Search PubMed⌕ Search

Biomedical subjects

R R Ruffolo

Publications and source records attributed to R R Ruffolo.

At least 91 records · Page 5Linked to original sources
PubMed1993

Myocardial protection by the novel vasodilating beta-blocker, carvedilol: potential relevance of anti-oxidant activity.

AIM: Carvedilol is a multiple action antihypertensive drug with potential use in angina and congestive heart failure. The pharmacological profile of carvedilol includes both beta-adrenoceptor blockade and vasodilation, the latter primarily a result of alpha 1-adrenoceptor blockade. Since many beta-blockers have cardioprotective properties, the present study was designed to determine whether carvedilol is also cardioprotective. Because oxygen radicals are believed to influence ischemic tissue injuries, a secondary study was designed to determine whether carvedilol has anti-oxidant actions which could contribute to cardioprotective properties of carvedilol. METHODS: Four different models of acute myocardial infarction in were examined in three animal species, and the effects of carvedilol were compared to those of propranolol. First, in rats subjected to 30 min of cardiac ischemia followed by 24 h of reperfusion, carvedilol was administered both pre- and post-ischemia (1 mg/kg, intravenously). Second, minipigs were subjected to 45 min of cardiac ischemia followed by 4 h of reperfusion, with carvedilol pretreatment (0.3 or 1 mg/kg intravenously). Third, dogs were subjected to 1 h of cardiac ischemia followed by 24 h of reperfusion with carvedilol pretreatment (1 mg/kg, intravenously) or to permanent coronary occlusion (6 h) with carvedilol pretreatment (0.3 or 1 mg/kg, intravenously). Finally, to examine the anti-oxidant activity of carvedilol, pig myocardial membranes were exposed to oxidizing systems that elicit lipid peroxide products assessed as thiobarbituric acid-reactive substances (TBARS). RESULTS: In the rats, carvedilol reduced the infarct size by 47% (P < 0.01), in contrast to propranolol, which is inactive in this model. In the minipigs the infarct size was reduced by 46 and 89% (P < 0.01) with carvedilol at 0.3 and 1 mg/kg, respectively; at comparable beta-adrenoceptor blocking doses, carvedilol produced a significantly greater reduction in the infarct size than propranolol (89 versus 48%). In dogs, carvedilol reduced the infarct size by 78% (P < 0.05) compared to the 64% reduction produced by propranolol. In dogs with permanent coronary occlusion, carvedilol produced dose-dependent reductions in the infarct size of 46 and 63% for 0.3 and 1 mg/kg, respectively (P < 0.05), compared to propranolol which did not reduce the infarct size in this model. Carvedilol inhibited lipid peroxidation in a dose-dependent manner with a 50% inhibitory concentration (IC50) of 5 mumol/l. Moreover, superoxide generation by activated human neutrophils in vitro was also inhibited by carvedilol with an IC50 of 28 mumol/l. Finally, carvedilol was shown to scavenge oxygen free radicals in a cell-free system with an IC50 of 25 mumol/l. CONCLUSIONS: Taken together, these data indicate that carvedilol is a potent cardioprotective drug, which presumably acts by multiple mechanisms, possibly including a novel anti-oxidant effect that is not shared by other beta-blockers.

Adrenergic beta-Antagonists↗
PubMed1993

Medicinal chemistry of adrenoceptor agonists.

Developments in the medicinal chemistry of alpha- and beta-adrenoceptor agonists have progressed rapidly during the past several years. Much is now known about the stereochemical requirements of alpha- and beta-adrenoceptors as well as the structure-activity relationships of agonists that interact with these receptors. Indeed, major differences exist in the stereochemical requirements and structure-activity relationships of alpha- and beta-adrenoceptor agonists, and these differences are now beginning to be explained at the molecular level of the interaction between the agonist and its receptor. These aspects of the medicinal chemistry of alpha- and beta-adrenoceptor agonists are the subject of this review.

Adrenergic alpha-Agonists↗
PubMed1993

Preclinical and clinical pharmacology of carvedilol.

