Effects of 1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino) propane hydrochloride on heart function, lactate dehydrogenase and its isoenzymes in rats with cardiac hypertrophy.
(17/952)
AIM: To investigate the effects of 1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino) propane hydrochloride (DDPH) on cardiac systolic and diastolic function, lactate dehydrogenase (LDH) activity, and LDH isoenzymes in rats with cardiac hypertrophy. METHODS: The cardiac hypertrophy of rats was induced by partly occluding abdominal aorta. The rats were given i.g. DDPH for 8 wk 4 wk after operation, and isolated working heart was made. RESULTS: Eight wk later, in model group, left ventricle systolic pressure (LVSP), LV + dp/dtmax, -dp/dtmax and aorta pressure (AP) decreased by 20.2%, 20.0%, 41.4%, and 13.6%, respectively. Left ventricle ending diastolic pressure (LVEDP) increased by 173.9%. The hemodynamic study showed that flowing liquid of aorta (AF) and coronary (CF) and cardiac output (CO) decreased by 49.4%, 41.2%, and 48.9%, respectively. After the rats were given i.g. DDPH, the all above-mentioned parameters recovered to different degrees. Under condition of cardiac hypertrophy, LDH isoenzymes and subunits changed significantly. Isoenzymes LDH3, LDH4, and LDH5, especially LDH5 increased, LDH1 decreased, subunit M in hypertrophied heart increased 1.69 times than that in normal heart. DDPH could decrease subunit M and increase subunit H. CONCLUSION: DDPH can increase cardiac function, coronary flow and reverse changes of LDH isoenzymes in rats with cardiac hypertrophy. (+info)
Exaggerated QT prolongation after cardioversion of atrial fibrillation.
(18/952)
OBJECTIVES: The purpose of this study was to test the hypothesis that the extent of drug-induced QT prolongation by dofetilide is greater in sinus rhythm (SR) after cardioversion compared with during atrial fibrillation (AF). BACKGROUND: Anecdotes suggest that when action potential-prolonging antiarrhythmic drugs are used for AF, excessive QT prolongation and torsades de pointes (TdP) often occur shortly after sinus rhythm is restored. METHODS: QT was measured in nine patients with AF who received two identical infusions of dofetilide: 1) before elective direct current cardioversion and 2) within 24 h of restoration of SR. RESULTS: During AF, dofetilide did not prolong QT (baseline: 368 +/- 48 ms vs. drug: 391 +/- 60, p = NS) whereas during SR, QT was prolonged from 405 +/- 55 to 470 +/- 67 ms (p < 0.01). In four patients (group I), the SR dofetilide infusion was terminated early because QT prolonged to >500 ms, and one patient developed asymptomatic nonsustained TdP. The remaining five patients (group II) received the entire dose during SR. Although deltaQT was greater in group I during SR (91 +/- 22 vs. 45 +/- 25 ms, p < 0.05), plasma dofetilide concentrations during SR were similar in the two groups (2.72 +/- 0.96 vs. 2.77 +/- 0.25 ng/ml), and in AF (2.76 +/- 1.22 ng/ml). DeltaQT in SR correlated inversely with baseline SR heart rate (r = -0.69, p < 0.05), and QT dispersion developing during the infusion (r = 0.79, p < 0.01). CONCLUSIONS: Shortly after restoration of SR, there was increased sensitivity to QT prolongation by this I(Kr)-specific blocker. Slower heart rates after cardioversion and QT dispersion during treatment appear to be important predictors of this response. (+info)
Effects of activation of renal adenosine A2 receptor on renal function and renin release in dogs.
(19/952)
Direct effects of adenosine A2 receptor activation on renal function were examined in dogs. When renal perfusion pressure was maintained constant at 100 mmHg, renal administration of a selective A2 receptor agonist, CGS 21680C (sodium salt of CGS 21680, 2-[p-(2-carboxyethyl) phenethylamino]-5'-N-ethylcarboxamido adenosine) (1 microg x kg(-) x min (-1)), although it decreased blood pressure by 20 mmHg, increased renal blood flow and renin release, whereas glomerular filtration rate and urine flow were unaffected. These results suggest that stimulation of renal A2 receptor led to both afferent and efferent arteriolar dilatation, whereas renal A2 receptor plays a minor role in urine formation. CGS 21680C induced renin release and tachycardia that were blocked by propranolol, indicating these effects of A2 receptor stimulation appeared to be indirect. (+info)
Small synthetic ligands of the cholecystokinin-B/gastrin receptor can mimic the function of endogenous peptide hormones.
