Non-N-Methyl D-Aspartate Receptors Are Involved in the Hypertension of D5 Dopamine Receptor Knockout Mice.
Dopamine receptors are important in the regulation of renal and cardiovascular function. Mice with disrupted D5 dopamine receptors develop vasopressin-dependent hypertension. Systolic and diastolic blood pressures (BP) were higher in homozygous, D5-/- (systolic BP 136±2 mmHg, diastolic BP 103±2 mmHg, n=45) and heterozygous, D5+/- (systolic BP 135±4 mmHg, diastolic BP 100±5 mmHg, n=8) compared with wild type mice, D5+/+ (systolic BP 104±1 mmHg, diastolic BP 79±1 mmHg, n=45). The maximum decrease in mean arterial pressure (MAPmax) caused by blockade of V1 vasopressin receptors [1-(β-mercapto-β, β-cyclopentamethylene propionic acid), 2-(O-methyl) tyrosine]-Arg8-vasopressin, 10 μg/kg) was greater in D5-/- mice (MAPmax -14±3%, n=13, P<0.05) than in D5+/+ mice (MAPmax -3±1%, n=8), suggesting that in the D5-/- mice V1 receptors were activated, presumably by a central nervous system (CNS) mechanism since circulating AVP levels were not elevated. α-adrenergic receptors were involved; α-adrenergic blockade with phentolamine decreased MAP to a greater and longer extent in D5-/- (MAPmax -21±3%,n=13) than in D5+/+ mice (MAPmax -12±5%, n=7, P<0.05). In the CNS, V1 receptors are linked to the sympathetic nervous system (SNS) via non-NMDA receptors. To prove a CNS-mediated mechanism of hypertension in D5-/- mice, we studied the effect of 2 non-NMDA antagonists on MAP. CNQX (1 mg/kg), a non-NMDA antagonist that does not cross the blood brain barrier had no effect on MAP in either D5-/- or D5+/+ mice. In contrast, the non-NMDA antagonist GYKI (8 mg/kg),which crosses the blood brain barrier, decreased MAP to a greater extent in D5-/- mice (MAPmax -12±4%, n=9, P<0.05) than in D5+/+ mice (MAPmax -3±1%, n=9). V1 and non-NMDA receptors were linked because the decrease in MAP in D5-/- mice caused by combined V1 and GYKI was similar to those caused by either drug, alone. Therefore, disruption of the D5 receptor produces a CNS-mediated hypertension via the interaction of V1 and non-NMDA receptors with the SNS.