Abstract
P185 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.
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