Carvedilol is a novel multiple-action cardiovascular drug that has recently been introduced to the market for the treatment of mild to moderate hypertension. Clinical studies have demonstrated that once daily therapy with carvedilol is efficacious and has a favourable side-effect profile. Clinical studies are in progress to establish the utility of carvedilol in angina and congestive heart failure. Carvedilol is a beta-adrenoceptor antagonist and a vasodilator, with the vasodilating activity resulting primarily from alpha 1-adrenoceptor blockade and possibly also from calcium channel blockade. The reduction in BP produced by carvedilol results from the vasodilating activity of the drug because peripheral vascular resistance is significantly reduced. The reduction in BP produced by carvedilol is not associated with reflex tachycardia owing to the beta-adrenoceptor blocking activity of the compound. Throughout its antihypertensive dose range, carvedilol has been a renal-sparing antihypertensive agent in animals and also in humans, inasmuch as renal blood flow, glomerular filtration rate and sodium excretion are all maintained. In preclinical experimental models of acute myocardial infarction, carvedilol has produced marked reductions in infarct size in the pig, rat and dog. The cardioprotection observed with carvedilol is greater than that provided by beta-adrenoceptor antagonists alone, suggesting that the additional activities of carvedilol may provide benefit in the setting of myocardial ischaemia.

Animals↗
PubMed1993

Altered coronary flow reserve in the hypertrophied heart: implications for therapy.

Coronary flow reserve has been shown to be abnormally low in several models of left ventricular hypertrophy induced by long-standing pressure overload. Because the presence of hypertrophy is a risk factor for the development of subendocardial ischaemia and sudden death, efforts to restore alterations in flow reserve may prove beneficial. In the following review, we discuss potential mechanisms which might contribute to this abnormal vasodilator capacity in the hypertrophied heart, with particular emphasis on how chronic therapy may potentially reverse such abnormalities. In addition, we report how the acute administration of various classes of pharmacological agents can alter measurements of coronary flow reserve, as observed in our anaesthetised swine model. Such factors must be considered before interpreting any changes in coronary flow reserve in models of hypertrophy following chronic administration of drugs.

Animals↗
PubMed1992

Carvedilol, a new beta-adrenoceptor antagonist and vasodilator antihypertensive drug, inhibits superoxide release from human neutrophils.

Carvedilol produced a dose-dependent inhibition of superoxide (O2-) release from human neutrophils (PMNs) (IC50 = 28 microM) and scavenged O2- generated during dihydroxyfumaric acid (DHF) autooxidation (IC50 = 41 microM). Other beta-blockers, such as celiprolol, labetalol and atenolol, or the antioxidant, 'lazaroid', U74500A had no effect on O2- either released from PMNs or generated during DHF autooxidation. Propranolol, at 0.3 mM, inhibited O2- release from PMNs (73%) but failed to scavenge O2- generated from DHF. The novel free radical-scavenging effect of carvedilol may contribute to the cardioprotective activity of the compound.

Adrenergic beta-Antagonists↗
PubMed1992

Antihypertensive activity of the non-peptide angiotensin II receptor antagonist, SK&F 108566, in rats and dogs.

