Laminin binding to beta1-integrins selectively alters beta1- and beta2-adrenoceptor signalling in cat atrial myocytes.
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1. Perforated patch recordings were used to determine how plating atrial cells on laminin alters beta-adrenergic receptor (beta-AR) regulation of L-type Ca2+ current (ICa,L). 2. Isoproterenol (isoprenaline; ISO; 0.01 microM), a non-selective beta-AR agonist, elicited a greater stimulation of ICa,L in cells plated on laminin (+79 +/- 16 %; n = 17) than on glass (+33 +/- 5 %; n = 23). Also, desensitization to ISO was greater in cells on laminin (-16 +/- 2 %) than on glass (-3 +/- 1 %). Atenolol (0.1 microM), a selective beta1-AR antagonist, inhibited the effects of ISO in cells on glass but not laminin. Conversely, 0.1 microM ICI 118,551, a selective beta2-AR antagonist, inhibited the effects of ISO in cells on laminin but not glass. With beta2-ARs blocked, ISO-induced stimulation of ICa,L was greater in cells on glass than laminin. 3. Zinterol (0.01-0.1 microM), a selective beta2-AR agonist, elicited a greater stimulation of ICa,L in cells on laminin than on glass. The effects of zinterol were blocked by ICI 118,551. 4. ISO-induced stimulation of ICa,L was greater in cells plated on an alphabeta1-integrin antibody than on glass. Also, addition of 20 microM cytochalasin D to cells on laminin prevented the enhanced effects of ISO typically elicited in cells on laminin alone. 5. We conclude that laminin binding to alphabeta1-integrins, in conjunction with the actin cytoskeleton, reduces beta1-AR and enhances beta2-AR signalling which regulates ICa,L. This novel mechanism may contribute to remodelling of beta-AR signalling in the failing heart. (+info)
Adenosine A(2a)-receptor activation increases contractility in isolated perfused hearts.
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Adenosine A(2a)-receptor activation enhances shortening of isolated cardiomyocytes. In the present study the effect of A(2a)-receptor activation on the contractile performance of isolated rat hearts was investigated by recording left ventricular pressure (LVP) and the maximal rate of LVP development (+dP/dt(max)). With constant-pressure perfusion, adenosine caused concentration-dependent increases in LVP and +dP/dt(max), with detectable increases of 4.1 and 4.8% at 10(-6) M and maximal increases of 12.0 and 11.1% at 10(-4) M, respectively. The contractile responses were prevented by the A(2a)-receptor antagonists chlorostyryl-caffeine and aminofuryltriazolotriazinyl-aminoethylphenol (ZM-241385) but were not affected by the beta(1)-adrenergic antagonist atenolol. The adenosine A(1)-receptor antagonist dipropylcyclopentylxanthine and pertussis toxin potentiated the positive inotropic effects of adenosine. The A(2a)-receptor agonists ethylcarboxamidoadenosine and dimethoxyphenyl-methylphenylethyl-adenosine also enhanced contractility. With constant-flow perfusion, 10(-5) M adenosine increased LVP and +dP/dt(max) by 5.5 and 6.0%, respectively. In the presence of the coronary vasodilator hydralazine, adenosine increased LVP and +dP/dt(max) by 7.5 and 7.4%, respectively. Dipropylcyclopentylxanthine potentiated the adenosine contractile responses with constant-flow perfusion in the absence and presence of hydralazine. These increases in contractile performance were also antagonized by chlorostyryl-caffeine and ZM-241385. The results indicate that adenosine increases contractile performance via activation of A(2a) receptors in the intact heart independent of beta(1)-adrenergic receptor activation or changes in coronary flow. (+info)
Effect of celiprolol on cardiac hypertrophy in hypertension.
