sch-23390 and Hypertension

D3 dopamine receptor (D3R)-deficient mice have renin-dependent hypertension associated with sodium retention, but the hypertension is mild. To determine whether any compensatory mechanisms in the kidney are involved in the regulation of blood pressure with disruption of Drd3, we measured the renal protein expression of all dopamine receptor subtypes (D1R, D2R, D4R, and D5R) in D3R homozygous (D3(-/-)) and heterozygous (D3(+/-)) knockout mice and their wild-type (D3(+/+)) littermates. The renal immunohistochemistry and protein expression of D5R were increased (n=5/group) in D3(-/-) mice; renal D4R protein expression was decreased, whereas renal protein expressions of D1R and D2R were similar in both groups. Renal D5R protein expression was also increased in D3(+/-) (n=5/group) relative to D3(+/+) mice, whereas D1R, D2R, and D4R protein expressions were similar in D3(+/-) and D3(+/+) mice. The increase in renal D5R protein expression was abolished when D3(-/-) mice were fed a high-salt diet. Treatment with the D1-like receptor antagonist, SCH23390, increased the blood pressure in anesthetized D3(-/-) but not D3(+/+) mice (n=4/group), suggesting that the renal upregulation of D5R may have minimized the hypertension in D3(-/-) mice. The renal D5R protein upregulation was not caused by increased transcription because renal mRNA expression of D5R was similar in D3(-/-) and D3(+/+) mice. Our findings suggest that the renal upregulation of D5R may have minimized the hypertension that developed in D3(-/-) mice.

Topics: Animals; Benzazepines; Hypertension; Immunohistochemistry; Kidney; Mice; Mice, Inbred C57BL; Receptors, Dopamine D3; Receptors, Dopamine D5; Sodium; Sodium Chloride, Dietary; Up-Regulation

Oral NaCl produces a greater natriuresis and diuresis than the intravenous infusion of the same amount of NaCl. Gastrin is the major gastrointestinal hormone taken up by renal proximal tubule (RPT) cells. We hypothesized that renal gastrin and dopamine receptors interact to synergistically increase sodium excretion, an impaired interaction of which may be involved in the pathogenesis of hypertension. In Wistar-Kyoto rats, infusion of gastrin induced natriuresis and diuresis, which was abrogated in the presence of a gastrin (cholecystokinin B receptor [CCKBR]; CI-988) or a D1-like receptor antagonist (SCH23390). Similarly, the natriuretic and diuretic effects of fenoldopam, a D1-like receptor agonist, were blocked by SCH23390, as well as by CI-988. However, the natriuretic effects of gastrin and fenoldopam were not observed in spontaneously hypertensive rats. The gastrin/D1-like receptor interaction was also confirmed in RPT cells. In RPT cells from Wistar-Kyoto but not spontaneously hypertensive rats, stimulation of either D1-like receptor or gastrin receptor inhibited Na(+)-K(+)-ATPase activity, an effect that was blocked in the presence of SCH23390 or CI-988. In RPT cells from Wistar-Kyoto and spontaneously hypertensive rats, CCKBR and D1 receptor coimmunoprecipitated, which was increased after stimulation of either D1 receptor or CCKBR in RPT cells from Wistar-Kyoto rats; stimulation of one receptor increased the RPT cell membrane expression of the other receptor, effects that were not observed in spontaneously hypertensive rats. These data suggest that there is a synergism between CCKBR and D1-like receptors to increase sodium excretion. An aberrant interaction between the renal CCK BR and D1-like receptors (eg, D1 receptor) may play a role in the pathogenesis of hypertension.

Topics: Animals; Benzazepines; Diuresis; Dopamine Agonists; Dopamine Antagonists; Fenoldopam; Gastrins; Hormone Antagonists; Hypertension; Indoles; Kidney; Meglumine; Natriuresis; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Dopamine D1

Signaling through both angiotensin AT1 receptors (AT1R) and dopamine D1 receptors (D1R) modulates renal sodium excretion and arterial BP. AT1R and D1R form heterodimers, but whether treatment with AT1R antagonists functionally modifies D1R via allosterism is unknown. In this study, the AT1R antagonist losartan strengthened the interaction between AT1R and D1R and increased expression of D1R on the plasma membrane in vitro. In rat proximal tubule cells that express endogenous AT1R and D1R, losartan increased cAMP generation. Losartan increased cAMP in HEK 293a cells transfected with both AT1R and D1R, but it did not increase cAMP in cells transfected with either receptor alone, suggesting that losartan induces D1R activation. Furthermore, losartan did not increase cAMP in HEK 293a cells expressing AT1R and mutant S397/S398A D1R, which disrupts the physical interaction between AT1R and D1R. In vivo, administration of a D1R antagonist significantly attenuated the antihypertensive effect of losartan in rats with renal hypertension. Taken together, these data imply that losartan might exert its antihypertensive effect both by inhibiting AT1R signaling and by enhancing D1R signaling.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Aortic Coarctation; Benzazepines; Cell Membrane; Cyclic AMP; Disease Models, Animal; HEK293 Cells; Humans; Hypertension; In Vitro Techniques; Kidney; Kidney Tubules, Proximal; Losartan; Male; Protein Binding; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptors, Dopamine D1; Signal Transduction

