Slowly Acting Calcium Antagonists and their Merits

Zwieten, PA van; Hansson, Lennart; Epstein, Murray

doi:10.3109/08037059709061803

Cited by 17 publications

(8 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…10). The L-arginine analogue and NOS inhibitor, L-NAME, which blocks NOS consumption of NADPH by interrupting electron flux has been used previously to investigate the role of NO in pathologic settings such as vascular hypertension (54), glomerular damage (55), and pre-eclampsia (56). L-NAME and ATII together increased p42/44 ERK activity beyond that observed in the presence of ATII alone (Fig.…”

Section: Atii Induction Of Pdgf-a and Egr-1 In Smcs Ismentioning

confidence: 99%

Angiotensin II (ATII)-inducible Platelet-derived Growth Factor A-chain Gene Expression Is p42/44 Extracellular Signal-regulated Kinase-1/2 and Egr-1-dependent and Mediated via the ATII Type 1 but Not Type 2 Receptor

Day

Rafty

Chesterman

et al. 1999

Journal of Biological Chemistry

View full text Add to dashboard Cite

Angiotensin II (ATII) and platelet-derived growth factor (PDGF) are two vasoconstrictors implicated in the maintenance of normal vascular homeostasis. PDGF Achain levels increase in cultured vascular smooth muscle cells (SMCs) exposed to ATII. The molecular mechanisms underlying this induction are not known. We used transient transfection analysis to show that ATII can increase reporter gene activity driven by fragments of the PDGF-A promoter bearing recognition elements for the transcription factor, Egr-1. Nuclear run-off experiments indicate that ATII induces Egr-1 expression at the level of transcription. Gel shift and supershift studies show that Egr-1 protein accumulates in the nuclei of SMCs exposed to ATII and binds to the proximal region of the PDGF-A promoter in a specific, time-dependent manner. ATII induced extracellular-signal regulated kinase (p42/44 ERK) activity as did phorbol 12-myristate 13-acetate. The specific MEK1/2 inhibitor, PD98059, suppressedbothPDGF-AandEgr-1endogenousandpromoter-dependent expression inducible by ATII. The ATII type 1 receptor (AT1) antagonist, Losartan, inhibited ATII-induction of p42/44 ERK, as well as Egr-1 and PDGF-A, whereas neither PD123319, an AT2 receptor antagonist, nor wortmannin, an inhibitor of phosphatidylinositol 3-kinase and c-Jun N-terminal kinase, had any effect. ATII-induction of Egr-1 and PDGF-A was blocked by SIN-1, a NO donor. In addition, this pathway was blocked by overexpression of NO synthase. Collectively, these findings demonstrate that ATII activation of the PDGF-A promoter is mediated via the MEK/ERK/Egr-1 pathway and AT1 receptor and that this process is antagonized by NO.Angiotensin II (ATII), 1 a peptide hormone with potent vasoconstrictor activity, has long been implicated in the pathobiology of hypertension. In vascular smooth muscle cells (SMCs), ATII stimulates protein synthesis (1), cellular hypertrophy (2-5), migration (6), extracellular matrix synthesis (7,8), and the activation of a large number of transcription factors. These include Jak/STAT (9), Ets-1 (10), SRF (11), MHox (11), c-Jun (12, 13), JunB (12), and c-Fos (14). ATII is produced in the vessel wall by the actions of renin, which converts angiotensinogen to ATI, which is then cleaved to ATII by angiotensin-converting enzyme. Two ATII receptor subtypes have been described, AT1 and AT2. Signal transduction through G-protein-coupled AT1 receptors involves phospholipase C, phospholipase A 2 , phospholipase D, adenylate cyclase, and the release of intracellular calcium (reviewed in Refs. 15 and 16). The AT1 receptor also regulates neointimal thickening after mechanical injury to the rat carotid artery wall and ATII infusion (17). AT2 receptor signaling is less well understood, but evidence suggests that this receptor is involved in growth inhibition (18), Bcl-2 dephosphorylation (19), and apoptosis (20, 21). Platelet-derived growth factor (PDGF) consists of an A-chain and B-chain held together in homo-or heterodimeric configuration by disulfide bonds (reviewed in Refs. 22 and 2...

show abstract

Section: Atii Induction Of Pdgf-a and Egr-1 In Smcs Ismentioning

confidence: 99%

Angiotensin II (ATII)-inducible Platelet-derived Growth Factor A-chain Gene Expression Is p42/44 Extracellular Signal-regulated Kinase-1/2 and Egr-1-dependent and Mediated via the ATII Type 1 but Not Type 2 Receptor

Day

Rafty

Chesterman

et al. 1999

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…This improvement is predominantly associated with a more favourable pharmacokinetic profile, which has, however, a profound impact on the haemodynamic behaviour and the dosage schedule. Clinically, the absence of sympathetic activation and reflex tachycardia is probably a more relevant advantage than the long duration of action and once-daily dosage schedule [23].…”