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The present study was undertaken to clarify whether celiprolol and atenolol, beta1-selective beta blockers with and without intrinsic sympathomimetic activity (ISA), respectively, might improve ischemic damage in the isolated perfused hearts of spontaneously hypertensive rats (SHR), and whether long-term treatment with celiprolol may reduce left ventricular hypertrophy (LVH) in patients with essential hypertension. Atenolol (50 mg/kg/day) or celiprolol (300 mg/kg/day) for 7 weeks significantly reduced the blood pressure in SHR to the same degree, and both drugs decreased the heart rate, but the magnitude of the fall in heart rate was significantly higher with atenolol treatment than with celiprolol treatment. Both treatments significantly reduced the ratio of LV weight to body weight in SHR and significantly improved the coronary reserve in SHR to the same extent. Both treatments significantly improved the extent of recovery of the pressure-rate product and the extent of percent recovery of the coronary flow after reperfusion following 30 min of ischemia in SHR. Celiprolol treatment in patients with essential hypertension for 12 months significantly decreased interventricular septal thickness (IVST)+LV posterior wall thickness (PWT) and LV mass index (LVMI), but there was no significant correlation between IVST+PWT or LVMI and blood pressure before and after treatment. IVST+PWT and LVMI were significantly decreased after 3 months of treatment and these LVH indices were significantly smaller after 6 and 12 months of treatment than after 3 months of treatment. In conclusion, both celiprolol and atenolol treatment reduced LVH and improved the ischemic damage in SHR. In essential hypertensive patients with LVH, celiprolol treatment effectively reduced blood pressure and achieved LVH regression. (+info)
Effects of antihypertensive therapy on glucose and insulin metabolism and on left ventricular mass: A randomized, double-blind, controlled study of 21 obese hypertensives.
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BACKGROUND: Glucose and insulin levels are associated with left ventricular mass (LVM) in insulin-resistant individuals. Antihypertensive drugs have different effects on glucose and insulin metabolism (GIM) and on LVM. To evaluate whether the effects of antihypertensive therapy on LVM are associated with its effects on GIM, we compared the effects of atenolol and perindopril on these parameters in a group of insulin-resistant, obese hypertensives. METHODS AND RESULTS: A total of 21 obese, nondiabetic hypertensives who were aged 55+/-12 years, had a body mass index of 32.8+/-5.0 kg/m(2), were free of coronary or valvular heart disease, and had normal LV function were randomized to treatment with atenolol (n=11) or perindopril (n=10). Echocardiographic LVM corrected for height (LVM/height) and GIM (3-hour intravenous glucose tolerance test) were measured after 4 to 6 weeks of washout and 6 months of treatment. Baseline characteristics were similar in both groups. Atenolol and perindopril effectively reduced blood pressure (from 149+/-13/98+/-4 to 127+/-8/82+/-6 mm Hg and from 148+/-9/98+/-4 to 129+/-9/82+/-6 mm Hg, respectively, for the atenolol and perindopril groups; P:=0.002). Atenolol significantly worsened GIM parameters, fasting glucose levels (5.3+/-0.9 to 6.0+/-1.5 mmol/L; P:=0.003), fasting insulin levels (121+/-121 to 189+/-228 pmol/L; P:=0.03), and most other relevant metabolic measures (P:<0.05 for all). Perindopril did not affect GIM. Atenolol did not affect LVM/height (119+/-12 to 120+/-17 g/m; P:=0.8), whereas perindopril significantly reduced LVM/height (120+/-13 to 111+/-19 g/m; P:=0.04). CONCLUSIONS: In obese, hypertensive individuals, adequate and similar blood pressure control was achieved with perindopril and atenolol. However, perindopril but not atenolol was associated with a more favorable GIM profile and led to a significant regression of LVM. (+info)
Atenolol and bendrofluazide in hypertension.
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The effect of atenolol, a new beta-1-adrenergic receptor blocking agent, was studied in a double-blind cross-over trial in 24 carefully selected hypertensive outpatients. After a four-week run-in period on matching placebo each patient received atenolol 200 mg/day, atenolol 400 mg/day, a combination of atenolol 200/mg day with bendrofluazide 5 mg/day, and bendrofluazide 5 mg/day alone, according to a random sequence. Atenolol at either dose produced a significantly greater reduction in all blood pressure levels except standing systolic pressure than bendrofluazide alone. There was no statistically significant difference between the effects of the two atenolol doses on either blood pressure or pulse rate. The addition of bendrofluazide to atenolol resulted in a further significant lowering of the blood pressure. A significant effect of thiazide on weight was noted. The study shows that atenolol, a cardioselective beta-blocker of similar potency to propranolol in animals but without membrane-stabilizing or partial agonist acitivity, is an effective and well-tolerated hypotensive agent. (+info)
Baseline characteristics in relation to electrocardiographic left ventricular hypertrophy in hypertensive patients: the Losartan intervention for endpoint reduction (LIFE) in hypertension study. The Life Study Investigators.