The antihypertensive activity of the nonpeptide angiotensin II receptor antagonist, SK&F 108566 (E)-alpha-[[2-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5- yl]methylene]-2-thiophene propanoic acid), was examined in rats and dogs. SK&F 108566 produced dose-dependent decreases in blood pressure in renin-dependent hypertensive rats. At 10 mg/kg intraduodenally, mean arterial blood pressure fell from between 150-160 mm Hg to approximately 124 mm Hg. A sustained infusion of SK&F 108566 at 25 micrograms/min intraduodenally normalized blood pressure during 3 days of infusion and for 18 h following cessation of the infusion. Evaluation of the systemic hemodynamic effects of SK&F 108566 in chronically instrumented renin-dependent hypertensive rats demonstrated that the antihypertensive effects of SK&F 108566 were accompanied by a significant increase in cardiac output with little change in stroke volume. In dogs made acutely hypertensive by an intravenous infusion of angiotensin I, SK&F 108566 resulted in dose-dependent decreases in blood pressure. The antihypertensive activity of SK&F 108566 at 10 mg/kg p.o. was maintained for between 13-15 h, a similar duration of action as observed with enalapril (1 mg/kg, p.o.). Administration of DuP 753 (losartan) intravenously caused a small and short-lived fall in blood pressure in the angiotensin I-infused hypertensive dog. However, the active metabolite of losartan, EXP 3174, resulted in a response of longer duration. In dogs made hypertensive by placement of an ameroid constrictor on the left renal artery, SK&F 108566 (10 mg/kg, p.o.) or enalapril (1 mg/kg, p.o.) resulted in antihypertensive responses of at least 12 h duration. The data indicate that SK&F 108566 is a long-acting antihypertensive agent in the rat and dog.

Acrylates↗
PubMed1992

Carvedilol, a new antihypertensive, prevents oxidation of human low density lipoprotein by macrophages and copper.

Growing evidence indicates that oxidized low-density lipoprotein (LDL) may promote atherogenesis. Therefore, inhibition of LDL oxidation may impede this process. Carvedilol is a vasodilating, beta-adrenoceptor blocking agent. As a new antihypertensive drug, carvedilol is unique by virtue of its potent antioxidant activity. Therefore, we tested the ability of carvedilol to inhibit the oxidation of LDL by either macrophages or Cu2+. Carvedilol inhibited LDL oxidation by macrophages in a dose-dependent manner, with an IC50 value of 3.8 microM, as assessed by a thiobarbituric acid reactive substance (TBARS) assay. Under the same conditions, propranolol showed only a mild inhibitory effect (IC50 > 100 microM), while pindolol, atenolol and labetalol had almost no effect. Carvedilol, at 10 microM, almost completely inhibited the macrophage-induced increase in electrophoretic mobility of LDL, while other beta-blockers at 50-300 microM had no significant effect. Carvedilol inhibited superoxide release from mouse macrophages, which correlated well with its inhibition of LDL oxidation. Carvedilol also inhibited Cu(2+)-induced LDL oxidation with an IC50 value of 17 microM, while all other beta-blockers were inactive up to 300 microM. These observations suggest that carvedilol might not only be an effective antihypertensive drug, but might also be effective in prevention of atherosclerosis.

Adrenergic beta-Antagonists↗
PubMed1992

Development of GPIIb/IIIa antagonists as antithrombotic drugs.

Thrombosis represents a major target for development of drugs to prevent and treat a variety of cardiovascular and cerebrovascular diseases, which are the leading cause of morbidity and mortality in the Western world. This review by Andy Nichols and colleagues focuses on a central process in thrombosis, namely platelet aggregation, and how it can be inhibited by antagonists of the adhesion molecule GPIIb/IIIa. Successful and future therapeutic applications of GPIIb/IIIa antagonists, and their pharmacology, are considered in detail.

Amino Acid Sequence↗
PubMed1992

Cardioprotective effects of carvedilol, a novel beta adrenoceptor antagonist with vasodilating properties, in anaesthetised minipigs: comparison with propranolol.