Section: Discussionmentioning

confidence: 99%

The Pharmacological Properties of Lipophilic Calcium Antagonists

ZWIETEN¹

1998

Blood Pressure

Self Cite

View full text Add to dashboard Cite

van Zwieten PA. The pharmacological properties of lipophilic calcium antagonists. Blood Pressure 1998; 7 (Suppl 2): 5-9.Several types of calcium antagonists (CA) (verapamil, diltiazem, nifedipine and related drugs) may be used as antihypertensives. In practice, the dihydropyridines (nifedipine and related drugs) are the CA used most frequently as antihypertensives. Apart from the lowering of blood pressure CA may lead to other, theoretically beneficial, effects: regression of left ventricular and vascular hypertrophy, renal protection, weak natriuretic, weak antiplatelet, anti-ischaemic and antiatherogenic activity. Several new dihydropyridine CA have been introduced in recent years. The advantages of the newer compounds, such as amlodipine, felodipine, isradipine, lacidipine and lercanidipine, may include: vasoselectivity, hence little or no cardiodepressant activity; an improved kinetic profile, resulting in a slow onset and long duration of action, fewer side-effects such as reflex tachycardia and headache, owing to the slow onset of the antihypertensive action. For a few newer CA a predominant effect on specialized circulatory beds (renal, coronary and cerebral) has been claimed. The new CA, which are clearly lipophilic, deserve special attention. Owing to the lipophilic character of such compounds considerable concentration occurs in lipid-containing membrane depots. The CA thus concentrated are slowly released from these depots and, subsequently, reach their targets, the L-type calcium channels. This phenomenon explains both the slow onset and the long duration of action of these CA. Owing to the slow onset of action reflex tachycardia is virtually absent. The long duration of action allows satisfactory control of blood pressure in hypertensives by means of a single daily dose. A few lipophilic dihydropyridine CA are vasoselective. This property implies that at therapeutic, vasodilatory dosages no cardiodepressant activity occurs. Lercanidipine is a recently introduced example of a lipophilic and vasoselective dihydropyridine CA. It is an effective vasodilator/antihypertensive drug, with a slow onset and long duration of action, which is associated with neither reflex tachycardia nor cardiodepressant activity. Other examples of recently introduced lipophilic CA are lacidipine, barnidipine and manidipine.

show abstract

“…Nicardipine, a dihydropyridine calcium channel antagonist, is effective for the treatment of hypertension, myocardial ischaemia and vasospasm with coronary and peripheral vasodilatation by blocking the influx of extracellular calcium across cell membranes in surgical patients 1, 2. It has also been used experimentally as a probe to study the effects of calcium channel antagonists on the role of sympathetic nervous system activity in the development of cardiovascular risk 3. In humans, the extent of absolute oral bioavailability ( F ) was not complete, about 0.35, following a 30 mg dose at steady state due to the hepatic first‐pass extraction 4, 5.…”

Section: Introductionmentioning

confidence: 99%

Effects of lovastatin on the pharmacokinetics of nicardipine in rats

Chung

Yang

Choi

2010

Biopharm & Drug Disp

View full text Add to dashboard Cite

It has been reported that both nicardipine and lovastatin are substrates of both the cytochrome P450 (CYP) 3A subfamily and P-glycoprotein (P-gp), and P-gp transport is unlikely to be a significant factor. Thus, the effects of oral lovastatin on the pharmacokinetics of intravenous and oral nicardipine were investigated in rats. Nicardipine was administered intravenously (4 mg/kg) and orally (12 mg/kg) with 0 (control), 0.3 and 1 mg/kg of oral lovastatin to rats. Lovastatin was administered 30 min before nicardipine administration. After intravenous administration of nicardipine with 0, 0.3 and 1 mg/kg of lovastatin, the total areas under the plasma concentration-time curve from time zero to infinity (AUCs) of nicardipine were not changed by lovastatin. However, after oral administration of nicardipine with 1 mg/kg of oral lovastatin, the AUC of nicardipine was significantly greater (by 67.4%), and the extent of absolute oral bioavailability (F) of nicardipine was increased (by 38.5%). The above data suggest that lovastatin did not considerably inhibit the metabolism of nicardipine via the hepatic CYP3A subfamily, but inhibited intestinal P-gp and/or the CYP3A subfamily.

show abstract

Slowly Acting Calcium Antagonists and their Merits

Cited by 17 publications

References 12 publications

Angiotensin II (ATII)-inducible Platelet-derived Growth Factor A-chain Gene Expression Is p42/44 Extracellular Signal-regulated Kinase-1/2 and Egr-1-dependent and Mediated via the ATII Type 1 but Not Type 2 Receptor

Angiotensin II (ATII)-inducible Platelet-derived Growth Factor A-chain Gene Expression Is p42/44 Extracellular Signal-regulated Kinase-1/2 and Egr-1-dependent and Mediated via the ATII Type 1 but Not Type 2 Receptor

The Pharmacological Properties of Lipophilic Calcium Antagonists

Effects of lovastatin on the pharmacokinetics of nicardipine in rats

Contact Info

Product

Resources

About