Disruption of the dopamine D3 receptor gene produces renin-dependent hypertension.

Since dopamine receptors are important in the regulation of renal and cardiovascular function, we studied the cardiovascular consequences of the disruption of the D3 receptor, a member of the family of D2-like receptors, expressed in renal proximal tubules and juxtaglomerular cells. Systolic and diastolic blood pressures were higher (approximately 20 mmHg) in heterozygous and homozygous than in wild-type mice. An acute saline load increased urine flow rate and sodium excretion to a similar extent in wild-type and heterozygous mice but the increase was attenuated in homozygous mice. Renal renin activity was much greater in homozygous than in wild-type mice; values for heterozygous mice were intermediate. Blockade of angiotensin II subtype-1 receptors decreased systolic blood pressure for a longer duration in mutant than in wild-type mice. Thus, disruption of the D3 receptor increases renal renin production and produces renal sodium retention and renin-dependent hypertension.

Impact of local guidelines and an integrated dispensing system on antibiotic prophylaxis quality in a surgical centre.

Surgical antibiotic prophylaxis is effective in preventing postoperative wound infections. Guidelines are designed to optimize antimicrobial use in this setting. The aim of this study was to assess antibiotic use in surgical prophylaxis in a surgical hospital before and after the implementation of both local antibiotic prophylaxis guidelines and a specific medication set for various surgical procedures. The appropriateness of surgical antibiotic prophylaxis increased from 50.9% in the pre-implementation stage to 94.9% in the postimplementation stage (P<0.001). The implementation of a multidisciplinary protocol and design of medication sets helped to improve the practice of surgical antibiotic prophylaxis.

Pharmacological evidence for the presence of a peripheral postjunctional D2-like dopamine receptor in rabbit splenic artery.

1. This study was designed to investigate the involvement of postjunctional D2-like receptors in a rabbit vasculature model used to evaluate the D1-like agonist activity. Dopamine, epinine and (-)-DP-5,6-ADTN, three mixed D1/D2-like agonists, fenoldopam and SKF 82958, two selective D1-like agonists and SKF 89124, a selective D2-like agonist, were administered cumulatively in precontracted and alpha/beta-blocked rabbit splenic artery rings in order to evaluate their D1-like-mediated vasorelaxant activity before and after pretreatment with the selective D2-like antagonist YM 09151-2 (1 nM). 2. Dopamine (pD2=6.35+/-0.09), epinine (pD2=6.73+/-0.13), (-)-DP-5,6-ADTN (pD2=7.56+/-0.09) and SKF 82958 (pD2=8.55+/-0.10) reversed completely the U46619-induced contracture whereas SKF 89124 was inactive up to 10 microM and fenoldopam acted like a partial agonist (pD2=8.31+/-0.09, alpha=0.62). The selective D2-like dopamine receptor antagonist YM 09151-2 (1 nM) significantly (P<0.05) potentiated the vasorelaxant activity of dopamine (pD2=7.01+/-0.07), epinine (pD2=7.14+/-0.08), (-)-DP-5,6-ADTN (pD2=8.19+/-0.09) and SKF 89124 (40% relaxation at 10 microM), whereas it did not alter the effects of fenoldopam (pD2=8.40+/-0.09, alpha=0.68) and SKF 82958 (pD2=8.58+/-0.08). 3. The D2-like antagonist YM 09151-2 induced the same degree of effect with all the substances tested in both endothelium-denuded and endothelium-intact preparations. 4. The selective D2-like dopamine receptor agonist SKF 89124 did not produce any intrinsic effect on the splenic artery, but was able to produce a rightward shift of the forskolin-induced relaxation. 5. The results of these experiments support the existence of a non-endothelial postjunctional D2-like dopamine receptor counteracting the D1-like-mediated vasodilatation in rabbit splenic artery, probably by the inhibition of adenylate cyclase.

Effects of dopamine and selective dopamine agonists upon platelet accumulation in the cerebral and pulmonary vasculature of the rabbit.