(20/952)
The gastric cholecystokinin-B/gastrin receptor (CCK-BR) is a key regulator of enterochromaffin-like cell function and proliferation. Over the last decade, a number of small non-peptide CCK-BR "antagonists" have been discovered. Here, we demonstrate that some of these non-peptide ligands in fact possess significant ability to activate the human CCK-BR, and are, therefore, more properly categorized as partial agonists. When tested in COS-7 cells transiently expressing the recombinant human CCK-BR, saturating concentrations of the small "peptoid" ligands PD 135,158 and PD 136,450 stimulated inositol phosphate formation to 23 and 43 percent, respectively, of the maximum response induced by a considerably larger endogenous peptide agonist, cholecystokinin octapeptide. In contrast, the benzodiazepine-derived CCK-BR ligand, YM022, acted as a "true" high-affinity antagonist of cholecystokinin-induced inositol phosphate formation (pA2 = 9.69). Consistent with recent findings in animal experiments, our data reveal that small synthetic ligands have the potential to function as either CCK-BR agonists or antagonists. These dual properties of synthetic molecules must be considered when evaluating candidate drugs for human disease. (+info)
Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group.
(21/952)
BACKGROUND: Atrial fibrillation occurs frequently in patients with congestive heart failure and commonly results in clinical deterioration and hospitalization. Sinus rhythm may be maintained with antiarrhythmic drugs, but some of these drugs increase the risk of death. METHODS: We studied 1518 patients with symptomatic congestive heart failure and severe left ventricular dysfunction at 34 Danish hospitals. We randomly assigned 762 patients to receive dofetilide, a novel class III antiarrhythmic agent, and 756 to receive placebo in a double-blind study. Treatment was initiated in the hospital and included three days of cardiac monitoring and dose adjustment. The primary end point was death from any cause. RESULTS: During a median follow-up of 18 months, 311 patients in the dofetilide group (41 percent) and 317 patients in the placebo group (42 percent) died (hazard ratio, 0.95; 95 percent confidence interval, 0.81 to 1.11). Treatment with dofetilide significantly reduced the risk of hospitalization for worsening congestive heart failure (risk ratio, 0.75; 95 percent confidence interval, 0.63 to 0.89). Dofetilide was effective in converting atrial fibrillation to sinus rhythm. After one month, 22 of 190 patients with atrial fibrillation at base line (12 percent) had sinus rhythm restored with dofetilide, as compared with only 3 of 201 patients (1 percent) given placebo. Once sinus rhythm was restored, dofetilide was significantly more effective than placebo in maintaining sinus rhythm (hazard ratio for the recurrence of atrial fibrillation, 0.35; 95 percent confidence interval, 0.22 to 0.57; P<0.001). There were 25 cases of torsade de pointes in the dofetilide group (3.3 percent) as compared with none in the placebo group. CONCLUSIONS: In patients with congestive heart failure and reduced left ventricular function, dofetilide was effective in converting atrial fibrillation, preventing its recurrence, and reducing the risk of hospitalization for worsening heart failure. Dofetilide had no effect on mortality. (+info)
Adenosine A(2A) receptors mediate coronary microvascular dilation to adenosine: role of nitric oxide and ATP-sensitive potassium channels.
(22/952)
Adenosine is a potent vasodilator that plays an important role in the regulation of coronary microvascular diameter. Although multiple adenosine receptor subtypes have been recently cloned, the specific adenosine receptor subtypes and the underlying mechanisms responsible for the vasodilation to adenosine in the coronary microcirculation remain unknown. Therefore, in the present study we determined the receptor subtypes for coronary arteriolar dilation to adenosine and investigated the role of nitric oxide (NO) and ATP-sensitive potassium (K(ATP)) channels in this vasodilatory response. Pig coronary arterioles (50-100 microm in situ) were isolated, cannulated, and pressurized without flow for in vitro study. Arterioles developed basal tone and dilated in a concentration-dependent manner to adenosine and to adenosine receptor agonists (2S)-N(6)-[2-endo-norbornyl]adenosine (A(1)), 2-[p-(2-carboxyethyl)]phenylethyl-amino-5'-N-ethylcarboxamidoadenosin e (CGS21680; A(2A)), N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide (A(3)), and N-ethylcarboxamidoadenosine (nonselective adenosine receptor activation). The selective A(2A) receptor antagonist 4-(2-[7-amino-2-(2-furyl)[1,2,4]-triazolo[2,3-a][1,3,5]triazin-5-y l amino]ethyl)phenol attenuated vasodilation to adenosine and to all adenosine receptor agonists tested, suggesting that the vasodilatory responses were primarily mediated by A(2A) receptors. Adenosine- and CGS21680-induced dilations were attenuated in a similar manner by endothelial removal and by the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester. In denuded vessels, both adenosine- and CGS21680-induced dilations were nearly abolished by the K(ATP) channel inhibitor glibenclamide. The selective A(2A) agonist CGS21680 mechanistically mimics the vasodilation in response to adenosine. Collectively, our results suggest that the dilation of coronary arterioles to adenosine is mediated predominantly by A(2A) receptors. Activation of this receptor subtype elicits vasodilation by endothelial release of NO and by the smooth muscle opening of K(ATP) channels. (+info)
Alpha(1)-adrenoceptor subtypes mediating inotropic responses in rat heart.
