amlodipine Norvasc
A study of the renal actions of amlodipine in the normotensive and spontaneously hypertensive rat.

Johns EJ.

Department of Physiology, Medical School, Birmingham.

1. Normotensive Sprague-Dawley and spontaneously hypertensive rats anaesthetized with sodium pentobarbitone were used to determine the systemic and renal actions of amlodipine, a new calcium channel blocking drug. 2. Amlodipine, 200 micrograms kg-1 plus 50 micrograms kg-1 h-1, decreased blood pressure by 12 +/- 3 mmHg in normotensive rats, although the fall was not statistically significant in the hypertensive rats; did not change renal haemodynamics and caused significant increases in urine flow, absolute and fractional sodium excretions of 70%, 91% and 113%, respectively, in normotensive rats and 65%, 91% and 96%, respectively in hypertensive rats. Fractional lithium excretion was unchanged in the normotensive rats but increased by 28% in the hypertensive animals while absolute fluid reabsorption in the proximal tubule did not change in either group. Absolute water and sodium reabsorption in the segments beyond the proximal tubule were unchanged in the normotensive rats but increased in the hypertensive animals by 24% and 22%, respectively, while fractional sodium excretion in this portion of the nephron increased by 88% and 51% in the normotensive and hypertensive rats, respectively. 3. Amlodipine, 400 micrograms kg-1 plus 100 micrograms kg-1 h-1, decreased blood pressure by 12 +/- 4 mmHg in the normotensive and by 27 +/- 5 mmHg in the hypertensive rats. Renal blood flow was not changed in either group of rats and glomerular filtration rate increased by 25% in the spontaneously hypertensive animals. There were significant increases in urine flow, absolute and fractional sodium excretions of 105%, 145% and 142%, respectively, in the normotensive rats and 224%, 421% and 259%, respectively, in the hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)

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amlodipine Norvasc
Amlodipine and captopril in moderate-severe essential hypertension.

Maclean D, Mitchell ET, Wilcox RG, Walker P, Tyler HM.

Department of Pharmacology and Clinical Pharmacology, Ninewells Hospital, Dundee, UK.

The therapeutic usefulness of adding once-daily amlodipine (10 mg) for four weeks in moderate-severe hypertensive patients uncontrolled on low dose captopril (25 mg twice daily) alone was studied in 29 patients in a double-blind, placebo-controlled two-way crossover comparison. Once daily amlodipine was shown to be an effective antihypertensive drug when combined with captopril. The amlodipine minus placebo differences in mean changes from captopril baseline values were: -18/-12 mmHg and -20/-12 mmHg for supine and standing systolic/diastolic pressures (P less than 0.001 for all four pressure variables). The combination was well tolerated, and no patient discontinued therapy. Five patients experienced ankle oedema and four patients reported flushing while receiving amlodipine/captopril.

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amlodipine Norvasc
Inhibition of oxidized LDL aggregation with the calcium channel blocker amlodipine: role of electrostatic interactions.

Phillips JE, Preston Mason R.

Department of Medicine, MCP Hahnemann University School of Medicine, Allegheny Campus, Pittsburgh, PA, USA.

Atherogenic low-density lipoproteins (LDL) are characterized by elevations in cholesterol content and increased electronegativity, factors that contribute to aggregation and foam cell formation. This study was designed to test the effect of the positively charged calcium channel blocker (CCB) amlodipine on the aggregation properties of oxidized LDL lipids. Large unilamellar vesicles (LUVs) (100 nm diameter) labeled with a non-exchangeable marker [3H]cholesteryl hexadecyl ether were prepared with lipids extracted from human LDL following oxidation. The LUVs were shown to bind, in a reversible fashion, to charged diethylaminoethyl Sephadex columns. The addition of amlodipine inhibited binding of the oxidized LDL lipids in a dose-dependent fashion with an IC(50) in the nanomolar range as a result of its high lipophilicity and positively charged amino group (pK(a) of 9.02). The activity of amlodipine was reproduced in model membranes that contained fixed amounts of charged phospholipid (glycerophospholipid) in a concentration-dependent manner. By contrast, drugs lacking a formal positive charge, including CCBs (felodipine, nifedipine, diltiazem, verapamil) and an angiotensin-converting enzyme-inhibitor (ramiprilate) had no effect on the column binding of the modified, electronegative lipids. These effects of amlodipine on LDL lipid aggregation and electrostatic properties may represent a novel antiatherosclerotic mechanism of action.

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amlodipine Norvasc
Pharmacokinetics of amlodipine and its occupancy of calcium antagonist receptors.

Yamada S, Sugimoto N, Uchida S, Deguchi Y, Kimura R.

Department of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka, Japan.

We characterized the occupancy of dihydropyridine (DHP) calcium antagonist receptors by amlodipine in spontaneously hypertensive rats (SHR) in relation to its pharmacokinetics. Oral administration of amlodipine (10 mg/kg) in SHR produced a significant (20-70%) decrease in the number of specific (+)[3H]PN 200-110 binding sites in cardiac tissues 0.5-18 h later, and the effect was greatest 3 h later. In these rats, there was little change in cerebral cortical (+)[3H]PN 200-110 binding. Occupancy of cardiac calcium antagonist receptors after oral administration of amlodipine correlated well with its plasma concentration. In vitro blockade of cardiac (+)[3H]PN 200-110 binding sites induced by amlodipine also persisted after the tissues were washed by centrifugation and suspension, whereas that induced by nifedipine was reversible under these conditions. Thus, our results suggest that the gradual onset and long-lasting pharmacologic effect of amlodipine are due to its slow binding kinetics (association and dissociation) of cardiovascular receptor sites in addition to its slow pharmacokinetics.