1. A selection of novel compounds were shown to exhibit dopaminergic activity in vitro. 2. 111Indium-labelled platelets were continuously monitored in the cerebral and pulmonary vasculature of anaesthetized rabbits. The effects of dopamine and selective dopamine receptor agonists on ADP and thrombin induced platelet accumulation were recorded. 3. Pretreatment with dopamine (2 mg kg(-1) min(-1), i.v.) significantly reduced ADP (20 microg kg(-1), i.v.) induced platelet accumulation in the pulmonary vasculature whereas lower doses had no effect. 4. Dopamine (100 microg kg(-1) min(-1) intra-carotid, i.c.) potentiated thrombin (90 u kg(-1), i.c.) induced platelet accumulation in the cerebral vasculature whereas higher doses (1-2 mg kg(-1) min[-1]) inhibited accumulation. 5. The selective dopamine receptor agonists tested did not significantly inhibit platelet accumulation induced by ADP or thrombin. Two of these selective agonists, at doses higher than the intended therapeutic doses, induced thrombocytopaenia and an associated increase in platelet accumulation in the lung in response to thrombin. 6. These results extend previous in vitro studies regarding the dual actions of dopamine upon platelets and show for the first time the effects of selective dopamine receptor agonists upon platelet aggregation in vivo.

The effect of selective phosphodiesterase 3 and 4 isoenzyme inhibitors and established anti-asthma drugs on inflammatory cell activation.

1. This study aimed to evaluate the effects of phosphodiesterase (PDE) inhibitors and currently prescribed anti-asthma drugs for their ability to inhibit inflammatory cell activation in vitro. 2. Alveolar macrophages and eosinophils were isolated from the bronchoalveolar lavage (BAL) fluid of ovalbumin (Ovalb)-sensitized guinea-pigs. Opsonized zymosan (OZ) and PAF stimulated leukotriene B4 (LTB4) release from eosinophils was measured by radioimmunoassay. Ovalb-induced superoxide generation was measured by reduction of cytochrome C. 3. Monocytes were separated from human peripheral venous blood and mast cells were dispersed from human lung fragments. Lipopolysaccharide (LPS)-induced tumour necrosis factor-alpha (TNF-alpha) release from monocytes was measured by ELISA and anti-IgE stimulated histamine release from mast cells was measured by a radioenzymatic method. 4. The beta 2 agonist, salbutamol inhibited TNF-alpha release from monocytes and histamine release from mast cells whilst having no effect on eosinophil-derived LTB4 release or macrophage superoxide generation. 5. The PDE 3 inhibitor, milrinone produced a concentration-related inhibition of TNF-alpha release from monocytes which achieved statistical significance at 10(-5) M but inhibited LTB4 release from eosinophils and superoxide generation from macrophages only at the highest concentration (10(-3) M) examined. Milrinone had no effect on histamine release from mast cells. 6. The selective PDE 4 inhibitors, denbufylline and rolipram and the corticosteroid, beclomethasone produced a concentration-related inhibition of LTB4 release from eosinophils, TNF-alpha release from monocytes and superoxide generation from alveolar macrophages whilst having no effect on histamine release from mast cells. 7. The mixed PDE 3/4 inhibitor, benzafentrine produced a concentration-related inhibition of LTB4 release from eosinophils, TNF-alpha release from monocytes, superoxide generation from alveolar macrophages and histamine release from mast cells. 8. In conclusion these data clearly show that both established anti-asthma medication as well as PDE inhibitors have the potential to inhibit inflammatory cell activation in vitro but that the anti-secretory actions of beta 2 agonists, corticosteroids and PDE inhibitors are distinct.

Renal function studies with propildazine alone and in combination with propranolol in dogs.

