Renal medullary effects of transient prehypertensive treatment in young spontaneously hypertensive rats.
OBJECTIVE
Transient angiotensin II receptor blockade (ARB) leads to prolonged blood pressure (BP) lowering, but the underlying mechanism remains uncertain. Long-term BP control is regulated by the medullary microcirculation with the pericyte as contractile cell. We hypothesize that the prolonged BP effect is caused by increased medullary blood flow (MBF) associated with structural alterations based on reduced medullary pericyte number.


METHODS
Four-week-old spontaneously hypertensive rats (SHR) were treated for 4 weeks with losartan (SHR-Los: 20 mg kg(-1) day(-1)), hydralazine (SHR-Hyd: 15 mg kg(-1) day(-1)), losartan and pan-caspase inhibitor zVAD (SHR-Los + 1 mg kg(-1) day(-1) zVAD), losartan and glycogen synthase kinase-3beta (GSK) inhibitor valproate (SHR-Los + 10 mg kg(-1) day(-1) Val) or placebo. BP, MBF and pericyte number were determined under and after treatment (8 and 12 weeks). Apoptotic pericytes were determined with alpha-actin and TUNEL double staining. Sodium concentration was determined in renal medulla and urine.


RESULTS
Antihypertensive treatment equipotently reduced BP at 8 weeks of age. After drug withdrawal (12 weeks of age) BP reduction was restricted to SHR-Los (SHR-Los: 153 +/- 5, SHR-Hyd: 177 +/- 2, SHR: 184 +/- 3 mmHg). Simultaneously, MBF was increased and pericyte number reduced, while medullary and urinary sodium concentration increased. Transient ARB in combination with zVAD or valproate resulted in more medullary pericytes and higher BP (SHR-Los/zVAD: 164 +/- 7; SHR-Los/Val: 168 +/- 6 mmHg) compared with transient ARB alone.


CONCLUSIONS
After drug withdrawal, transient ARB leads to increased MBF and is associated with a reduction in medullary pericytes. This may be associated with pericyte apoptosis as anti-apoptosis during transient ARB increases pericyte number and BP.
Baumann
M
M
Department of Pharmacology & Toxicology, CARIM, University Maastricht, Maastricht, the Netherlands. marcus.baumann@lrz.tum.de
Janssen
B J A
BJ
Rob Hermans
J J
JJ
Bartholome
R
R
Smits
J F M
JF
Struijker Boudier
H A J
HA
D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004359:Drug Therapy, Combination; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006830:Hydralazine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D006973:Hypertension / Q000517:prevention & control*; D007679:Kidney Medulla / Q000098:blood supply / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D009994:Osmolar Concentration; D020286:Pericytes / Q000166:cytology / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012079:Renal Circulation / Q000187:drug effects; D012964:Sodium / Q000378:metabolism / Q000652:urine; D014556:Urine / Q000737:chemistry; D014635:Valproic Acid / Q000008:administration & dosage / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid; D006830:Hydralazine; D014635:Valproic Acid; D012964:Sodium; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D019808:Losartan