OBJECTIVE: The aim was to evaluate in a minipig model of acute myocardial infarction the cardioprotection provided by the beta adrenoceptor blocking and vasodilating activities present in carvedilol; comparison was made to the pure beta adrenoceptor antagonist, propranolol. METHODS: Experiments were performed in 25 Yucatan minipigs (9-12 kg), randomly assigned to receive vehicle (n = 7), carvedilol 0.3 mg.kg-1 (n = 6), carvedilol 1 mg.kg-1 (n = 6), or propranolol 1 mg.kg-1 (n = 6). Myocardial infarction was produced by occlusion of the left anterior descending coronary artery for 45 min followed by 4 h of reperfusion. Vehicle, carvedilol (0.3 and 1 mg.kg-1) or propranolol (1 mg.kg-1) were given intravenously 15 min before the coronary artery occlusion. At the end of the reperfusion period, infarct size was determined using Evans blue dye and triphenyltetrazolium chloride staining. Infarct volumes were visualised using computer assisted three dimensional image analysis of the stained myocardial tissue sections. Myeloperoxidase activity was measured in tissue samples removed from normal, infarcted, and at risk areas. RESULTS: Carvedilol (1 mg.kg-1) reduced infarct size by over 90% without producing pronounced changes in systemic haemodynamic variables. The ability of carvedilol to reduce infarct size was clearly dose dependent. Thus infarct size, which represented 27.5(SEM 2.3)% of the area at risk in the vehicle treated group, was only 13.1(4.0)% (p < 0.05) and 2.4(1.5)% (p < 0.01) in pigs treated with carvedilol at 0.3 and 1 mg.kg-1, respectively. In animals treated with propranolol (1 mg.kg-1), infarct size represented 10.9(2.4)% of the area at risk (p < 0.05). The 60% and 91% reductions in infarct size produced by propranolol (1 mg.kg-1) and carvedilol (1 mg.kg-1), respectively, were clearly evident upon three dimensional image analysis. The reduction in infarct size was significantly greater for carvedilol (1 mg.kg-1) compared to propranolol (1 mg.kg-1) at equivalent beta adrenoceptor blocking doses. Pretreatment with propranolol did not reduce the increases in myeloperoxidase activity observed in the area at risk or in the infarcted area. In contrast, carvedilol produced a dose dependent reduction in myeloperoxidase activity in these areas. CONCLUSIONS: Carvedilol limits myocardial necrosis resulting from coronary artery occlusion and reperfusion in a more pronounced manner than the pure beta adrenoceptor antagonist, propranolol. The cardioprotective effect of carvedilol, which reduced infarct size by 91%, may result from the combined effects of beta adrenoceptor blockade and vasodilatation, and possibly also from inhibition of intracellular calcium overload in cardiac cells resulting from antagonism of myocardial alpha 1 adrenoceptors and/or calcium channel blockade. The cardioprotection provided by carvedilol may ultimately be of benefit in hypertensive patients who are at risk for acute myocardial infarction.

Adrenergic beta-Antagonists↗
PubMed1992

Myocardial protection with carvedilol.

Carvedilol is a multiple-action cardiovascular agent that is both a beta-adrenoceptor antagonist and a vasodilator and has recently been made available for the treatment of mild-to-moderate hypertension. Clinical trials are ongoing to establish the efficacy of carvedilol in angina and congestive heart failure. beta-Adrenoceptor antagonists are known to reduce myocardial work secondary to reductions in heart rate and contractility; accordingly, they have been shown to be cardioprotective in animals and in humans. Because carvedilol has beta-adrenoceptor antagonist activity, it also should provide significant cardioprotection. The additional vasodilating activity of carvedilol, which will further reduce myocardial work by decreasing afterload and myocardial wall tension, should provide more salvage of ischemic myocardium than that afforded by a pure beta-adrenoceptor antagonist, such as propranolol. We investigated the ability of carvedilol and propranolol to reduce infarct size in experimental models of acute myocardial infarction in the rat, pig, and dog. The left anterior descending coronary artery was occluded for 30 (rat) or 45 min (pig) and then reperfused for 24 h (rat) or 4 h (pig). In the dog, the left circumflex coronary artery was occluded for 60 min and reperfused for 24 h. Vehicle, carvedilol, or propranolol was administered intravenously 15 min before ischemia (and, in the rat only, repeated 4 h after ischemia). An additional group of dogs was subjected to permanent left anterior descending coronary artery occlusion for 6 h, and carvedilol or propranolol was given 15 min after occlusion. Infarct size was examined on stained tissue sections using quantitative image analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1992

Cardiovascular actions of a new selective postjunctional alpha-adrenoceptor antagonist, SK&F 104856, in normotensive and hypertensive dogs.