The vasodilator antihypertensive propildazine acutely administered in awake dogs (0.1 mg/kg i.v.) produced an arterial blood pressure drop accompanied by tachycardia, decreased urine volume and urinary sodium excretion, and increased urinary potassium excretion. A transient, quickly reversible decrease in glomerular filtration rate was observed; on the contrary, the reduction in urine volume and urinary sodium excretion was longer lasting. There was indirect evidence that sodium retention was mainly caused by increased tubular reabsorption. Decreases in renal resistance, renal extraction of p-aminohippurate, and filtration fraction were observed together with an increase in renal plasma flow. Propildazine at the above dose in combination with propranolol (1 mg/kg i.v.) had a hypotensive effect with a smaller increase in heart rate and without significant variations in urine volume or urinary sodium excretion. These effects could be attributed to antagonism of the reflex-activated sympathoadrenal system by propranolol. In these conditions, the glomerular filtration rate was not significantly modified, while the effects on other renal parameters were similar to those observed with propildazine.

The dopamine receptor agonist Z1046 reduces ischaemia severity in a canine model of coronary artery occlusion.

Z1046, (S)-6[[6-[[2-(2-methoxyphenoxy)ethyl]amino]propyl]amino]-5,6,7,8-tetra-h ydro-1,2-naphtalenediol dihydrochloride, is an agonist at both dopamine D1 and D2 receptors. Since stimulation of dopamine D2 receptors inhibits noradrenaline release, and because cardiac noradrenaline release has been implicated in the genesis of early ischaemia-induced, life-threatening ventricular arrhythmias, the effect of Z1046 has been examined for its effects on coronary artery occlusion in chloralose urethane anaesthetised mongrel dogs. Z1046 (10 microg kg(-1) intravenously or 1 microg kg(-1) by local intracoronary injection) decreased heart rate and reduced arterial blood pressure and coronary blood flow, effects prevented by the prior administration of domperidone (40 microg kg(-1) i.v.). The ischaemic changes induced by a 25-min occlusion of the left anterior descending coronary artery (including ST-segment elevation and ventricular ectopic activity) were much less marked in those dogs administered Z1046 and survival from the combined ischaemia reperfusion insult was increased from 7% to 36% (P < 0.05). These effects of Z1046 were partly attenuated by domperidone. We conclude that the anti-ischaemic effects of Z1046 are due to inhibition of cardiac sympathetic responses. Studies using rat isolated perfused mesenteric vascular bed preparations subjected to sympathetic nerve stimulation confirmed that Z1046 inhibits synaptic transmission without modifying vascular responses to noradrenaline.

Peripheral vascular and neuronal effects of dopamine receptor agonists. A comparison with receptor binding studies in rat striatum.

A series of dopamine (DA)-receptor agonists was tested in vitro on vascular DA1- and neuronal DA2-receptors and the activity observed was compared to their ability to compete with [3H]-SCH23390 and [3H]-domperidone binding to rat striatal membranes. In rabbit splenic artery, where the presence of the DA1-receptor is established, DA and related agonists produced a complete concentration-dependent relaxation of the thromboxane A2-mimetic U46619-induced tone in IBMX (3-isobutyl-1-methylxanthine) treated preparations. The DA vasorelaxant effect proved to be mediated by DA1-receptors, being inhibited by the selective DA1-receptor antagonist SCH23390. Fenoldopam proved to be the most potent agonist in the rabbit splenic artery consistent with the result obtained in the D1-receptor binding assay. Epinine was about 5 times more potent than DA and only 3 times less active than fenoldopam on DA1-receptors although the D1-receptor binding study did not reveal major differences from DA. An opposite profile was observed with N,N-di-n-propyl dopamine (DPDA) showing a functional potency lower than that expected from the binding assay. In cat right atrium, DA and related agonists caused concentration-dependent inhibition of the tachycardia induced by electrical stimulation. The DA effects proved to be mediated by presynaptic DA2-receptor activation, being inhibited by the selective DA2-receptor antagonist domperidone. The DA2-receptor agonist 6-(di-n-propylamino)-5,6,7,8-tetrahydro-1,2-naphthalenediol (DP-5,6-ADTN) was the most potent compound both in the cat atrium and in the binding assay. Epinine was 2 times more potent than DA on DA2-receptors but it showed no differences in the D2-receptor binding assay.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect duration of selective phosphodiesterase inhibitors in the guinea pig.

