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Biomedical subjects

M F Lokhandwala

Publications and source records attributed to M F Lokhandwala.

At least 37 records · Page 2Linked to original sources
PubMed1997

Alterations in dopamine DA1 receptor and G proteins in renal proximal tubules of old rats.

The present study examines the effect of dopamine DA1-receptor agonists on the renal proximal tubular Na(+)-K(+)-adenosinetriphosphatase (Na(+)-K(+)-ATPase) activity and quantitates DA1 receptors and the coupled G proteins in Fischer 344 model of adult (6 mo old) and old (23 mo old) rats. Dopamine and the preferential DA1-receptor agonist, SKF-38393, produced a concentration-dependent inhibition of Na(+)-K(+)-ATPase activity in proximal tubules from adult rats, whereas the enzyme activity was unaffected by these agonists in the old rats. The binding of DA1-receptor antagonist [3H]Sch-23390 in the proximal tubular basolateral membranes showed a marked decrease (approximately 47%) in the receptor numbers in old compared with adult rats, whereas dissociation constant (Kd) values in old compared with adult rats were not significantly different. Dopamine and SKF-38393 stimulated 35S-labeled guanosine 5'-O-(3-thiotriphosphate) binding in adult rats, but there was no significant effect on the binding in the old rats. Quantification of G2 alpha and Gq/11 alpha using Western analysis revealed a significant increase in quantities of both the G proteins in old rats. The data suggest that a reduction in DA1 receptor number and subsequently reduced G protein activation may be the causative factors for the impairment in DA1 receptor-mediated inhibition of Na(+)-K(+)-ATPase activity in the proximal tubules of old rats.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1996

Effect of pharmacological interventions in the prevention of lipid peroxidation and respiratory depression induced by oxygen free radicals in anesthetized rats.

We have recently reported that in an anesthetized rat model, generation of oxygen free radicals (OFR) via i.v. administration of Xanthine plus Xanthine Oxidase [X + XO] resulted in death of about 90% of the animals within a 120-min observation period. Pretreatment of the rats with endogenous scavengers Superoxide Dismutase and Catalase, or with felodipine, a dihydropyridine calcium channel blocker, and/or with dopexamine, an agonist of beta 2 adrenoceptors as well as dopamine (DA-1) receptors significantly enhanced the survival rate to over 70%. The present study was designed to investigate whether lipid peroxidation and ensuing respiratory depression contributed to the lethal toxicity of the free radicals. In the control group, the death of the rats administered [X + XO] was proceeded by significant increases in the plasma lipid peroxides (PLP) and by a severe hypertensive response characteristic of an intense ischemic state, which was confirmed by the presence of hypercapnia, hypoxemia, and acidosis. Placement of the animals on the positive pressure ventilation prior to the administration of [X + XO] did not prevent increases in PLP but, prevented any adverse alterations in the respiratory markers and significantly enhanced survival rate up to 70%. In contrast, both felodipine as well as dopexamine prevented any increases in PLP, normalized blood gas profile, and significantly increased survival rate to 80 to 90%. These observations suggest that the lethal toxicity produced by oxygen free radical was due to respiratory distress. The relationship between increases in the PLP and respiratory depression and the mechanisms via which two pharmacologically distinct agents, felodipine and dopexamine, facilitated the salutary effects cannot be conclusively stated at this time. It is further suggested that although the doses of these two drugs employed in the present studies are not adequate to function as antioxidants, such a possibility cannot be entirely ruled out.

Anesthesia↗
PubMed1996

Altered arachidonic acid metabolism contributes to the failure of dopamine to inhibit Na+,K(+)-ATPase in kidney of spontaneously hypertensive rats.

