Hyperpolarization-activated currents in presynaptic terminals of mouse cerebellar basket cells.
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Using patch-clamp techniques, a hyperpolarization-activated current (I(h)) was recorded from synaptic terminals of mouse cerebellar basket cells. Ih was blocked quickly and reversibly by 2 mM Cs(+), and subtraction revealed a rapidly activating and deactivating I(h) current. Similar gating and block of presynaptic I(h) were also seen with the more selective inhibitor ZD 7288 (10 microM). The time constant of activation (tau (a))of presynaptic I(h) current became faster with membrane hyperpolarization, being approximately 74 ms at -130 mV, changing e-fold for a 33 mV change in membrane potential. Whole-cell recordings from basket cell somata also revealed an I(h) current, which was similarly sensitive to block by ZD 7288. Inhibition of I(h) by 10 microM ZD 7288 reduced the frequency ( approximately 34 %) and amplitude ( approximately 26 %) of spontaneous IPSCs (sIPSCs) recorded in Purkinje cells, one of the principal synaptic targets of basket neurones. This is the first report of an I(h) current in mammalian inhibitory presynaptic terminals, which may be an important target for neuromodulation in the cerebellum. Comparing the biophysical properties and distribution of cloned hyperpolarization-activated cation channels, we also suggest a molecular candidate underlying I(h) at these synapses. (+info)
A novel pharmacological approach to treating cardiac ischemia. Binary conjugates of A1 and A3 adenosine receptor agonists.
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Adenosine released during cardiac ischemia exerts a potent, protective effect in the heart via activation of A(1) or A(3) receptors. However, the interaction between the two cardioprotective adenosine receptors and the question of which receptor is the more important anti-ischemic receptor remain largely unexplored. The objective of this study was to test the hypothesis that activation of both receptors exerted a cardioprotective effect that was significantly greater than activation of either receptor individually. This was accomplished by using a novel design in which new binary conjugates of adenosine A(1) and A(3) receptor agonists were synthesized and tested in a novel cardiac myocyte model of adenosine-elicited cardioprotection. Binary drugs having mixed selectivity for both A(1) and A(3) receptors were created through the covalent linking of functionalized congeners of adenosine agonists, each being selective for either the A(1) or A(3) receptor subtype. MRS 1740 and MRS 1741, thiourea-linked, regioisomers of a binary conjugate, were highly potent and selective in radioligand binding assays for A(1) and A(3) receptors (K(i) values of 0.7-3.5 nm) versus A(2A) receptors. The myocyte models utilized cultured chick embryo cells, either ventricular cells expressing native adenosine A(1) and A(3) receptors, or engineered atrial cells, in which either human A(3) receptors alone or both human A(1) and A(3) receptors were expressed. The binary agonist MRS 1741 coactivated A(1) and A(3) receptors simultaneously, with full cardioprotection (EC(50) approximately 0.1 nm) dependent on expression of both receptors. Thus, co-activation of both adenosine A(1) and A(3) receptors by the binary A(1)/A(3) agonists represents a novel general cardioprotective approach for the treatment of myocardial ischemia. (+info)
Changes in the treatment and outcomes of acute myocardial infarction in Quebec, 1988-1995.
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BACKGROUND: Few studies have reported population-based information on the treatment trends and outcomes of patients who have had an acute myocardial infarction (AMI). We therefore examined patterns of care and outcomes for AMI patients in Quebec, Canada, between 1988 and 1995. METHODS: Longitudinal data files of hospital admissions in Quebec (Med-Echo database) and inpatient and outpatient services (Regie de l'Assurance Maladie du Quebec database) were used to construct cohorts of all AMI patients in the province between 1988 and 1995. Temporal trends in the use of cardiac procedures after an AMI, discharge prescriptions and mortality rates were examined. RESULTS: Between 1988 and 1995 the age- and sex-adjusted rates of AMI in the Quebec population declined (148 per 100,000 in 1988 to 137 per 100,000 in 1995). The use of intensive cardiac procedures increased in the same period; the 1-year cumulative incidence rate of catheterization increased from 28% in 1988 to 31% in 1994, that of angioplasty rose from 8% to 15% and that of coronary artery bypass surgery from 6% to 8%. Prescriptions for ASA, beta-blockers, lipid-lowering agents and angiotensin-converting enzyme inhibitors increased, and prescriptions for nitrates and calcium antagonists decreased. These temporal changes were paralleled by a decrease in mortality rates post-AMI. All-cause 1-year cumulative incidence mortality rates decreased from 23% in 1988 to 19% in 1994. INTERPRETATION: The decrease in AMI-related mortality in Quebec between 1988 and 1995 may be linked to changes in treatment strategies (i.e., increased use of cardiac surgical procedures and medications shown to increase survival). (+info)
Intravenous diltiazem and CYP3A-mediated metabolism.
