNA administration (500 mg/L of drinking water⁵). Under control conditions, there were no differences in SBP between genotypes. Left ventricular (LV) weight/body weight and increases in SBP and LV/body weight during L-NNA (both P<0.01; 2-way ANOVA) were similar in all 3 of the groups (Table). Furthermore, under control conditions or L-NNA treatment, no differences were found in proteinuria, plasma urea and creatinine, and renal morphology (data not shown).

SERT-deficient mice also display normal blood pressure, although LV weight is reduced.⁶ It is at this functional level that the present data complement the data presented by Ni et al.² From our analysis in the SERT^–/– rat, it seems that the integrative role for SERT on blood pressure control by systemic hemodynamics and by the kidney to protect against the hypertensive effects of NO-shortage is limited. Furthermore, a protective role against glomerular damage caused by NO deficiency could not be substantiated.

	Acknowledgments

 
Disclosures

None.

	References

Top References

 
1. Watts SW. 5-HT in systemic hypertension: foe, friend or fantasy? Clin Sci (Lond). 2005; 108: 399–412.[Medline] [Order article via Infotrieve]

2. Ni W, Lookingland K, Watts SW. Arterial 5-hydroxytryptamine transporter function is impaired in deoxycorticosterone acetate and N{omega}-nitro-L-arginine but not spontaneously hypertensive rats. Hypertension. 2006; 48: 134–140.[Abstract/Free Full Text]

3. Chon H, Gaillard CA, van der Meijden BB, Dijstelbloem HM, Kraaijenhagen RJ, van Leenen D, Holstege FC, Joles JA, Bluyssen HA, Koomans HA, Braam B. Broadly altered gene expression in blood leukocytes in essential hypertension is absent during treatment. Hypertension. 2004; 43: 947–951.[Abstract/Free Full Text]

4. Smits BM, Mudde JB, van de Belt J, Verheul M, Olivier J, Homberg J, Guryev V, Cools AR, Ellenbroek BA, Plasterk RH, Cuppen E. Generation of gene knockouts and mutant models in the laboratory rat by ENU-driven target-selected mutagenesis. Pharmacogenet Genomics. 2006; 16: 159–169.[Medline] [Order article via Infotrieve]

5. Attia DM, Verhagen AM, Stroes ES, van Faassen EE, Grone HJ, De Kimpe SJ, Koomans HA, Braam B, Joles JA. Vitamin E alleviates renal injury, but not hypertension, during chronic nitric oxide synthase inhibition in rats. J Am Soc Nephrol. 2001; 12: 2585–2593.[Abstract/Free Full Text]

6. Eddahibi S, Hanoun N, Lanfumey L, Lesch KP, Raffestin B, Hamon M, Adnot S. Attenuated hypoxic pulmonary hypertension in mice lacking the 5-hydroxytryptamine transporter gene. J Clin Invest. 2000; 105: 1555–1562.[Medline] [Order article via Infotrieve]

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This Article Extract Full Text (PDF) All Versions of this Article: 48/6/e115    most recent 01.HYP.0000246306.61289.d8v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Homberg, J. Articles by Joles, J. A. Search for Related Content PubMed PubMed Citation Articles by Homberg, J. Articles by Joles, J. A. Pubmed/NCBI databases Medline Plus Health Information High Blood Pressure Related Collections Other hypertension