Dopamine decreases tubular sodium reabsorption in part by inhibition of Na+,K(+)-ATPase activity in renal proximal tubules. The signaling mechanism involved in dopamine-mediated inhibition of Na+,K(+)-ATPase is known to be defective in spontaneously hypertensive animals. The present study was designed to evaluate the role of phospholipase A2 (PLA2) and its metabolic pathway in dopamine-induced inhibition of Na+,K(+)-ATPase in renal proximal tubules from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). Renal proximal tubular suspensions were prepared and Na+,K(+)-ATPase activity was measured as ouabain-sensitive adenosine triphosphate hydrolysis. Dopamine inhibited Na+,K(+)-ATPase activity in a concentration (1 nM-10 microM)-dependent manner in WKY rats while it failed to inhibit the enzyme activity in SHR. Dopamine (10 microM)-induced inhibition of Na+,K(+)-ATPase activity in WKY rats was significantly blocked by mepacrine (10 microM), a PLA2 inhibitor, suggesting the involvement of PLA2 in dopamine-mediated inhibition of Na+,K(+)-ATPase. Arachidonic acid (a product released by PLA2 action) inhibited Na+,K(+)-ATPase in a concentration-dependent (1-100 microM) manner in WKY rats while the inhibition in SHR was significantly attenuated (IC50: 7.5 and 80 microM in WKY rats and SHR, respectively). Furthermore, lower concentrations of arachidonic acid stimulated (30% at 1 microM) Na+,K(+)-ATPase activity in SHR. This suggests a defect in the metabolism of arachidonic acid in SHR. Proadifen (10 microM), an inhibitor of cytochrome P-450 monoxygenase (an arachidonic acid metabolizing enzyme) significantly blocked the inhibition produced by arachidonic acid in WKY rats and abolished the difference in arachidonic acid inhibition of Na+,K(+)-ATPase between WKY rats and SHR. These data suggest that PLA2 is involved in dopamine-induced inhibition of Na+,K(+)-ATPase and altered arachidonic acid metabolism may contribute to reduced dopaminergic inhibition of Na+,K(+)-ATPase activity in spontaneously hypertensive rats.

Animals↗
PubMed1995

Identification of alpha 1-adrenoceptor subtypes involved in the antinatriuretic response to intrarenal infusion of phenylephrine.

It is reported that alpha 1-adrenoceptors located in the renal vasculature and renal tubules play a major role in mediating antinatriuretic response to renal nerve stimulation as well as to the infusion of alpha 1-adrenoceptor agonist. In the present study intrarenal infusion of alpha 1-adrenoceptor agonist phenylephrine (0.25 microgram/kg/min) to Inactin-anesthetized Sprague-Dawley rats produced approximately 50% reduction in urine output, Na+ excretion and glomerular filtration rate without causing significant alterations in mean blood pressure, heart rate and fractional Na+ excretion. These changes were completely abolished by prior intrarenal infusion of prazosin (0.5 microgram/kg/min for 30 min). In separate groups of experiments, the animals received either a selective irreversible alpha 1A-adrenoceptor antagonist, SZL-49 [1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-bicyclo[2,2,2]octa-2,5- diene-2-carbonyl)piperazine], or an alpha 1B-adrenoceptor antagonist, chloroethylclonidine, intrarenally prior to phenylephrine infusion. Neither SZL-49 nor chloroethylclonidine alone significantly altered glomerular filtration rate and renal electrolyte excretion. However, SZL-49 (0.15 microgram/kg/min), but not chloroethylclonidine (50 micrograms/kg/min), completely abolished phenylephrine-induced changes in urine output, Na+ excretion and glomerular filtration rate. These results demonstrate that phenylephrine decreases urine output and Na+ excretion, mainly due to a reduction in glomerular filtration rate resulting from activation of alpha 1A-adrenoceptors, and that proximal tubular alpha 1A- or alpha 1B-adrenoceptors do not appear to contribute to this response.

Adrenergic alpha-Agonists↗
PubMed1995

Dopamine causes stimulation of protein kinase C in rat renal proximal tubules by activating dopamine D1 receptors.

