DOPAMINE-3 RECEPTOR SUBTYPE AND HYPERTENSION

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DESCRIPTION: (Adapted from the application) Disruption of the D3-dopamine receptor gene in mice is associated with diastolic hypertension and an impaired ability to excrete an acute NaCl load. The investigator will test the hypothesis that postsynaptic or extrasynaptic D3 receptors are involved in the regulation sodium transport, renal hemodynamics and renin release, variables that are abnormal in genetic hypertension. Presynaptic dopamine D3 receptors may function as autoreceptors regulating norepinephrine and dopamine release from nerve terminals. Thus, the hypothesis that an increased norepinephrine release in peripheral noradrenergic nerves (the renal nerves) occurs as a result of disruption of presynaptic dopamine D3 receptors will be tested. The first Specific Aim will determine the mechanism(s) causing the high blood pressure that occurs with the disruption of the D3 dopamine receptor gene in mice. Three hypotheses will be tested. After disruption of the D3 receptor gene high blood pressure could occurs due to: (a) decreased ability of the D3 receptor, functioning as an autoreceptor, to inhibit norepinephrine release in noradrenergic nerve terminals; (b) increased renin secretion because of a withdrawal of the inhibitory action of post- or extrasynaptic D3 receptors on renin secretion; decreased synergism between D1, and D3 receptors impairing the ability to excrete a sodium load. 2. While disruption of the D3 receptor in mice produces high blood pressure, it is not known if a spontaneously occurring abnormal dopamine gene of the D3 class or its regulation causes genetic hypertension. The 2nd specific aim will determine if an abnormality of the D3 gene or its regulation exists in rats that develop hypertension spontaneously. Post- or extra-synaptic from pre-synaptic D3 gene expression and function will be distinguished by surgical/chemical unilateral renal denervation. If there are differences in D3 gene expression and/or function, then the D3 receptor gene will be sequenced and compared with the Wistar-Kyoto rat. The relevance of any changes in the D3 receptor function and gene expression in hypertension will be determined in F2 generation of SHR and WKY. The 3rd specific aim will test the hypothesis that the D3 dopamine receptor participates in the regulation of renin release by antagonizing the stimulatory effect of D1 receptors. Studies will be performed in isolated juxtaglomerular cells from WKY and SHR and mice lacking the D, or D3 dopamine receptor. These studies will determine the importance of the D3 receptor in the regulation of blood pressure and renal function in genetic hypertension.