Intracerebroventricularly injected tachykinin NK(3) receptor (R) antagonists normalize mean arterial blood pressure (MAP) in spontaneously hypertensive rats (SHR). This study was pursued to define the role played by NK(3)R located on dopamine neurones of the ventral tegmental area (VTA) in the regulation of MAP in SHR.. SHR (16 weeks) were implanted permanently with i.c.v. and/or VTA guide cannulae. Experiments were conducted 24 h after catheterization of the abdominal aorta to measure MAP and heart rate (HR) in freely behaving rats. Cardiovascular responses to i.c.v. or VTA-injected NK(3)R agonist (senktide) and antagonists (SB222200 and R-820) were measured before and after systemic administration of selective antagonists for D(1)R (SCH23390), D(2)R (raclopride) or non-selective D(2)R (haloperidol), and after destruction of the VTA with ibotenic acid.. I.c.v. or VTA-injected SB222200 and R-820 (500 pmol) evoked anti-hypertension, which was blocked by raclopride. Senktide (10, 25, 65 and 100 pmol) elicited greater increases of MAP and HR when injected in the VTA, and the cardiovascular response was blocked by R-820, SCH23390 and haloperidol. VTA-injected SB222200 prevented the pressor response to i.c.v. senktide, and vice versa, i.c.v. senktide prevented the anti-hypertension to VTA SB222200. Destruction of the VTA prevented the pressor response to i.c.v. senktide and the anti-hypertension to i.c.v. R-820.. The NK(3)R in the VTA is implicated in the maintenance of hypertension by increasing midbrain dopaminergic transmission in SHR. Hence, this receptor may represent a therapeutic target in the treatment of hypertension.

Topics: Animals; Benzazepines; Blood Pressure; Dopamine; Haloperidol; Heart Rate; Hypertension; Ibotenic Acid; Indoles; Male; Oligopeptides; Peptide Fragments; Quinolines; Raclopride; Rats; Rats, Inbred SHR; Receptors, Neurokinin-3; Substance P; Ventral Tegmental Area

Locally produced dopamine in the renal proximal tubule inhibits salt and fluid reabsorption, and a dysfunctional intrarenal dopaminergic system has been reported in essential hypertension and experimental hypertension models. Using catechol-O-methyl-transferase knockout (COMT(-/-)) mice, which have increased renal dopamine because of deletion of the major renal dopamine-metabolizing enzyme, we investigated the effect of intrarenal dopamine on the development of hypertension in the deoxycorticosterone acetate/high-salt (DOCA/HS) model. DOCA/HS led to significant increases in systolic blood pressure in wild-type mice (from 115+/-2 to 153+/-4 mm Hg), which was significantly attenuated in COMT(-/-) mice (from 114+/-2 to 135+/-3 mm Hg). In DOCA/HS COMT(-/-) mice, the D1-like receptor antagonist SCH-23390 increased systolic blood pressure (156+/-2 mm Hg). DOCA/HS COMT(-/-) mice also exhibited more urinary sodium excretion (COMT(-/-) versus wild-type: 3038+/-430 versus 659+/-102 micromol/L per 24 hours; P<0.01). Furthermore, DOCA/HS-induced renal oxidative stress was significantly attenuated in COMT(-/-) mice. COX-2-derived prostaglandins in the renal medulla promote sodium excretion, and dopamine stimulates medullary prostaglandin production. Renal medullary COX-2 expression and urinary prostaglandin E2 excretion were significantly higher in COMT(-/-) than in wild-type mice after DOCA/HS treatment. In DOCA/HS-treated COMT(-/-) mice, the COX-2 inhibitor SC-58236 reduced urinary sodium and prostaglandin E(2) excretion and increased systolic blood pressure (153+/-2 mm Hg). These studies indicate that an activated renal dopaminergic system attenuates the development of hypertension, at least in large part through activating medullary COX-2 expression/activity, and also decreases oxidative stress resulting from DOCA/HS.

Topics: Analysis of Variance; Animals; Benzazepines; Blood Pressure Determination; Blotting, Western; Cyclooxygenase 2; Desoxycorticosterone; Dinoprostone; Disease Models, Animal; Dopamine; Hypertension; Immunohistochemistry; Kidney Medulla; Mice; Mice, Knockout; Probability; Random Allocation; Sodium Chloride, Dietary