Effects of adenosine deaminase inhibition on blood pressure in old spontaneously hypertensive rats.
Adenosine is an ubiquitously occurring endogenous nucleoside that via cell surface receptors exerts multiple antihypertensive actions, and mediates a number of biological responses that may reduce cardiovascular disease risk. Therefore modulation of endogenous levels of adenosine may offer beneficial effects in hypertension. The objective of this study was to determine whether inhibition of adenosine deaminase lowers blood pressure in spontaneously hypertensive rats (SHR). We investigated the effects of erythro-9-(2-hydroxyl-3-nonyl) adenine (EHNA), an adenosine deaminase inhibitor, on hemodynamic and renal parameters in 16-week-old and 36-week-old SHR and normotensive Wistar Kyoto rats (WKY) and in 36-week-old SHR and WKY pretreated with 1,3-dipropyl-8-p-sulfopheznylxanthine (DPSPX, an adenosine antagonist that does not enter the brain and is restricted to the extracellular space). Adenosine deaminase inhibition with EHNA (10 mg/kg, iv.) produced a marked fall in arterial blood pressure in older (MABP 162.0+/-7.6 mmHg and 120.7+/-11.7 mmHg for baseline and EHNA period, respectively; p<0.01), but not younger, SHR, whereas no effects on blood pressure were observed in age-matched normotensive WKY rats. EHNA did not affect renal hemodynamic and excretory function in any of six groups of animals. DPSPX blocked the antihypertensive effects of EHNA, suggesting that the effects of EHNA on blood pressure are mediated via peripheral adenosine receptors. Further studies are required to elucidate why inhibition of adenosine deaminase lowers blood pressure only in older SHR. The present data suggest that inhibition of adenosine deaminase may provide beneficial effects in older hypertensives and lead us to propose that design and use of extracellular adenosine deaminase inhibitors may offer cardiovascular protection in hypertension.
Tofovic
S P
SP
Center for Clinical Pharmacology, Department of Medicine, University of Pittsburgh Medical Center, Pennsylvania 15213-2582, USA. TOFOVIC@NOVELL2.DEPT-MED.PITT.EDU
Kusaka
H
H
Li
P
P
Jackson
E K
EK
D000225:Adenine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000241:Adenosine / Q000037:antagonists & inhibitors; D058892:Adenosine Deaminase Inhibitors; D000375:Aging / Q000502:physiology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000503:physiopathology* / Q000652:urine; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR / Q000502:physiology* / Q000652:urine; D011921:Rats, Inbred WKY; D014970:Xanthines / Q000494:pharmacology
D058892:Adenosine Deaminase Inhibitors; D004791:Enzyme Inhibitors; D014970:Xanthines; C010192:9-(2-hydroxy-3-nonyl)adenine; C053896:1,3-dipropyl-8-(4-sulfophenyl)xanthine; D000225:Adenine; D000241:Adenosine