The beta-adrenoceptor agonists, isoprenaline, salbutamol and salmeterol, the non-selective phosphodiesterase (PDE) isoenzyme inhibitors, theophylline, trequinsin; the PDE3 isoenzyme inhibitor, milrinone; the PDE3/4 isoenzyme inhibitor, benzafentrine; and the PDE4 isoenzyme inhibitors, denbufylline, nitraquazone, RP 73401, Ro-20-1724, rolipram and tibenelast all induced concentration-dependent reversal of prostaglandin F2alpha-induced contraction of guinea-pig superfused trachea in vitro. The relaxant response of the non-selective PDE isoenzyme inhibitor trequinsin was slow in onset and demonstrated very slow recovery, similar to that observed with the long-acting beta2-adrenoceptor agonist, salmeterol and the PDE4 inhibitor, RP 73401. The relaxant agonists also significantly reversed bombesin-induced bronchospasm in anaesthetised guinea-pigs and there was a highly significant correlation between the ability of drugs to reverse PGF2alpha-induced contraction of guinea-pig isolated trachea in vitro and bombesin-induced bronchoconstriction in vivo. Furthermore, both salmeterol and trequinsin demonstrated long lasting bronchodilator responses consistent with the in vitro data. These results show that PDE isoenzyme inhibitors demonstrate different pharmacodynamic profiles that is not determined by PDE4 inhibitory potency and indicate that other factors may be important in this regard.

Attempt to improve transcutaneous bilirubinometry: a double-blind study of Medick BiliMed versus Respironics BiliCheck.

OBJECTIVES: To compare the accuracy of a new transcutaneous bilirubinometer, BiliMed (Medick SA, Paris, France) with BiliCheck (Respironics, Marietta, GA, USA), a widely available instrument, and with total serum bilirubin measurement. DESIGN: A prospective double-blind study comparing the two devices was carried out. 686 healthy newborns needing measurement of their bilirubin were enrolled over a 4-month period. Serum and transcutaneous bilirubin measurements were taken with both devices within 15 minutes. The order of use of the instruments was randomised. SETTING: Well-baby nursery ward in a university hospital, tertiary referral centre. RESULTS: The linear regression analysis showed a better correlation between BiliCheck and serum bilirubin (r = 0.75) than between BiliMed and serum bilirubin (r = 0.45). BiliCheck variability (+/-2 SD of the mean bias from serum bilirubin) was within -87.2 to 63.3 micromol/l, while BiliMed variability was within -97.5 to 121.4 micromol/l. The receiver operating characteristic analysis (for serum bilirubin levels >205.2 micromol/l or >239.4 micromol/l) showed significantly higher areas under the curve for BiliCheck than those for BiliMed (p<0.001). CONCLUSIONS: Despite the potential practical advantages of BiliMed, its reduced diagnostic accuracy in comparison with BiliCheck does not justify its use in clinical practice.

Interleukin 6 variable number of tandem repeats (VNTR) gene polymorphism in centenarians.

Recent population-based studies identified the magnitude of interleukin 6 (IL6) serum levels as a marker for functional disability, and a predictor of disability and mortality among the elderly. We investigated whether there was evidence in Southern Italy of an association between the IL6 gene variable number of tandem repeats (VNTR) polymorphism and extreme longevity, and tested for the possible interaction of apolipoprotein E (APOE) alleles with the IL6 VNTR alleles. Four alleles coding for variants of four different lengths have been identified: allele A [760 base pairs (bp)], allele B (680 bp), allele C (640 bp), and allele D (610 bp). IL6 VNTR and APOE allele and genotype frequencies were studied in a total of 61 centenarians and 94 middle-aged subjects from Southern Italy. The IL6 VNTR allele B was overrepresented in the younger control group compared with centenarians (odds ratio: 0.56, 95% confidence interval: 0.35-0.88, Bonferroni p-value < 0.05). No interactions between IL6 VNTR alleles and APOE alleles on the odds ratios to reach extreme longevity were evaluated for the smallest number of subjects in centenarians and younger controls. Our findings suggested that the presence of the IL6 VNTR allele B could be detrimental for reaching extreme longevity.

