Vasodilatory Action of Amlodipine on Rat Aorta, Pig Coronary Artery, Human Coronary Artery, and on Isolated Langendorff Rat Heart Preparations

Matlib, Mohammed A.; French, John F.; Grupp, I L; Gorp, Cornelius Van; Grupp, Günter; Schwartz, Arthur G.

doi:10.1097/00005344-198812007-00011

Cited by 31 publications

(18 citation statements)

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“…This selectivity of calcium antagonists has been reported in several vascular beds (Schuman et al, 1975;Kondo et al, 1980;Godfraind et al, 1986), and specifically for some new 1,4-DHP derivatives such as felodipine in rat resistance mesenteric vessels (Nyborg & Mulvany, 1984) and amlodipine in rat aorta (Matlib et al, 1988). In addition, the electrophysiological study by Mulvany et al (1982) demonstrates that NA (10pM) induces a significant depolarization in rat mesenteric arteries; therefore, the possibility cannot be excluded that at least a part of the noradrenaline contraction in these arteries is due to the influx of calcium through POCs, since it is known that NA responses in rat resistance mesenteric arteries are mostly dependent on the influx of extracellular calcium (Mulvany & Nyborg, 1980;Hogestatt, 1984;Nyborg & Mulvany, 1984).…”

Section: Discussionsupporting

confidence: 70%

“…This property has also been described for amlodipine in rat aorta and portal vein (Burges et al, 1987) and pig and human coronary arteries (Matlib et al, 1988), and for lacidipine in rabbit ear artery (Michelli et al, 1990). This pharmacological feature of amlodipine has been attributed to its low lipid solubility due to the presence of the side chain in the 2-position of the DHP ring carrying a basic amino group which gives the molecule a pKa of 8.6, thus rendering the molecule more than 90% ionized at physiological pH (Burges et al, 1989).…”

Section: Discussionmentioning

confidence: 61%

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(+)‐S‐12967 and (–)‐S‐12968: 1,4‐dihydropyridine stereoisomers with calcium channel agonistic and antagonistic properties in rat resistance arteries

Prieto

Mulvany

Nyborg

1991

British J Pharmacology

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1 The actions of (+)-S-12967 and (-)-S-12968 two isomers of a new 1,4-dihydropyridine (DHP) derivative, were studied on 125 mm K + -, Ca2+-and noradrenaline-induced contractions in rat isolated mesenteric resistance arteries and compared to those of nifedipine. 2 The action of (+)-S-12967 and (-)-S-12968 was slow in onset in contrast to nifedipine. Both isomers had a dual contractile and relaxant action in arteries contracted with 125 mm K+; however, the (-)-isomer was about 300 times more potent than the (+)-isomer. The response to 125 mm K+, being depressed by 70%, recovered within 20 to 30 min for all DHP derivatives. All vessels were treated with 1 X 1O6 M phenoxybenzamine thus excluding the possibility that the contraction is mediated by activation of amine-receptors.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 61%

(+)‐S‐12967 and (–)‐S‐12968: 1,4‐dihydropyridine stereoisomers with calcium channel agonistic and antagonistic properties in rat resistance arteries

Prieto

Mulvany

Nyborg

1991

British J Pharmacology

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“…29 Amlodipine is known to release nitric oxide into coronary microvessels, as do angiotensin-converting enzyme inhibitors, 30 and it has coronary vasodilator capacity. 31 It is likely that modulation of the sympathetic nervous system by angiotensin-converting enzymes also contributes to the reduction in QT dispersion seen in heart failure 13 and in hypertension. 22,24 It is tempting to suggest that LVH regression related to BP lowering plays a part in reducing QT dispersion.…”

Section: Lim Et Al February 1999 715mentioning

confidence: 99%

Irbesartan Reduces QT Dispersion in Hypertensive Individuals

et al. 1999

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Abstract-Angiotensin type 1 receptor antagonists have direct effects on the autonomic nervous system and myocardium.Because of this, we hypothesized that irbesartan would reduce QT dispersion to a greater degree than amlodipine, a highly selective vasodilator. To test this, we gathered electrocardiographic (ECG) data from a multinational, multicenter, randomized, double-blind parallel group study that compared the antihypertensive efficacy of irbesartan and amlodipine in elderly subjects with mild to moderate hypertension. Subjects were treated for 6 months with either drug. Hydrochlorothiazide and atenolol were added after 12 weeks if blood pressure (BP) remained uncontrolled. ECGs were obtained before randomization and at 6 months. A total of 188 subjects (118 with baseline ECGs) were randomized. We analyzed 104 subjects who had complete ECGs at baseline and after 6 months of treatment. Key Words: irbesartan Ⅲ amlodipine Ⅲ electrocardiography Ⅲ QT dispersion Ⅲ aged Ⅲ hypertension, essential Q T dispersion is the difference between maximal and minimal QT intervals within a 12-lead surface electrocardiogram (ECG). 1 It is thought to represent the degree of repolarization inhomogeneity in the heart. 2 Abnormal values are found in heart failure and after myocardial infarction, and these are predictive of a high rate of malignant arrhythmias and of sudden death. [3][4][5][6][7] In the healthy elderly population, a raised QTc dispersion (Ͼ60 milliseconds) is associated with a 2-fold increase in sudden cardiac death. 8 A reduction in QT dispersion is observed after successful thrombolytic therapy in acute myocardial infarction and parallels a decreased risk of arrhythmic cardiac death. 9 It is also used as a marker of therapeutic efficacy in treating patients with idiopathic long QT syndrome. 10 Another index, the QTc max, which is the longest heart rate-corrected QTc interval within a 12-lead ECG, has similar prognostic value. It predicts sudden death in diabetics 11 and in patients with ischemic heart disease. 12 It is also reduced along with QT dispersion in treating heart failure with angiotensin-converting enzyme inhibitors. 13 QT dispersion is increased in left ventricular hypertrophy (LVH) 14 and in hypertension, 15 and abnormal QT dispersion may be an early indicator of end-organ damage involving the heart in hypertension. Since angiotensin II and aldosterone have been implicated in myocyte hypertrophy 16 and cellular matrix modification, 17 respectively, we hypothesized that an angiotensin II antagonist would reduce QT dispersion. The aim of the present study was to test the hypothesis that irbesartan would favorably reduce indexes of QT dispersion compared with amlodipine, a highly selective vasodilator. Methods SubjectsMales and postmenopausal females aged 65 years or older with established or newly diagnosed mild to moderate essential hypertension (diastolic blood pressure [DBP] 95 to 110 mm Hg) were recruited. Exclusion criteria included seated systolic BP (SBP) Ͼ200 mm Hg and known or suspected seconda...