Although it is suggested that in the renal proximal tubules, dopamine D1 receptor activation causes inhibition of Na+/K+ATPase via a phospholipase C and protein kinase C coupled pathway, the direct stimulation of protein kinase C by dopamine has not been reported. The present study was designed to examine the effects of dopamine and selective dopamine D1 receptor and dopamine D2 receptor agonists on protein kinase C activity. The renal proximal tubule suspensions were obtained from male Sprague-Dawley rats. The tubules were incubated separately with dopamine and fenoldopam in the presence or absence of dopamine D1 receptor antagonist, SCH 23390 ([(R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine]). The protein kinase C activity was measured by using a kinase target peptide, conjugated to a fluorescent molecule in water. The amino acid sequence of this peptide is, Proline-Leucine-Serine-Arginine-Threonine-Leucine-Serine-Valine-Alanine- Alanine-Lysine(PKSRTLSVAAK). We found that dopamine and fenoldopam [6-chloro-2,3,4,5-tetrahydro-1-(4-hydroxyphenyl)-1H-3-benzazepine-7,8-di ol] produced concentration-dependent increases in protein kinase C activity, which was blocked by SCH 23390. However, the dopamine D2 receptor agonist, bromocriptine [(5' alpha)-2-bromo-12'-hydroxy-2'-(1-methyl-ethyl)-5'-(2-methylpropyl)erg o- taman-3',6',18-trione] failed to stimulate protein kinase C activity at all the concentrations tested. These results provide direct evidence that dopamine stimulates protein kinase C activity via activation of dopamine D1 receptors.

Animals↗
PubMed1995

Alpha 1-adrenoceptor subtypes mediating stimulation of Na+,K(+)-ATPase activity in rat renal proximal tubules.

Although both alpha 1A- and alpha 1B-adrenoceptors are present in renal proximal tubules, the involvement of these receptor subtypes in the stimulation of Na+,K(+)-ATPase activity is not known. This study was undertaken to delineate the receptor subtype(s) involved in alpha 1-adrenoceptor-mediated increase in Na+,K(+)-ATPase activity and to identify the cellular signaling mechanisms such as stimulation of inositol triphosphate formation (IP3) and protein kinase C activation in this phenomenon. It was found that norepinephrine-induced increase in Na+,K(+)-ATPase activity was attenuated by prazosin, but not by rauwolscine, indicating the involvement of alpha 1-adrenoceptors. Furthermore, this response was selectively inhibited by the alpha 1B-adrenoceptor inactivator, chloroethylclonidine (100 microM), but not by the alpha 1A-adrenoceptor antagonist, WB4101 (0.01 microM). We examined whether these effects on Na+,K(+)-ATPase activity are mediated via the activation of IP3 and protein kinase C. Phenylephrine-induced increase in IP3 levels was abolished by prazosin, and significantly inhibited by WB4101, but not by chloroethylclonidine. Similarly, phenylephrine-induced activation of protein kinase C was sensitive to blockade by WB4101, but not by chloroethylclonidine. These results suggest that whereas both alpha 1A- and alpha 1B-adrenoceptors are present in proximal tubules, alpha 1B-adrenoceptors are involved in stimulating Na+,K(+)-ATPase activity and alpha 1A-adrenoceptors are predominantly linked to renal tubular IP3 production and protein kinase C activation. Therefore, it appears that norepinephrine-induced stimulation of Na+,K(+)-ATPase activity does not involve phospholipase-C-coupled protein kinase C pathway.

Adrenergic alpha-1 Receptor Agonists↗
PubMed1995

Potentiation by enalaprilat of fenoldopam-evoked natriuresis is due to blockade of intrarenal production of angiotensin-II in rats.

We have previously shown that the natriuretic response to DA-1 receptor agonist fenoldopam is markedly potentiated by angiotensin converting enzyme inhibitor captopril. Since inhibition of angiotensin converting enzyme can lead to decreased production of angiotensin-II and increased levels of kinins (e.g., bradykinin), it is likely that both of these mechanisms might be involved in this phenomenon. However, it is not known whether and to what degree the accumulation of kinins contributes to the overall potentiation of natriuretic response to fenoldopam seen during angiotensin converting enzyme inhibition. In the present study, we have examined the effect of angiotensin converting enzyme inhibitor enalaprilat and angiotensin-II receptor antagonist losartan as well as bradykinin-2 receptor antagonist HOE 140 on fenoldopam-induced natriuresis. Intravenous infusion of fenoldopam (1 microgram/kg/min) for 30 min produced significant increases in urine output and urinary sodium excretion without causing any changes in glomerular filtration rate, renal blood flow and mean arterial blood pressure, a phenomenon suggestive of a direct tubular site of action. In animals treated with either the angiotensin converting enzyme inhibitor enalaprilat or angiotensin-II receptor antagonist losartan, the diuretic and natriuretic effects of fenoldopam were potentiated to a similar degree. Whereas no significant changes in glomerular filtration rate occurred when fenoldopam alone was given to control rats, in animals treated with either enalaprilat or losartan, fenoldopam produced a modest but significant increase in glomerular filtration rate. In a separate group of animals, the effects of bradykinin-2 receptor antagonist HOE 140 on potentiation of fenoldopam-induced natriuresis by enalaprilat was examined.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1995