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AIMS: To study whether intravenous diltiazem, a calcium channel blocker commonly prescribed for hypertension and stable angina, is an inhibitor of the CYP3A enzymes by using oral lovastatin, an HMG Co-A reductase inhibitor, as a substrate. METHODS: Ten healthy volunteers were studied in a randomized two-way crossover design. The two arms were 1) administration of a 20 mg dosage of lovastatin orally and 2) administration of a 20 mg dosage of lovastatin orally 1 h after an intravenous loading dosage and constant infusion of diltiazem. Blood samples were collected up to 25 h in order to quantify lovastatin and diltiazem concentrations in the separated serum. Lovastatin and diltiazem concentrations were quantified by GC-MS and h.p.l.c., respectively. RESULTS: Intravenous diltiazem did not significantly affect the oral AUC, Cmax, t(1/2), or tmax of lovastatin. CONCLUSIONS: These data suggest that the interaction of lovastatin with diltiazem does not occur systemically and is primarily a first-pass effect. Thus, drug interactions with diltiazem may become evident when a patient is moved from intravenous to oral dosing. (+info)
The economic burden of congestive heart failure in a managed care population.
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OBJECTIVE: To examine the economic burden of and treatment patterns for congestive heart failure (CHF) in a managed care population. STUDY DESIGN: Retrospective review of medical and pharmacy claims. PATIENTS AND METHODS: We reviewed integrated medical and pharmacy claims data from 6 independent-practice-association model health maintenance organizations to identify patients diagnosed with CHF. Of the approximately 1.4 million people enrolled in these managed care plans during the study period (January through December 1994), a total of 2777 patients (mean age, 56.9 years) met the study criteria, which included diagnostic codes for CHF and claims eligibility of at least 1 year. We reviewed the charges incurred by patients diagnosed with CHF for the 6 months after the initial CHF medical claim. We also examined the treatment received by each of these patients. RESULTS: During the study period, 378 of the 2777 patients with CHF (14%) were admitted to the hospital at a cost of almost $3 million (an average of $7863 per hospitalized patient). Seventy-eight percent of the study population received prescription drugs, at an average per-patient cost of $942. The most commonly prescribed drug class was angiotensin-converting enzyme inhibitors, prescribed for 38% of patients. Calcium channel blockers were prescribed for 33% of patients, but beta-blockers were prescribed for only 18% of patients. Hospitalization accounted for 54% of the total cost for CHF treatment, with prescription drugs accounting for 38%. CONCLUSION: Congestive heart failure represents a significant financial burden within a non-elderly managed care population. Improved management of the condition is needed to reduce the morbidity and mortality, as well as the costs of treatment, associated with CHF. Considerable data indicate that drugs such as beta-blockers and angiotensin-converting enzyme inhibitors can significantly decrease the morbidity and mortality of CHF. Further investigation is needed into whether increased use of prescription pharmaceuticals may reduce hospitalization rates and overall costs for CHF in this setting. (+info)
Prognostic implications of Tc-99m sestamibi viability imaging and subsequent therapeutic strategy in patients with chronic coronary artery disease and left ventricular dysfunction.
