Angiotensin-II type 1 receptor-mediated hypertension in D4 dopamine receptor-deficient mice.
Dopamine receptors are important in systemic blood pressure regulation. D4 receptors are expressed in the kidney and brain, but their role in cardiovascular regulation is unknown. In pentobarbital-anesthetized mice, systolic and diastolic blood pressures were elevated in sixth-generation D4 receptor-deficient (D4(-/-)) mice and in tenth-generation D4(-/-) mice compared with D4 wild-type (D4(+/+)) littermates. The conscious blood pressures measured via a chronic arterial (femoral) catheter or telemetry (carotid) were also higher in D4(-/-) mice than in D4 littermates. Basal renal and plasma renin concentrations were similar in the 2 mouse strains. The protein expression of angiotensin II type 1 receptor was increased in homogenates of kidney (330+/-53%, n=5) and brain (272+/-69%, n=5) of D4(-/-) mice relative to D4(+/+) mice (kidney: 100+/-12%, n=5; brain: 100+/-32%, n=5). The expression of the receptor in renal membrane was also increased in D4(-/-) mice (289+/-28%, n=8) relative to D4(+/+) mice (100+/-14%, n=10). In contrast, the expression in the heart was similar in the 2 strains. Bolus intravenous injection of angiotensin II type 1 receptor antagonist losartan initially decreased mean arterial pressures to a similar degree in D4(-/-) and D4(+/+) littermates. However, the hypotensive effect of losartan dissipated after 10 minutes in D4(+/+) mice, whereas the effect persisted for >45 minutes in D4(-/-) mice. We conclude that the absence of the D(4) receptor increases blood pressure, possibly via increased angiotensin II type 1 receptor expression.
Bek
Martin J
MJ
Department of Pediatrics, Georgetown University Medical Center, Washington, DC 20057, USA.
Wang
Xiaoyan
X
Asico
Laureano D
LD
Jones
John E
JE
Zheng
Shaopeng
S
Li
Xiaoxi
X
Eisner
Gilbert M
GM
Grandy
David K
DK
Carey
Robert M
RM
Soares-da-Silva
Patricio
P
Jose
Pedro A
PA
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D002396:Catechols / Q000652:urine; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism*; D050638:Receptors, Dopamine D4 / Q000172:deficiency*; D012083:Renin / Q000097:blood / Q000378:metabolism; D012964:Sodium / Q000378:metabolism / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D002396:Catechols; D044140:Receptor, Angiotensin, Type 1; D050638:Receptors, Dopamine D4; D012964:Sodium; D012083:Renin; D000254:Sodium-Potassium-Exchanging ATPase; D019808:Losartan