Dopaminergic modulation of Na,K-ATPase activity in the proximal tubules of normotensive and hypertensive rats.

Renal proximal tubular Na,K-ATPase plays an important role in the maintenance of sodium homeostasis and it is known that dopamine (DA) exerts an inhibitory effect on the activity of this enzyme. We have found that DA-induced inhibition of Na,K-ATPase is abolished in the spontaneously hypertensive rats (SHR) in comparison with age-matched Wistar-Kyoto (WKY) rats. Dopamine inhibits Na,K-ATPase via phospholipase C coupled protein kinase C pathway. The enzyme protein kinase C subsequently causes inhibition of Na,K-ATPase. In the SHR, DA-induced activation of phospholipase C is diminished, which in turn is responsible for the abolished inhibition of Na,K-ATPase. We have now shown that DA-induced activation of protein kinase C, which results from activation of DA-1 receptors is also abolished in the SHR which would account for the failure of DA to inhibit Na,K-ATPase in the hypertensive animals. Recently, we have examined the possibility that the failure of DA to inhibit Na,K-ATPase activity may be related to abnormal expression of DA receptors. In radioligand binding studies with [3H] SCH 23390 as a DA-1 receptor ligand and [3H] spiroperidol as a DA-2 receptor ligand we showed that both [3H] SCH 23390 and [3H] spiroperidol bindings are best fit to one site model in either WKY or SHR. Both Bmax and KD of either ligand binding to proximal tubule in the SHR were not statistically different from their WKY counterparts.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Dopamine fails to stimulate protein kinase C activity in renal proximal tubules of spontaneously hypertensive rats.

We have previously reported that dopamine-1 receptor-mediated activation of phospholipase C is diminished in renal cortical slices of spontaneously hypertensive rats. The present study was carried out to examine the effect of dopamine on protein kinase C (PKC), which is one of the enzymes involved in the signal-transduction pathway leading to dopamine-induced inhibition of Na+/K(+)-ATPase in the renal proximal tubule. Renal proximal tubule suspensions were obtained from spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats of 10-12 weeks old. The tubules were incubated with dopamine in the presence or absence of DA-1 receptor antagonist SCH 23390. The PKC activity was measured by using a specific fluorescent peptide substrate (sequence, PKSRTLSVAAK). We found that dopamine produced a concentration-dependent increase in protein kinase C activity in the WKY rats, however, it failed to stimulate PKC activity in the SHR. Peak stimulation of 3.828 +/- 0.35 (ng/micrograms) protein in the WKY rats was observed at dopamine concentration of 1 microM, which was blocked in a concentration-dependent manner by SCH 23390 (0.25 microM). These results provide evidence that dopamine directly stimulates PKC activity via activation of DA-1 receptors in WKY rats. Furthermore, we discovered that dopamine fails to stimulate PKC activity in the SHR. This phenomenon may be responsible for the failure of dopamine to inhibit Na+/K(+)-ATPase activity in the hypertensive animals.

Amino Acid Sequence↗
PubMed1994

Studies on the pharmacological interventions to prevent oxygen free radical (OFR)-mediated toxicity; effects of dopexamine, a DA1 receptor and beta 2 adrenoceptor agonist.