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OBJECTIVES: The aim of the study was to verify the prognostic implications of viability detection using baseline-nitrate sestamibi imaging in patients with left ventricular (LV) dysfunction due to chronic coronary artery disease (CAD) submitted to different therapeutic strategies. BACKGROUND: The prognostic meaning of preserved viability in these patients is still debated. Sestamibi is increasingly used for myocardial perfusion scintigraphy and is being accepted also as viability tracer, but no data are available about the relationship between viability in sestamibi imaging, subsequent treatment, and patient's outcome. METHODS: Follow-up data were collected in 105 CAD patients with LV dysfunction who had undergone baseline-nitrate sestamibi perfusion imaging for viability assessment and had been later treated medically (group 1), or submitted to revascularization, which was either complete (group 2A) or incomplete (group 2B). RESULTS: Eighteen hard events (cardiac death or nonfatal myocardial infarction) were registered during the follow-up. A significantly worse event-free survival curve was observed in the patients of group 1 (p < 0.0002) and group 2B (p < 0.03) compared to those of group 2A. Using a Cox proportional hazard model, the most powerful prognostic predictors of events were the number of nonrevascularized asynergic segments with viability in sestamibi imaging (p < 0.003, risk ratio [RR] = 1.4), and the severity of CAD (p < 0.02, RR = 1.28). CONCLUSIONS: Viability detection in sestamibi imaging has important prognostic implications in CAD patients with LV dysfunction. Patients with preserved viability kept on medical therapy or submitted to incomplete revascularization represent high-risk groups. (+info)
Effect of indomethacin on blood pressure lowering by captopril and losartan in hypertensive patients.
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NSAIDs are known to attenuate the effects of some antihypertensive medications. It is not known whether the new class of angiotensin II receptor antagonists is similarly affected. We conducted a multicenter study assessing the effect of indomethacin on the antihypertensive effects of losartan and captopril. After 4 weeks of placebo washout, hypertensive patients received 6 weeks of active antihypertensive therapy with either 50 mg losartan once daily (n=111) or 25 mg captopril twice daily for 1 week, which was increased to 50 mg twice daily for 5 weeks (n=105). This was followed by 1 week of concomitant therapy with indomethacin (75 mg daily). The primary outcome measure was the change in mean 24-hour ambulatory diastolic blood pressure after the addition of indomethacin. Both captopril and losartan significantly lowered ambulatory diastolic blood pressure (losartan -5.3 mm Hg, P:<0.001; captopril -5.6 mm Hg, P:<0.001) after 6 weeks of therapy. Indomethacin significantly attenuated the 24-hour ambulatory diastolic blood pressure for both losartan (2.2 mm Hg, P:<0.05) and captopril (2.7 mm Hg, P:<0.001) and also attenuated the effect of captopril on trough sitting diastolic blood pressure. Changes in daytime diastolic blood pressure (7:00 AM to 11:00 PM) were similar to the 24-hour response in both groups. Nighttime diastolic blood pressure (11:01 PM to 6:59 AM) was significantly attenuated in captopril-treated patients (2.0 mm Hg, P:<0.05), but losartan was unaffected (0.4 mm Hg). Thus, concurrent treatment with indomethacin similarly attenuates the 24-hour antihypertensive response to losartan and captopril. (+info)
Local and systemic effects of peritoneal lavage with high concentrations of adenosine in rats.
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BACKGROUND: Adenosine exerts actions which may be beneficial in treating diseases of the gastrointestinal tract. However, administered systemically, adenosine causes a 'stress reaction' and may adversely affect blood pressure and cardiac and renal function. AIM: To determine whether peritoneal lavage with adenosine provides pharmacological levels of adenosine in the intestines without elevating adenosine levels in the systemic circulation. METHODS: Rats received an intramesenteric artery infusion of angiotensin II (30 ng/min) plus methoxamine (3 microg/min) to reduce mesenteric blood flow by approximately 60%, and adenosine solutions were instilled into the abdominal cavity. In a second study, microdialysis probes were placed in the mesenteric vein and aortic arch of rats, and the peritoneal cavity was continuously lavaged with adenosine solutions. RESULTS: High concentrations (10(-3)M) of adenosine normalized the mesenteric blood flow without affecting blood pressure or heart rate. High concentrations of adenosine (10(-3)M) induced micromolar levels of adenosine and inosine in the mesenteric vein, without affecting adenosine or inosine levels in the aorta. CONCLUSIONS: Peritoneal lavage with high concentrations of adenosine provides pharmacological levels of adenosine in the gastrointestinal tract without systemic side-effects. Peritoneal lavage with high concentrations of adenosine may be useful for the treatment of a number of diseases of the gastrointestinal tract. (+info)