Pharmacological studies on cadralazine: a new antihypertensive vasodilator drug.

Cadralazine is a new, orally effective antihypertensive vasodilator. Acute experiments indicate that the compound reduces blood pressure and increases heart rate. The doses which reduce systolic blood pressure by 25% (ED25) are very similar after oral and intravenous administration (spontaneously hypertensive rats, 1.8 mg/kg, p.o.; 2.3 mg/kg, i.v.; renal hypertensive dogs, 0.26 mg/kg, p.o.; 0.24 mg/kg, i.v.; awake normotensive dogs, 0.98 mg/kg, p.o.; 1.01 mg/kg, i.v.). By both routes the peak effect is reached after 3-5 hr, and the activity lasts more than 24 hr. Repeated oral administration in spontaneously hypertensive rats reduces blood pressure with no evidence of tolerance. Cadralazine reverses hypertensive responses to epinephrine in awake normotensive dogs and anesthetized cats. The inhibition of the increase in blood pressure induced by sympathetic outflow activation in pithed rats parallels the antihypertensive activity in onset, intensity, and duration. The effects of cadralazine are not due to a blockade of alpha-adrenoceptors, sympathetic neurons, or ganglionic transmission. Cadralazine has no antihistaminic, anticholinergic, or spasmolytic activity and no specific effect on behavioral tests. In comparison with hydralazine, cadralazine has less acute toxicity and a greater activity by the oral route.

Hemodynamic profile of the antihypertensive vasodilator cadralazine in conscious dogs.

Hemodynamic activity of cadralazine (ethyl-2-[6-(2-hydroxypropyl)-ethylaminol-3-pyridazinyl hydrazine carboxylate), a new, long-acting antihypertensive agent, was evaluated on systemic and regional circulation in conscious dogs. Cadralazine given i.v. (1 mg/kg) caused a sustained fall in total peripheral vascular resistances and mean blood pressure (from 103 to 90 mmHg) and an increase in heart rate (from 97 to 161 beats/min). Heart rate variations paralleled the drop in peripheral resistances. Cadralazine produced a consistent increase in cardiac output, and this effect was related to the increase in heart rate. No significant change in myocardial contractility was observed. Blood flow was increased and vascular resistances decreased in coronary, iliac and mostly in renal vascular beds, whereas the variations in the mesenteric district were not significant. This hemodynamic pattern characterizes cadralazine as a vasodilator. Changes in hemodynamic responses to epinephrine (1 microgram/kg i.v.) after cadralazine treatment were also evaluated. Cadralazine reduced hypertension and bradycardia effects, increased hypotension and tachycardia responses, and caused a further increase in cardiac output and coronary blood flow. These effects of cadralazine are not due to alpha-blocking or to beta-stimulating properties.

Renal function studies with cadralazine in conscious dogs: a comparison with hydralazine.

The effect of the antihypertensive vasodilator, cadralazine, on renal function in the conscious dog was compared to that of hydralazine using inulin and para-aminohippurate clearances. Both drugs were administered as intravenous bolus, at the dose of 1 mg/kg. As expected, hydralazine rapidly decreased mean blood pressure (from 110 to 89 mmHg), significantly increased heart rate (from 109 to 190 beats/min), markedly decreased urine volume (from 0.90 to 0.47 ml/min) and sodium excretion (from 101 to 45 microEq/min), and increased potassium excretion (from 28 to 53 microEq/min). Cadralazine displayed a similar activity on blood pressure and on heart rate, but differently from hydralazine, these effects appeared more slowly and were not accompanied by sodium and water retention. Hydralazine, but not cadralazine, caused a quick and transient decrease in glomerular filtration rate (from 55 to 40 ml/min), whereas both compounds increased renal plasma flow and reduced renal vascular resistance, renal extraction of para-aminohippurate and filtration fraction. Moreover, cadralazine increased plasma renin activity to a lesser extent than hydralazine, and this could explain the different effect on water and sodium excretion after acute administration of the two drugs.