We have previously demonstrated that the lethal effects of free radicals generated by intravenous administration of Xanthine (X: 0.225 mg kg-1) and Xanthine Oxidase (XO: 5 u kg-1) were prevented by calcium channel blockers such as felodipine (a dihydropyridine calcium antagonist) and verapamil. These studies have implicated that there may be potential interactions between free radicals and cell calcium. However, alternate mechanisms such as hemodynamic changes in the overall effects of calcium antagonists cannot be ruled out. Therefore, the present studies are conducted to further investigate the efficacy of various cardiovascular agents such as Dopexamine (DPX) on [X+XO]-induced mortality. Intravenous administration of [X+XO] to anesthetized rats produced a rapid decrease in blood pressure and a mortality rate of over 90%. Pretreatment with dopexamine, a dopamine receptor (DA1) and beta 2 adrenoceptor agonist significantly enhanced survival upto 70%. Neither dobutamine nor prenalterol, (preferential beta 1 agonists) both of which produced similar increases in heart rate as DPX, enhanced survival rate thus suggesting that cardiac stimulation alone, did not contribute to the protective effects of DPX. Likewise, fenoldopam, a DA1 agonist and a vasodilator also failed to have any significant protective effect on [X+XO]-induced mortality suggesting that the DA1 receptor activation alone cannot account for the salutary effects of dopexamine. Pretreatment of the rats with Salbutamol, a preferential beta 2 agonist significantly enhanced survival upto 50% and a beta 2 antagonist ICI 118,551 significantly attenuated the ability of dopexamine to promote survival.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic Agonists↗
PubMed1994

Contribution by bradykinin to the natriuretic response to the angiotensin converting enzyme inhibitor ramiprilat in spontaneously hypertensive rats.

It is well documented that angiotensin converting enzyme inhibitors decrease blood pressure, which is associated with natriuresis in humans and certain animal models of hypertension. However, it is not clear whether these beneficial effects are due solely to blockade of angiotensin-II production and/or also involves any contribution by kinins. The present study was performed in Inactin (5-ethyl-5-(1-methylpropyl)-2-thio-barbiturate sodium)-anesthetized spontaneously hypertensive rats aged 10-13 wks to examine the relative influence of the angiotensin receptor antagonist losartan (2-n-butyl-4-chloro-5-hydroxymethyl-1- [(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl] imidazole potassium salt) and the bradykinin receptor 2 antagonist HOE 140 (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8] bradykinin) on renal and hemodynamic responses to the angiotensin converting enzyme inhibitor ramiprilat. We found that ramiprilat (1 mg/kg, i.v.) caused sustained reduction in mean blood pressure, marked increases in urine output and urinary sodium excretion without alteration in glomerular filtration rate. In a separate group of animals, it was found that losartan (1 mg/kg, i.v.) decreased blood pressure to a similar degree as ramiprilat and the magnitude of blood pressure fall seen following the combined administration of ramiprilat and losartan was similar to that caused by either compound alone. However, the increase in urinary sodium excretion seen following losartan administration was significantly smaller than that following ramiprilat or ramiprilat plus losartan.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin Receptor Antagonists↗
PubMed1994

Attenuation of adenylate cyclase-induced increases in renal sodium excretion by the dopamine D-2 receptor agonist SK&F 89124.

1. Although the existence of D-2 receptor binding sites in kidney has been identified, their functional significance in terms of influencing renal sodium excretion is not clear. In the present study we have examined the renal effects of a selective D-2 receptor agonist, SK&F 89124, in anaesthetized rats. 2. Intravenous infusion of SK&F 89124 (0.3, 1 and 3 micrograms kg-1 min-1 respectively) produced dose-dependent decreases in mean arterial blood pressure, heart rate and renal blood flow without causing any significant changes in urine output, urinary sodium excretion, renal vascular resistance or glomerular filtration rate. The changes in blood pressure, heart rate and renal blood flow caused by SK&F 89124 were abolished by a selective D-2 receptor antagonist, domperidone (50 micrograms kg-1 i.v. bolus; 10 micrograms kg-1 min-1). 3; Treatment with 3-isobutyl-1-methylxanthine (IBMX, 1 mg kg-1 bolus i.v.) or forskolin (200 micrograms kg-1 bolus i.v.) produced increases in heart rate, urine output and urinary sodium excretion, but there was no change in mean blood pressure. The natriuretic and diuretic response, but not tachycardiac response to IBMX or forskolin, was attenuated by SK&F 89124 (0.3 micrograms kg-1 min-1). 4. These results suggest that the selective D-2 receptor agonist, SK&F 89124, produced a significant decrease in blood pressure and heart rate via prejunctional D-2 receptor-mediated inhibition of noradrenaline release from postganglionic sympathetic nerve terminals. Although activation of renal tubular D-2 receptors had no significant effect on renal excretory function under basal conditions, it is likely that these receptors may exert an opposing effect on cAMP-mediated increases in renal sodium and water excretion.