(23/952)
We studied the distribution of alpha(1)-adrenoceptor subtypes by radioligand binding assays using (125)I-labeled 2-beta(4-hydroxyphenyl)-ethylaminomethyl)-tetralone (BE2254) and RNase protection assays, and determined the role of each subtype in mediating the inotropic response in rat heart. Chlorethylclonidine preincubation causes a approximately 72% decrease in the maximal binding capacity (B(max)). On the other hand, protection from phenoxybenzamine alkylation by 5-methyl-urapidil or BMY7378 decreased B(max) by 59 and 70%. By competitive inhibition, we have identified 19 to 28% and 30% high-affinity binding sites for the alpha(1A)- and alpha(1D)-selective antagonists in rat ventricles, with the alpha(1B)-adrenoceptor estimated as 45%. Consistent with the receptor-binding result, a similar distribution of mRNAs encoding alpha(1A), alpha(1B,) and alpha(1D) (22, 39, and 39%), based on RNase protection assays, was observed. In addition, we demonstrated that the noradrenaline response through alpha(1)-adrenoceptor was antagonisted by 5-methyl-urapidil, RS-17053, BMY7378, and WB4101 in contraction functional experiments. K(I) values for the above compounds were defined for all three alpha(1)-adrenoceptor subtypes expressed in the human embryonic kidney 293 cell stably, and were further compared with the corresponding pA(2) values. Interestingly, the correlation was significantly higher for alpha(1A) (r(2) = 0.73) and alpha(1B) (r(2) = 0.66) than alpha(1D) (r(2) = 0.35) in these experiments. Because the potential of alpha(1D) measured to be 21% based on protection from phenoxybenzamine-caused inhibition by BMY7378, the combined potential of alpha(1A) and alpha(1B) can be estimated as approximately 80%. Taken together, these results suggest that the three alpha(1)-adrenoceptor subtypes coexist in rat heart, with alpha(1A) and alpha(1B) playing a more prominent role in the positive inotropic response to noradrenaline. (+info)
Activation of leukotriene synthesis in human neutrophils by exogenous arachidonic acid: inhibition by adenosine A(2a) receptor agonists and crucial role of autocrine activation by leukotriene B(4).
(24/952)
We report here that the apparent inability of isolated human polymorphonuclear leukocytes (PMNs) to efficiently transform arachidonic acid (AA) is the consequence of A(2a) receptor engagement by endogenous adenosine accumulating in incubation media. Indeed, when adenosine is eliminated from PMN suspensions by the addition of adenosine deaminase, or when cells are incubated with adenosine A(2a) receptor antagonists, important quantities (40-80 pmol/10(6) cells) of 5-lipoxygenase products are synthesized by PMN incubated with 1 to 5 microM exogenous AA. The selective A(2a) receptor agonist CGS21680 was a very potent inhibitor of the AA-induced leukotriene (LT) synthesis, showing an IC(50) of approximately 1 nM. The mechanism of AA-induced stimulation of LT synthesis observed in the absence of extracellular adenosine was investigated. In adenosine deaminase-treated PMN, exogenous AA induced Ca(2+) mobilization and the translocation of 5-lipoxygenase to nuclear structures. A time lag of 20 to 60 s (variable between PMN preparations) was observed consistently between the addition of AA and the elevation of intracellular Ca(2+) concentration (and LT synthesis), indicating that AA itself did not trigger the Ca(2+) mobilization in PMN. This AA-induced Ca(2+) mobilization, as well as the corresponding 5-lipoxygenase translocation and stimulation of LT synthesis, was blocked efficiently by the LT synthesis inhibitor MK0591, the LTB(4) receptor antagonists CP105696 and LY223982, and the LTA(4) hydrolase inhibitor SC57461A. These data demonstrate that AA is a highly potent and effective activator of LT synthesis and acts through a mechanism that requires an autocrine stimulatory loop by LTB(4). (+info)