1. SK&F 104856 (2-vinyl-7-chloro-3,4,5,6-tetrahydro-4- methylthieno[4,3,2ef][3]benzazepine) is a novel postjunctional alpha 1- and alpha 2-adrenoceptor antagonist. 2. SK&F 104856 as well as prazosin and SK&F 86466 reduced blood pressure in the anaesthetized normotensive dog. 3. SK&F 86466 and rauwolscine but not SK&F 104856 or prazosin, produced a marked increase in myocardial contractility which corresponds with their ability to block prejunctional alpha 2-adrenoceptors. 4. Intravenous or oral administration of SK&F 104856 resulted in dose-dependent antihypertensive responses in 1-kidney, 1-clip (1-K, 1-C) Goldblatt hypertensive dogs with baseline blood pressure of approximately 140 mmHg. At 0.1 and 1 mg kg-1, i.v., mean arterial blood pressure fell by 11 +/- 5 and 23 +/- 5 mmHg, respectively. At 3 and 10 mg kg-1, p.o., blood pressure fell by 9 +/- 3 and 22 +/- 5 mmHg, respectively. At 10 mg kg-1, p.o., the antihypertensive effect of SK&F 104856 was still evident at 4 h. 5. The data indicate that SK&F 104856 shows selectivity in vivo for postjunctional versus prejunctional alpha-adrenoceptors and is a potent and long-acting antihypertensive agent in 1-K, 1-C Goldblatt hypertensive dogs.

Adrenergic alpha-Antagonists↗
PubMed1992

Activation of a single alpha-1-adrenoceptor subtype in rat aorta mobilizes intracellular and extracellular pools of calcium.

The calcium channel antagonist, nifedipine (0.1 microM), only slightly inhibited the response to the full alpha 1-adrenoceptor agonist, (-)-norepinephrine, in rat aorta, but nearly completely inhibited the response to the partial alpha 1-adrenoceptor agonist, (-)-dobutamine, indicating that (-)-norepinephrine primarily utilizes intracellular stores of calcium to produce vasoconstriction, whereas (-)-dobutamine relies primarily upon the translocation of extracellular calcium. It has been proposed that the different pools of calcium mobilized by (-)-norepinephrine and (-)-dobutamine in rat aorta result from the activation of two different alpha 1-adrenoceptor subtypes by these agonists. Because the irreversible alpha 1-adrenoceptor antagonist, phenoxybenzamine, has been proposed to inactivate an alpha 1-adrenoceptor subtype coupled specifically to the mobilization of intracellular stores of calcium, this compound should selectively inhibit the response of (-)-norepinephrine, and not the response of (-)-dobutamine, if two distinct alpha 1-adrenoceptor subtypes exist in rat aorta. In the present study, phenoxybenzamine produced concentration-dependent, noncompetitive inhibition of the responses to both agonists in rat aorta, and the pA2' values for phenoxybenzamine were 8.12 +/- 0.23 and 7.74 +/- 0.27 against (-)-dobutamine and (-)-norepinephrine, respectively, which are not significantly different from each other (p greater than 0.05). In addition, the phasic and tonic components of the response to (-)-norepinephrine, which are mediated by the mobilization of intracellular calcium and the translocation of extracellular calcium, respectively, are also inhibited to the same extent by phenoxybenzamine. The results do not support the hypothesis of two alpha 1-adrenoceptor subtypes in rat aorta, one of which being coupled to the translocation of extracellular calcium, and the other to the mobilization of intracellular calcium. Rather, the results support our previous hypothesis that a single alpha 1-adrenoceptor subtype exists in vascular smooth muscle, and this alpha 1-adrenoceptor is coupled to two distinct signal transduction processes, one of which elicits the mobilization of intracellular calcium, and the other opens membrane calcium channels to permit the influx of extracellular calcium.

Animals↗
PubMed1992

Receptor protection studies with phenoxybenzamine indicate that a single alpha 1-adrenoceptor may be coupled to two signal transduction processes in vascular smooth muscle.