1-Methyl-3-isobutylxanthine↗
PubMed1994

Lack of renal dopamine production during acute volume expansion in Dahl salt-sensitive rats.

Endogenous kidney dopamine (DA) is reported to contribute to the natriuretic response to acute volume expansion (VE). Several studies suggest that a defect in renal DA-ergic system may play a role in genetic hypertension in humans and rats. The present study was performed to determine the role of renal DA and tubular DA-1 receptors in the natriuretic response to VE in age-matched inbred Dahl salt sensitive (SS/Jr) and salt resistant (SR/Jr) rats of 9-11 weeks of age. In pentobarbital anesthetized rats, VE was carried out by intravenous infusion of isotonic sodium chloride (5% body weight) over a period of 60 min. This maneuver evoked marked increases in urine output and urinary sodium excretion in both SR/Jr and SS/Jr species. However, the natriuretic and diuretic response to VE was significantly reduced in SS/Jr as compared to SR/Jr rats. It was also observed that the urinary excretion of DA was significantly increased during VE only in SR/Jr, but not in SS/Jr rats. In separate group of animals, infusion of DA (1 microgram/kg/min) produced similar increases in urine output and urinary sodium excretion without causing any alterations in blood pressure or heart rate in either SS/Jr or SR/Jr rats. These results suggest that SS/Jr rats are not able to eliminate an acute increase in sodium load as efficiently as SR/Jr, which may be partly due to an impaired endogenous kidney DA production.

Animals↗
PubMed1993

Identification of alpha 1-adrenoceptor subtypes in rat renal proximal tubules.

Although the existence of alpha 1-adrenoceptor subtypes has been suggested in the kidney, their characterization in the proximal tubules has not been reported. This study was undertaken to characterize the alpha 1-adrenoceptor subtypes in the renal proximal tubules. [3H]Prazosin bound to proximal tubules with a KD of 106 +/- 17 pM and a Bmax of 152 +/- 9 fmol/mg protein. Pretreatment of the tubules with chloroethylclonidine, 100 microM, reduced the Bmax of [3H]prazosin binding by about 50%, indicating the presence of the alpha 1B-adrenoceptor subtype. Competition studies performed with the alpha-adrenoceptor antagonists, WB 4101, (+)-niguldipine, 5-methylurapidil and phentolamine were shallow and could be distinguished into a high affinity (alpha 1A) and a low affinity site (alpha 1B) with an approximately equal distribution of both receptor subtypes. These observations clearly demonstrate the existence of alpha 1A- and alpha 1B-adrenoceptor subtypes in the renal proximal tubules.

Adrenergic alpha-Antagonists↗
PubMed1993

Inhibition of Na+,K(+)-ATPase in rat renal proximal tubules by dopamine involved DA-1 receptor activation.

Endogenous kidney dopamine (DA) causes natriuresis and diuresis, at least partly, via inhibition of proximal tubular Na+,K(+)-ATPase. The present study was done to identify the dopamine receptor subtype(s) involved in dopamine-induced inhibition of Na+,K(+)-ATPase activity. Suspensions of renal proximal tubules from Sprague-Dawley rats were incubated with dopamine, the DA-1 receptor agonist fenoldopam or the DA-2 receptor agonist SK&F 89124 in the presence or absence of either the DA-1 receptor antagonist SCH 23390 or the DA-2 receptor antagonist domperidone. Dopamine and fenoldopam (10(-5) to 10(-8) mol/l) produced a concentration-dependent inhibition of Na+,K(+)-ATPase activity. However, SK&F 89124 failed to produce any significant effect over the same concentration range. Incubation with fenoldopam (10(-5) to 10(-8) mol/l) in the presence of SK&F 89124 (10(-6) mol/l) inhibited Na+,K(+)-ATPase activity to a degree similar to that with fenoldopam alone. Furthermore, DA-induced inhibition of Na+,K(+)-ATPase activity was attenuated by SCH 23390, but not by domperidone. Since alpha-adrenoceptor activation is reported to stimulate Na+,K(+)-ATPase activity and, at higher concentrations, dopamine also acts as an alpha-adrenoceptor agonist, the potential opposing effect from alpha-adrenoceptor activation on DA-induced inhibition of Na+,K(+)-ATPase activity was investigated by using the alpha-adrenoceptor blocker phentolamine. We found that, in the lower concentration range (10(-5) to 10(-7) mol/l), dopamine-induced inhibition of Na+,K(+)-ATPase activity in the presence of phentolamine was similar in magnitude to that observed with dopamine alone.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1993