Pharmacokinetics and disposition of the novel dopamine agonist Z-7760 in rat after intravenous and oral administration.

1. Z-7760 (S(-)-N-[N-2-phenylethyl)-6-hexylamino]-N-propyl-5,6-dihydroxy-1,2,3,4-tetrahydro-2-naphthylamine dihydrobromide) is a potent dopamine D-1 and D-2 agonist synthesized during a search for agents to treat heart failure. Reported is the fate of the drug in rat. 2. 3H-Z-7760 was administered p.o. and i.v. to male Sprague-Dawley rats (0.4 mg and 400 microCi/kg in 0.1% ascorbic acid) and venous blood samples collected at intervals up to 48 h. Comparison of the AUC for total 3H showed that 37% of an oral dose of Z-7760 was absorbed. The percentage plasma 3H present as the parent compound fell from 82% 30 min after i.v. dosing to 12% after 24 h. After oral dosing, the fraction of plasma 3H present as unchanged Z-7760 was < 5% and this was essentially unaltered throughout the study. The long terminal elimination phase evident from 6 h was notable after both routes of administration. 3. The bile duct-cannulated rat was given 3H-Z-7760 p.o. (0.4 mg and 40 microCi/kg) and bile was collected for up to 22 h. Biliary excretion accounted for 30% of the dose. No parent compound was detected in the bile. 4. In further studies, other rats were dosed p.o. or i.v. with 3H-Z-7760 (0.4 mg and 400 microCi/kg) and urine and faeces were collected daily for 3 days. The major route of excretion was the faeces with 94-97% 3H recovered after oral and 70-73% after i.v. dosing. A further 4-7% was recovered in the urine after oral and 12-13% after i.v. dosing. 5. After oral administration of Z-7760 (100 mg/kg, 40 microCi/kg) to rats, the major metabolites in the urine were identified as the 5-O-methyl and glucuronic acid conjugates of Z-7760 by LC and MS. The glucuronide was only seen in urine after oral administration but 5-O-methyl-Z-7760 was present in urine and faeces after both routes of administration. 6. The low bioavailability of Z-7760 is the consequence of its poor absorption from the gastrointestinal tract as well as extensive first-pass metabolism that further reduces systemic blood concentrations after oral administration.

Cardiovascular and renal action of dopaminergic prodrugs.

The possibility of exploiting the cardiovascular and renal action of dopamine for therapeutic purposes is enhanced by its conversion into orally active prodrugs. Following an outline of the medicinal chemistry bases of the development of these prodrugs, laboratory and clinical pharmacology of ibopamine, levodopa, gludopa, and TA-870 are reviewed, pointing out the interesting indications of various preliminary studies in heart failure, essential hypertension, and renal failure on the one hand, and the extensive therapeutic experience with ibopamine as an "inodilator" in the chronic treatment of congestive heart failure on the other hand. New experimental results are also reported for ibopamine and for the novel prodrug Sim 2055, i.e., epinine-4-O-phosphate. The latter is shown to act as a selective renal vasodilator on oral administration in dogs and it is therefore proposed for clinical investigation in renal failure and in essential hypertension.

Lacidipine: a calcium antagonist with potent and long-lasting antihypertensive effects in animal studies.