Full alpha 1-adrenoceptor agonists, such as (-)-norepinephrine, produce vasoconstriction in the rat aorta primarily through the mobilization of intracellular stores of calcium, whereas partial alpha 1-adrenoceptor agonists, such as (-)-dobutamine, produce vasoconstriction primarily through the translocation of extracellular calcium. The different pools of calcium utilized by full and partial alpha 1-adrenoceptor agonists have been proposed to result from the activation of different alpha 1-adrenoceptor subtypes. The irreversible alpha 1-adrenoceptor antagonist, phenoxybenzamine, selectively eliminates only that component of an alpha 1-adrenoceptor-mediated response in the rat aorta that is dependent upon the mobilization of intracellular stores of calcium. In order to determine whether in the rat aorta there exist two distinct alpha 1-adrenoceptor subtypes linked separately to the mobilization of intracellular and extracellular calcium, we utilized the full and partial alpha 1-adrenoceptor agonists, (-)-norepinephrine and (-)-dobutamine, respectively, and the irreversible antagonist, phenoxy-benzamine, as pharmacologic tools in a classical receptor-protection study to probe these alpha 1-adrenoceptor-mediated vasoconstrictor process(es). Our logic was that if the intracellular and extracellular pools of calcium were coupled to different alpha 1-adrenoceptor subtypes, then only (-)-norepinephrine, and not (-)-dobutamine, would protect against alpha 1-adrenoceptor alkylation by phenoxybenzamine, since phenoxybenzamine only eliminates the process that depends on intracellular calcium. Alternatively, if both (-)-norepinephrine and (-)-dobutamine produce a similar degree of alpha 1-adrenoceptor protection against phenoxybenzamine, our results would suggest that a single alpha 1-adrenoceptor subtype exists which activates both the translocation of extracellular calcium and the mobilization of intracellular calcium. Phenoxybenzamine (30 nM) abolished contractions of the rat aorta produced by (-)-norepinephrine, as expected. Pretreatment of the tissues with either (-)-norepinephrine or (-)-dobutamine, at concentrations that produced equivalent degrees of alpha 1-adrenoceptor occupancy, resulted in equal protection against alkylation of alpha 1-adrenoceptors by phenoxybenzamine, arguing against the existence of two distinct alpha 1-adrenoceptor subtypes in the rat aorta. These results are consistent with our previous hypothesis that two different signal-transduction processes may be activated in the rat aorta by a single alpha 1-adrenoceptor population, with the intrinsic efficacy of the agonist determining which signal-transduction process is activated.

Adrenergic alpha-Agonists↗
PubMed1992

The effect of pertussis toxin treatment on alpha-1-adrenoceptor-mediated pressor responses in the pithed rat: dependence on agonist efficacy but not chemical class.

The role of pertussis-toxin-sensitive guanine nucleotide regulatory proteins (G proteins) in the signal transduction processes involved in post-junctional vascular alpha 1-adrenoceptor-mediated vasoconstriction has been investigated in the pithed rat using two chemical classes of alpha-adrenoceptor agonists, the phenethylamines and imidazolines, in order to determine if they utilize different signal transduction mechanisms. Pertussis toxin pretreatment (50 micrograms/kg, i.v., 3 days prior to experimentation) slightly inhibited the pressor response to the full alpha 1-adrenoceptor agonist of the phenethylamine class (-)-norepinephrine (in the presence of rauwolscine, 1 mg/kg, i.v.), whereas it markedly inhibited the pressor response to the partial alpha 1-adrenoceptor agonist of the imidazoline class oxymetazoline (in the presence of rauwolscine, 1 mg/kg, i.v.). However, after elimination of the alpha 1-adrenoceptor reserve for (-)-norepinephrine with phenoxybenzamine (0.1 mg/kg, i.v.), the pressor response to this agonist became sensitive to inhibition by pertussis toxin treatment. The pattern of inhibition of alpha 1-adrenoceptor-mediated pressor responses produced by pertussis toxin was similar to that produced by the calcium channel antagonist nifedipine (1 mg/kg, i.a.). The results support the hypothesis that vascular alpha 1-adrenoceptors may be coupled to a G protein which is sensitive to pertussis toxin and which couples the alpha 1-adrenoceptor to the influx of extracellular calcium, which possibly another G protein that is insensitive to pertussis toxin that couples the alpha 1-adrenoceptor to the release of intracellular calcium. The intrinsic efficacy of the agonist, and not its chemical class, determines which signal transduction mechanisms will be utilized.