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amlodipine Norvasc
Renal protective effects of amlodipine on partially nephrectomized spontaneously hypertensive rats fed a high-salt diet.

Kanno Y, Suzuki H, Okada H, Saruta T.

Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.

We examined the effects of a calcium-channel blocker amlodipine on progression of renal failure in 5 of 6 nephrectomized spontaneously hypertensive rats (SHR) fed a high-salt diet. Twelve SHR, 5 of 6 with nephrectomy and salt-loading, were divided into two group: group 1 as control (n = 6) and group 2 treated with 2 mg/kg/day amlodipine (n = 6). During the 10 study weeks, body weight, systolic blood pressure (SBP), and daily urinary protein excretion were measured every 2 weeks. At the end of the study, serum creatinine, urea nitrogen, and total protein and albumin were determined. Renal tissues were obtained for light microscopic examination. The increase in SBP after 10 study weeks was significantly less in the treated group than in the control group (control 287 +/- 5 mm Hg; amlodipine 237 +/- 23 mm Hg (p < 0.01)). Urinary protein excretion was also suppressed in the amlodipine-treated group (p < 0.01). Although in the control group glomerular sclerosis and hyalinosis were marked, they were significantly less in the amlodipine-treated group. These results illustrate that amlodipine can attenuate BP increase and inhibit progression of hypertensive renal injury in this rat model.

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amlodipine Norvasc
Selective interaction of the calcium antagonist amlodipine with calcium channels in arteries of spontaneously hypertensive rats.

Morel N, Godfraind T.

Laboratoire de Pharmacologie, Universite Catholique de Louvain, Brussels Belgium.

The mechanism of the antihypertensive action of the 1,4-dihydropyridine Ca2+ antagonist amlodipine was investigated by measuring dihydropyridine receptor occupation and the contractile responses to Ca2+ channel activation in aortas and mesenteric arteries from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) after chronic administration of amlodipine. Amlodipine treatment (10 mg/kg/day orally) significantly reduced the increase in blood pressure (BP) in SHR, but did not change BP in WKY. It more potently decreased the contractile response induced by Bay K 8644 in SHR than in WKY aorta. In both SHR and WKY arteries, the functional effect of chronic amlodipine treatment was related to occupation of the specific dihydropyridine binding sites similar to that which occurs after in vitro exposure to amlodipine 5 nM. Resting membrane potential (RMP) of aortic smooth muscle cells (SMC) from SHR was depolarized by 12 mV as compared with SMC from WKY, indicating that the higher potency of amlodipine in arteries from SHR could be related to the depolarization-induced increase in affinity for amlodipine of Ca2+ channels in SHR.

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amlodipine Norvasc
Hemodynamic effects of amlodipine and benazeprilat in spontaneously hypertensive rats.

Bazil MK, Webb RL.

Research Department, Ciba-Geigy, Summit, New Jersey 07901.

We wished to assess the hemodynamic effects of administration of the combination of the calcium channel blocking agent amlodipine and the angiotensin-converting enzyme (ACE) inhibitor benazeprilat in conscious spontaneously hypertensive rats (SHR). In SHR previously instrumented for measurement of mean arterial blood pressure (MAP) and heart rate (HR), intravenous (i.v.) injection of amlodipine (0.25-4 mg/kg) produced dose-dependent decreases in blood pressure (BP). Administration of benazeprilat (0.1-10 mg/kg i.v.) decreased arterial MAP, and benazeprilat (10 mg/kg) effectively blocked the effects of exogenously administered angiotensin I (AI). In animals surgically prepared for measurement of BP, HR, and hindquarter, renal, and mesenteric blood flows, administration (i.v.) of the combination of amlodipine (0.5 mg/kg) with benazeprilat (10 mg/kg) evoked a decrease in BP that was greater than that elicited by monotherapy. The tachycardic response observed after administration of the combination was no different from that observed after monotherapy with amlodipine. Simultaneous administration of amlodipine and benazeprilat produced reductions in vascular resistance in the hindquarter, renal and mesenteric beds that were greater than the responses evoked by injection of either agent. The major finding of these studies was that dual therapy with amlodipine and benazeprilat produced an additive hypotensive effect in conscious SHR. Regional vasodilation accompanied the large degree of hypotension evoked by the combination.

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amlodipine Norvasc
[The effect on left ventricular mass of treatment with amlodipine and diet therapy in obese patients with arterial hypertension]

[Article in Italian]

Ruvolo G, Greco E, Speziale G, Di Natale M, Marino B.

Istituto di Chirurgia del Cuore e dei Grossi Vasi, Universita degli Studi di Roma La Sapienza.

Increased parietal stress, in hypertensive obese patients, produces a left ventricular hypertrophy. In this study we demonstrated that the association of amlodipine with hypocaloric diet can decrease the parietal stress. MATERIALS AND METHODS. From February to July 1993 32 hypertensive obese patients (17 males, 15 females) were treated with amlodipine 10 mg/day for six months. Sixteen patients were treated with amlodipine 10 mg/day (Group A) and 16 patients were treated with amlodipine 10 mg/day and hypocaloric diet (Group B). All patients included had a Body Mass Index > 30 and diastolic blood pressure > 100 mmHg. The patients were studied with 2D guided M-mode echocardiogram before treatment and after 6 months. RESULTS. In Group A the septal thickness, the posterior wall thickness and the left ventricular mass decreased significatively (p < 0.05). In the Group B also the left ventricular diastolic diameter and the left atrial diameter decreased. CONCLUSION. The association of a hypocaloric diet with amlodipine therapy, in hypertensive obese patients, improves the effect of the drug on ventricular hypertrophy.

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