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The Losartan Intervention For Endpoint (LIFE) reduction in hypertension study is a double-blind, prospective, parallel group study designed to compare the effects of losartan with those of atenolol on the reduction of cardiovascular morbidity and mortality. A total of 9194 patients with hypertension and ECG left ventricular hypertrophy (LVH) by Cornell voltage-duration product and/or Sokolow-Lyon voltage criteria were enrolled in the study, with baseline clinical and ECG data available in 8785 patients (54% women; mean age, 67+/-7 years). ECG LVH by Cornell voltage-duration product criteria was present in 5791 patients (65.9%) and by Sokolow-Lyon voltage in 2025 patients (23.1%). Compared with patients without ECG LVH by Cornell voltage-duration product criteria, patients with ECG LVH by this method were older; more obese; more likely to be female, white, and to have never smoked; more likely to be diabetic and have angina; and had slightly higher systolic, diastolic, and pulse blood pressures. In contrast, patients with ECG LVH by Sokolow-Lyon criteria were slightly younger; less obese; more likely to be male, black, and current smokers; less likely to have diabetes; more likely to have angina and a history of cerebrovascular disease; and had higher systolic and pulse blood pressure but slightly lower diastolic blood pressure than patients without ECG LVH by this method. By use of multivariate logistic regression analyses, presence of ECG LVH by Cornell voltage-duration product criteria was predominantly associated with higher body mass index, increased age, and female gender, whereas presence of ECG LVH by Sokolow-Lyon voltage criteria was predominantly related to lower body mass index, male gender, and black race. Thus, hypertensive patients who meet Cornell product and Sokolow-Lyon voltage criteria are associated with different, but potentially equally adverse, risk factor profiles. (+info)
Cardiogenic shock triggered by verapamil and atenolol: a case report of therapeutic experience with intravenous calcium.
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Cardiogenic shock developed in a 72-year-old Japanese woman during combination therapy with verapamil and atenolol for recurrent supraventricular arrhythmia. She had coronary atherosclerosis, liver cirrhosis and bradycardia-tachycardia syndrome. Despite of the high-dose catecholamines and counterpulsation, she progressively deteriorated. Bolus administration of intravenous calcium chloride (CaCl2) immediately resolved her hemodynamic collapse. (+info)
Usefulness of head-up tilt test in the evaluation and management of unexplained syncope or pre-syncope.
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This study included 87 consecutive patients with unexplained syncope or pre-syncope who had undergone the head-up tilt (HUT) test with concomitant isoproterenol infusion. A positive response was defined as development of syncope or pre-syncope in association with substantial hypotension (decline of systolic blood pressure > or = 20 mmHg). Coronary artery spasm was suggested from the clinical symptoms and electrocardiographic findings in 1 patient (1/87= 1.1%). Intolerance to isoproterenol infusion was noted in 8 cases (8/87 = 9%). Of the 78 patients who completed the study, 73 showed positive responses (73/78 = 94%). (baseline systolic blood pressure = 125 +/- 23 mmHg endpoint systolic blood pressure = 76 +/- 11 mmHg, p < 0.05; baseline heart rate = 73 +/- 14 beats per minute vs endpoint HR = 80 +/- 24 beats per minute, p < 0.05). In 73 patients who showed positive responses, the systolic blood pressure (SBP) and heart rate (HR) returned to a safe level at 2 minutes when the patients were returned to a supine position (post-study 2 minutes SBP = 124 +/- 18 mmHg vs baseline SBP 125 +/- 23 mmHg, p = NS; post-study 2 minutes HR = 82 +/- 18 beats per minute vs baseline HR = 73 +/- 14 beats per minute, p < 0.05). All 73 patients with a positive HUT test received Atenolol therapy (50 mg daily). Only 35 of these 73 patients took Atenolol regularly and had a repeat HUT test. After atenolol therapy, persistent positive responses were observed in 19 cases (19/35 = 54%) and negative responses were noted in 16 cases (16/35 = 46%). The mean dosage of isoproterenol needed to provoke a positive HUT test in 19 patients who had received Atenolol therapy and had a positive repeat HUT test was 2.3 +/- 1.2 microg/min at baseline and 3.5 +/- 0.9 microg/min for post-Atenolol therapy (p < 0.001). Sixteen patients with a negative repeat HUT test were treated continuously with Atenolol and followed for a mean period of 13 +/- 11 months (range, 1-34 months). All 16 patients were free of syncope or pre-syncope during the period of follow up. In conclusion, the HUT test is mostly well tolerated and safe, even though the test has a low rate of adverse effects. Atenolol is effective for the prevention of provoked or spontaneous recurrent syncope or pre-syncope. (+info)