Lacidipine, currently being evaluated as a once-daily antihypertensive agent, acted as a calcium entry blocker on rabbit ear artery (pA2 = 9.4) with a markedly slower onset of action than that of nitrendipine; this effect was not reversed after 9 h of drug washout. Calcium entry blocker activity was also evaluated on nonvascular smooth muscles: Lacidipine showed a more pronounced vascular selectivity than nitrendipine; for both drugs, concentrations required to induce negative inotropic effects in guinea pig ventricular strip were approximately 100 times higher than concentrations needed to antagonize calcium contraction in vascular smooth muscle. In spontaneously hypertensive rats (SHR), by the tail-cuff method, lacidipine (ED25 = 0.35 mg/kg orally, p.o.) proved approximately 30 times more potent, slower in onset, and longer-acting than nitrendipine in reducing blood pressure. These features were confirmed in chronically implanted SHR after oral and intravenous (i.v.) administration (ED25 = 0.19 mg/kg p.o. and 0.006 mg/kg i.v.). A short-lasting tachycardia was detected with both drugs. No evidence of acquired tolerance emerged after repeated oral administrations over a 3-week period. Lacidipine induced a natriuretic effect in saline-loaded SHR at antihypertensive doses. In renal hypertensive dogs, lacidipine proved more potent (three to seven times), slower in onset, and longer-lasting than nitrendipine after p.o. (ED25 = 0.22 mg/kg) and i.v. (ED25 = 0.004 mg/kg) administrations.

The role of dopaminergic agonists in congestive heart failure.

Congestive Heart Failure is a clinical syndrome characterised by myocardial dysfunction and sympathetic activation. Plasma norepinephrine (NE) levels have been related to the poorest survival. Large-scale clinical trials have proved the clinical benefits of Angiotensin Converting Enzyme inhibitors in reducing the risk of death and hospitalisation. However, mortality remains high in the treated group underlining the need to explore new therapeutic approaches. Specific activation of peripheral dopamine receptors exerts profound hemodynamic effects and neurohormonal control such as peripheral and renal vasodilation, diuresis and natriuresis and inhibition of NE release. Z1046, a mixed D1/D2-like agonist, reduces peripheral and renal vascular resistance increasing renal blood flow. In anaesthetised dogs the compound strongly reduces plasma NE without increasing plasma renin activity and plasma aldosterone. The inhibition of NE could be the basis of Z1046 potent cardioprotective effect observed in a dog model of myocardial ischemia and reperfusion, in which the severity of ventricular arrhythmias was markedly reduced, resulting in higher survival. These findings suggest that chronic oral treatment with specific dopaminergic agonists is able to alleviate the hemodynamic burden on the myocardium, and to suppress the sympatho-adrenal activity.

Z1046: biochemical characterization of its dopaminergic activity.

Affinity of Z1046 for dopamine receptor subtypes, its ability to modulate D1- and D5-mediated AC stimulation and D1-induced cAMP accumulation were evaluated. On D1-like receptors Z1046 and fenoldopam (fen) showed a similar high affinity, being more potent than DP-5,6-ADTN and 5,6-ADTN. For the D2-like receptors, the affinity rank orders were: D2: Z1046 > or = DP-5,6-ADTN > fen = 5,6-ADTN; D3: Z1046 > DP-5,6-ADTN > fen = 5,6-ADTN; D4: Z1046 = DP-5,6-ADTN > fen = 5,6-ADTN. In AC studies the rank order was: Z1046 = fen > DP-5,6-ADTN > 5,6-ADTN. Z1046 was more efficient than fen in stimulating cAMP accumulation. These results make Z1046 an innovative agent combining D1-like and D2-like activities.

Z1046: a new specific peripheral dopaminergic compound.

It is well established that peripheral dopamine receptors activation evokes vasodilation and neurohormonal modulation. Z1046 is a potent mixed dopaminergic agonist and is highly selective over adrenergic and serotoninergic (5-HT2) activities. In contrast, dopamine had agonist activities on all adrenergic receptors while it is known that dopexamine has a beta 2 agonist activity and is an inhibitor of the neuronal uptake. As far as fenoldopam is concerned, selective stimulation of D1-like receptors leads to an increase of renin release. In conclusion, Z1046 is a potent and specific drug for dopamine receptors. This profile makes Z1046 different from other dopaminergic agents.