Author: Ladines, Cecilia A. ; Pisegna, Joseph ; Asico, Laureano D. ; Semeraro, Claudio ; Wank, Stephen ; Pocchiari, Felice ; Zeng, Chunyu ; Jose, Pedro A. ; Yamaguchi, Ikuyo ; Eisner, Gilbert M. ; Sun, Xiaoguang

D1-like (D1, D5) and D2-like (D2, D3, D4) dopamine receptors interact in the kidney to produce a natriuresis and a diuresis. Disruption of D1or D3receptors in mice results in hypertension that is caused, in part, by a decreased ability to excrete an acute saline load. We studied D1-like and D2-like receptor interaction in anesthetized spontaneously hypertensive rats (SHR) by the intrarenal infusion of Z-1046 (a novel dopamine receptor agonist with rank order potency of D3≥D4>D2>D5>D1). Z-1046 increased glomerular filtration rate (GFR), urine flow, and sodium excretion in normotensive Wistar-Kyoto rats but not in SHRs. The lack of responsiveness to Z-1046 in SHRs was not an epiphenomenon, because intrarenal cholecystokinin infusion increased GFR, urine flow, and sodium excretion to a similar extent in the two rat strains. We conclude that renal D1-like and D2-like receptor interaction is impaired in SHRs. The impaired D1-like and D2-like receptor interaction in SHRs is not caused by alterations in the coding sequence of the D3receptor, the D2-like receptor expressed in rat renal tubules that has been shown to be involved in sodium transport. Because the diuretic and natriuretic effects of D1-like receptors are, in part, caused by an interaction with D2-like receptors, it is possible that the decreased Z-1046 action in SHRs is secondary to the renal D1-like receptor dysfunction in this rat strain.

01 Apr 2000·Journal of Cardiovascular PharmacologyQ4 · MEDICINE

Direct Vasodilating Effects of the New Dopaminergic Agonist Z1046 in Human Arteries

Q4 · MEDICINE

Article

Author: De Zeeuw, Dick ; Van Veldhuisen, Dirk J. ; Van Gilst, Wiek H. ; Buikema, Hendrik ; Teisman, Ard C. H.

Dopaminergic agonists remain of interest in the treatment of heart failure; however, concomitant stimulation of alpha- and beta-receptors should be avoided. This study evaluates the dopaminergic and adrenergic (vasodilating) properties of Z1046, epinine (the active metabolite of ibopamine), and dopamine. Isotonic contraction experiments were performed on human internal mammary artery rings in vitro. alpha1-Antagonistic effects of Z1046 were demonstrated by performing cumulative dose-response curves with the selective alpha1-agonist phenylephrine in the presence of Z1046. Furthermore, both alpha1- and dopamine-mediated receptor effects of Z1046, epinine, and dopamine were studied by performing cumulative dose-response relations both at baseline and in precontracted artery rings both with and without the D1-like antagonist SCH23390. In contrast to both epinine and dopamine, Z1046 is devoid of alpha1-receptor-mediated contraction. Furthermore, Z1046, epinine, and dopamine induced direct dopamine receptor-mediated vasodilation when interfering alpha1 effects were blocked. In contrast to epinine and dopamine, Z1046 is devoid of vasoconstricting properties at higher dosages. Because of its D1-like agonistic and alpha1-antagonistic properties, Z1046 is an effective vasodilator in the whole dosage range. Because of its total receptor profile, Z1046 appears to be more favorable for treatment of heart failure than is ibopamine.

01 Oct 1998·American Journal of Physiology-Regulatory, Integrative and Comparative Physiology

Effects of costimulation of dopamine D₁- and D₂-like receptors on renal function

Article

Author: Jose, Pedro A. ; Felder, Robin A. ; Pocchiari, Felice ; Eisner, Gilbert M. ; Asico, Laureano D. ; Semeraro, Claudio

In vitro studies have suggested that dopamine D1- and D2-like receptors interact to inhibit renal sodium transport. We used Z-1046, a dopamine receptor agonist with the rank-order potency D3≥ D4> D2> D5> D1, to test the hypothesis that D1- and D2-like receptors interact to inhibit renal sodium transport in vivo in anesthetized rats. Increasing doses of Z-1046, administered via the right renal artery, increased renal blood flow (RBF), urine flow, and absolute and fractional sodium excretion without affecting glomerular filtration rate. For determination of the dopamine receptor involved in the renal functional effects of Z-1046, another group of rats received Z-1046 at 2 μg ⋅ kg−1⋅ min−1( n = 10) in the presence or absence of the D2-like receptor antagonist domperidone and/or the D1-like antagonist SCH-23390. Domperidone alone had no effect but blocked the Z-1046-mediated increase in urine flow and sodium excretion; it enhanced the increase in RBF after Z-1046. SCH-23390 by itself decreased urine flow and sodium excretion without affecting RBF and blocked the diuretic, natriuretic, and renal vasodilatory effect of Z-1046. We conclude that the renal vasodilatory effect of Z-1046 is D1-like receptor dependent, whereas the diuretic and natriuretic effects are both D1- and D2-like receptor dependent.

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Indication	Highest Phase	Country/Location	Organization	Date
Heart Failure	Phase 1	-	-	-
Hypertension	Phase 1	-	-	-
Myocardial Ischemia	Phase 1	-	-	-
Myocardial Ischemia	Phase 1	IT	Zambon Company SpA	-
Hypertension	Discovery	-	Zambon GmbH	-

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