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“…In pilot experiments we noted the long (430 min) time needed to allow the decrease in force to reach a plateau especially with low concentrations and the complication with time-dependent fade in the contractile force in vehicle-treated muscle (Kjellstedt et al, 1985;Ljung et al, 1987). Slow onset may be a feature of some VOCC antagonists such as exhibited by amlodipine (Burges et al, 1985;Arrowsmith et al, 1986;Matlib et al, 1988;Stopher et al, 1988). Thus rather than use intervals of 60 min between dosing in a cumulative concentration-response protocol (Godfraind et al, 1984) or worse 30 min (Magnon et al, 1995) we chose to measure the e ect of just a single concentration in each tissue after 120 min equilibration and adjust the responses for the fade in contractile force observed in non-treated muscle.…”

Section: Atrial Preparationsmentioning

confidence: 99%

Human vascular to cardiac tissue selectivity of L‐ and T‐type calcium channel antagonists

Sarsero

Fujiwara

Molenaar

et al. 1998

British J Pharmacology

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1 Voltage-operated calcium channel (VOCC) antagonists are e ective antihypertensive and antianginal agents but they also depress myocardial contractility. 2 We compared four L-type calcium channel antagonists, felodipine, nifedipine, amlodipine and verapamil and a relatively T-type selective calcium channel antagonist, mibefradil, on human and rat isolated tissue assays to determine their functional vascular to cardiac tissue selectivity (V/C) ratio. 3 The V/C ratio was calculated as the ratio of the IC 50 value of the antagonist that reduced (by 50%) submaximally contracted (K + 62 mM) human small arteries from the aortic vasa vasorum (vascular, V) mounted in a myograph and the IC 50 value of the antagonist that reduced (7)-isoprenaline (6 nM) submaximally stimulated human right atrial trabeculae muscle (cardiac, C) mounted in organ chambers. 4 The average pIC 50 values (7log IC 50 M) for the human vascular preparations were felodipine 8.30, nifedipine 7.78, amlodipine 6.64, verapamil 6.26 and mibefradil 6.22. The average pIC 50 values for the cardiac muscle were felodipine 7.21, nifedipine 6.95, verapamil 6.91, amlodipine 5.94, and mibefradil 4.61. 5 The V/C ratio calculated as antilog [pIC 50 V-pIC 50 C] is thus mibefradil 41, felodipine 12, nifedipine 7, amlodipine 5 and verapamil 0.2. 5 In rat small mesenteric arteries the pIC 50 values for the ®ve drugs were similar to the values for human vasa vasorum arteries contracted by K + 62 mM. However for methoxamine (10 mM) contraction in the rat arteries the pIC 50 values were lower for felodipine 7.24 and nifedipine 6.23, but similar for verapamil 6.13, amlodipine 6.28 and mibefradil 5.91. 7 In conclusion, in the human tissue assays, the putative T-channel antagonist mibefradil shows the highest vascular to cardiac selectivity ratio; some 3 fold higher than the dihydropyridine, felodipine, and some 200 fold more vascular selective than the phenylalkylamine, verapamil. This favourable vascular to cardiac selectivity for mibefradil, from a new chemical class of VOCC antagonist, may be explained by its putative T-channel selectivity.

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Vasodilatory Action of Amlodipine on Rat Aorta, Pig Coronary Artery, Human Coronary Artery, and on Isolated Langendorff Rat Heart Preparations

Cited by 31 publications

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(+)‐S‐12967 and (–)‐S‐12968: 1,4‐dihydropyridine stereoisomers with calcium channel agonistic and antagonistic properties in rat resistance arteries

(+)‐S‐12967 and (–)‐S‐12968: 1,4‐dihydropyridine stereoisomers with calcium channel agonistic and antagonistic properties in rat resistance arteries

Irbesartan Reduces QT Dispersion in Hypertensive Individuals

Human vascular to cardiac tissue selectivity of L‐ and T‐type calcium channel antagonists

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