Evaluation of the effects of dopexamine, a novel DA1 receptor and beta 2-adrenoceptor agonist, on cardiac function and splanchnic circulation in a canine model of hemorrhagic shock.

In the present studies, the efficacy of dopexamine hydrochloride, a novel DA1-receptor and beta 2-adrenoceptor agonist in preventing deterioration of cardiovascular function in a canine model of hemorrhagic shock was investigated. Pentobarbital-anesthetized dogs were allowed to bleed into a height-regulated reservoir and the hypotensive state (about 40 mmHg) was maintained for a period of 150 min. Subsequently, blood was reinfused and recoveries in various hemodynamic variables were monitored for an additional period of 120 min. Either aqueous solvent or dopexamine HCl was randomly selected for i.v. infusion beginning 30 min before reinfusion of the blood and until the termination of the experiment. In the solvent-treated control group, various cardiovascular variables such as cardiac output, stroke volume, celiac and superior mesenteric arterial blood flows progressively declined to 50% or less of the basal values; these changes were associated with sustained increases in the regional as well as systemic vascular resistances. Dopexamine infusion lowered vascular resistances and facilitated recoveries in various hemodynamic variables to 80% to 100% of the basal values after reinfusion of the shed blood. With the exception of a transient inotropic effect during reinfusion in the dopexamine treated group, there were no essential alterations in the myocardial contractility, during the hypotensive state and/or after reinfusion of the blood. Hence, the results indicate that the efficacy of dopexamine to reduce vascular resistance by actions at DA1-receptors and beta 2-adrenoceptors would account for its ability to improve myocardial performance (secondary to reductions in afterload) and restoration of mesenteric and celiac hemodynamics.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗
PubMed1993

Dopamine fails to inhibit renal tubular sodium pump in hypertensive rats.

We have previously reported that dopamine-1 receptor-mediated activation of phospholipase C is diminished in renal cortical slices of adult spontaneously hypertensive rats. To determine the potential consequences of this phenomenon, we performed the present studies in which renal proximal tubule suspensions obtained from spontaneously hypertensive and Wistar-Kyoto rats of 10-12 weeks of age were used. The tubule suspensions were incubated with dopamine in the presence or absence of dopamine receptor antagonists, and sodium, potassium adenosine trisphosphatase (sodium pump) activity was measured as the ouabain-sensitive adenosine trisphosphate hydrolysis. We found that dopamine produced a concentration-related inhibition of sodium pump activity in the normotensive rats but not in the hypertensive rats. Dopamine-induced inhibition of sodium pump activity in the normotensive rats was abolished by the phospholipase C inhibitor U-73122 or the protein kinase C inhibitor sphingosine, suggesting the involvement of a phospholipase C-coupled protein kinase C pathway in this response. Dopamine-induced inhibition in the normotensive rats was attenuated by the dopamine-1 receptor antagonist SCH 23390 but not by the dopamine-2 receptor antagonist domperidone. To identify possible sites of defect in dopamine-1 receptor-coupled signaling pathways in the hypertensive rats, we incubated the proximal tubules with phorbol 12,13-dibutyrate or the synthetic diacylglycerol analogue 1-oleoyl-2-acetyl-rac-glycerol. The results showed that both compounds inhibited sodium pump activity as effectively in the hypertensive as in the normotensive rats, suggesting that the protein kinase C-coupled sodium pump pathway was not defective in the hypertensive animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