Impaired Ca2+ signaling attenuates P2X receptor-mediated vasoconstriction of afferent arterioles in angiotensin II hypertension.
This study tested the hypothesis that afferent arteriolar responses to purinoceptor activation are attenuated, and Ca2+ signaling mechanisms are responsible for the blunted preglomerular vascular reactivity in angiotensin II (Ang II) hypertension. Experiments determined the effects of ATP, the P2X1 agonist beta,gamma-methylene ATP or the P2Y agonist UTP on arteriolar diameter using the juxtamedullary nephron technique and on renal myocyte intracellular Ca2+ concentration ([Ca2+]i) using single cell fluorescence microscopy. Six or 13 days of Ang II infusion significantly attenuated the vasoconstrictor responses to ATP and beta,gamma-methylene ATP (P<0.05). During exposure to ATP (1, 10, and 100 micromol/L), afferent diameter declined by 17+/-2%, 29+/-3%, and 30+/-2% in normal control rats and 8+/-3%, 7+/-3%, and 22+/-3% in kidneys of Ang II-infused rats (13 days). Renal myocyte intracellular calcium responses to ATP or beta,gamma-methylene ATP were also decreased in Ang II hypertensive rats. In myocytes of control rats, peak increases in [Ca2+]i averaged 107+/-21, 170+/-38, and 478+/-79 nmol/L at ATP concentrations of 1, 10, and 100 micromol/L, respectively. Ang II infusion for 13 days decreased the peak responses to ATP (1, 10, and 100 micromol/L) to 65+/-13, 102+/-20, and 367+/-73 nmol/L, respectively. The peak increases in [Ca2+]i in response to beta,gamma-methylene ATP were also reduced in Ang II hypertensive rats. However, angiotensin hypertension did not change the UTP-mediated vasoconstrictor responses or the myocyte calcium responses to UTP. These results indicate that the impaired autoregulatory response observed in Ang II-dependent hypertension can be attributed to impairment of P2X1 receptor-mediated signal transduction.
Zhao
Xueying
X
Vascular Biology Center, Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30912-3000, USA.
Cook
Anthony K
AK
Field
Mary
M
Edwards
Brentan
B
Zhang
Shali
S
Zhang
Zhanying
Z
Pollock
Jennifer S
JS
Imig
John D
JD
Inscho
Edward W
EW
D000241:Adenosine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000804:Angiotensin II; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000503:physiopathology*; D001794:Blood Pressure; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D006706:Homeostasis; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D007425:Intracellular Membranes / Q000378:metabolism; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism; D008297:Male; D008833:Microcirculation; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D058910:Purinergic P2 Receptor Agonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D043682:Receptor, Adenosine A1 / Q000187:drug effects / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000187:drug effects / Q000378:metabolism*; D058469:Receptors, Purinergic P2X; D014544:Uridine Triphosphate / Q000494:pharmacology; D014661:Vasoconstriction
D058910:Purinergic P2 Receptor Agonists; D043682:Receptor, Adenosine A1; D018048:Receptors, Purinergic P2; D058469:Receptors, Purinergic P2X; D000804:Angiotensin II; C005147:5'-adenylyl (beta,gamma-methylene)diphosphonate; D000255:Adenosine Triphosphate; D000241:Adenosine; D002118:Calcium; D014544:Uridine Triphosphate