Adrenergic alpha-Agonists↗
PubMed1992

Pharmacological characterization of the nonpeptide angiotensin II receptor antagonist, SK&F 108566.

The angiotensin II (AII) antagonist activity of (E)-alpha-[[2-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5- yl]methylene]-2-thiophenepropanoic acid (SK&F 108566), was examined in a number of in vitro and in vivo assays. In rat and human adrenal cortical membranes, SK&F 108566 displaced specifically bound [125I]AII with IC50 of 9.2 and 3.9 nM, respectively. SK&F 108566 also inhibited [125I]AII binding to human liver membranes (IC50 = 1.7 nM) and to rat mesenteric artery membranes (IC50 = 1.5 nM). In rabbit aortic smooth muscle cells, SK&F 108566 caused a concentration-dependent inhibition of AII-induced increases in intracellular Ca++ levels. In rabbit aortic rings, SK&F 108566 produced parallel rightward shifts in the AII concentration-response curve without affecting the maximal contractile response. Schild analysis of the data yielded a KB value of 0.26 nM and a slope not different from 1, indicative of competition antagonism. SK&F 108566 had no effect on the contractile responses to KCl, norepinephrine or endothelin in rabbit aorta. In conscious normotensive rats, i.v. administration of SK&F 108566 (0.01-0.3 mg/kg) produced dose-dependent parallel shifts in the AII pressor dose-response curve. Administration of SK&F 108566 (3-10 mg/kg) intraduodenally or intragastrically to conscious normotensive rats resulted in a dose-dependent inhibition of the pressor response to AII (250 ng/kg, i.v.). At 10 mg/kg, i.d., significant inhibition of the pressor response to AII was observed for 3 hr. In this same rat model, SK&F 108566 had no effect on base-line pressure or on the pressor response to norepinephrine or vasopressin. The data demonstrate that SK&F 108566 is a potent, highly selective, competitive nonpeptide AII antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Acrylates↗
PubMed1992

Effect of fenoldopam on the acute and subacute nephrotoxicity produced by amphotericin B in the dog.

The effect of the selective dopamine DA1 receptor agonist fenoldopam (1 microgram/kg/min i.v.) on the acute nephrotoxic response to amphotericin B (2 mg/kg i.v.) has been studied in the anesthetized dog. Animals were prepared for the measurement of blood pressure, renal blood flow, urine flow, glomerular filtration rate and sodium and potassium excretion. Amphotericin B was given over 20 min and the animals were followed for an additional 160 min. The fenoldopam infusion was started 20 min before amphotericin B and was continued for the duration of the experiment. In control animals, amphotericin B markedly increased renal vascular resistance without affecting blood pressure and thus produced a significant reduction in renal blood flow. The renal vasoconstrictor response to amphotericin B was not attenuated by fenoldopam. Concomitant with the renal vasoconstriction produced by amphotericin B was a marked reduction in glomerular filtration rate, sodium excretion and urine flow rate, which lasted for at least 160 min after amphotericin B treatment. Fenoldopam did not have any effect on the initial reductions in glomerular filtration rate, sodium excretion and urine flow rate but did produce a significant return of these parameters toward control levels by 160 min, despite the continued renal vasoconstriction. The effect of fenoldopam (0.5 microgram/kg/min) given continuously by i.v. infusion on the subacute nephrotoxic response produced by amphotericin B given every other day for 8 days was also investigated. One day after the start of the fenoldopam infusion, venous samples were drawn for the analysis of serum creatinine and blood urea nitrogen.(ABSTRACT TRUNCATED AT 250 WORDS)

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