Vascular Protection of Lacidipine in Salt-Loaded Dahl-S Rats at Nonsustained Antihypertensive Doses

Cristofori, Patrizia; Terrón, Alberto; Micheli, D.; Bertolini, G.; Gaviraghi, G.; Carpi, C

doi:10.1097/00005344-199100174-00016

Cited by 11 publications

(11 citation statements)

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“…Furthermore, it is very interesting that cerebral malacia was not observed in rats treated with J-105859, even at a dosage of 0.1 mg/ kg per day. In salt-loaded DS rats, it was reported that brain lesions were the likely cause of death [4] and that vascular hypertrophy preceded the destruction of the internal elastic lamina, narrowing of the arterial lumen and periarteritis in cerebral arterioles [28]. ET-1 is not only a potent vasoconstrictor [7] but also a mitogenic agent.…”

Section: Discussionmentioning

confidence: 99%

“…The contribution of the renin±angiotensin system to the maintenance of high blood pressure is slight in this type of hypertension, as shown in deoxycorticosterone acetate (DOCA)-salt hypertensive rats [2,3]. Long-term salt loading eventually results in the death of these rats, usually due to brain lesions or cardiac disorders [4,5]. Recently, we observed increases in tissue levels of prepro-endothelin-1 (ET-1) mRNA as well as acute antihypertensive effects of ET antagonists in DS rats but not in Dahl salt-resistant (DR) rats [6].…”

Section: Introductionmentioning

confidence: 99%

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Marked reduction of mortality in salt-loaded Dahl salt- sensitive rats by the new, selective endothelin ETA receptor antagonist, J-105859

Okada¹,

Nishino²,

Saito³

et al. 2000

Journal of Hypertension

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Marked reduction of mortality in salt-loaded Dahl salt- sensitive rats by the new, selective endothelin ETA receptor antagonist, J-105859

Okada¹,

Nishino²,

Saito³

et al. 2000

Journal of Hypertension

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“…Lacidipine is a recently developed vascular-selective 1,4-dihidropyridine (DHP) calcium antagonist that has been reported to induce a potent and long-lasting antihypertensive effect in animal studies [37]. The newer DHPs, such as amlodipine, lercanidipine and lacidipine, are endowed with slow onset and long duration of vasodilator activity; they are able to reduce coronary resistance with little or no effect on heart rate.…”

Section: Ex-vivo Measurement Of No In Aortic Rings Of CD Rats: Influementioning

confidence: 99%

Dihydropyridines, Nitric Oxide and Vascular Protection

Crespi

2005

CVP

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For more than decades calcium antagonists (CEBs) have been widely used for the treatment of myocardial ischaemia (angina pectoris). Among the classes of CEBs, the 1,4-dihidropyridine (DHPs) have been used for this indication because of their haemodynamic and electrophysiological properties. In particular, DHPs are compounds capable of vascular protection on both smooth muscle and endothelium. The main protective activity is related to their calcium antagonist activity. In addition, they present vascular dilatation function, which has been related to an anti-endothelin efficacy. The newer DHPs are endowed with slow onset and long duration of vasodilator activity and reduce coronary resistance with little or no effect on heart rate. The more lipophilic DHP, lacidipine, is also able to reduce the formation of atheroma plaque in animal models at therapeutic doses. It has potent and long-lasting antihypertensive properties and appears to protect the arterial wall against the development of atherosclerotic lesions in animal models or human subjects with severe and multiple risk factors. Additionally, it has been observed that: i) NO/cyclic GMP pathway facilitates the inhibitory effect of Ca(++) antagonists on KCl-evoked contraction in rat aorta; ii) Vasodilator effect of lacidipine was significantly attenuated in the presence of NO-synthase inhibitors; iii) DHPs stimulate an electrochemical activity related to the nitric oxide (NO) system within the aortic vessel tissue, in rats and mice. In particular, they implement endothelial NO at "useful" and not toxic nanomolar levels. These activities join the already described positive effects of these compounds upon vascular functions.

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“…These include the stroke-prone spontaneously hypertensive rat (SHRSP) [31] and the Dahl-S rat [32]. In both of these models addition of NaCl to the diet causes increased blood pressure and tissue and vascular damage which eventually lead to death.…”

Section: Scientific Rationalementioning

confidence: 99%

Calcium antagonists as anti-atherosclerotic agents

Gaviraghi¹,

Trist²

1998

Emerging Drugs

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Hypercholesterolaemia and hypertension are two major risk factors for atherosclerosis. Each contributes to the progression of plaque, which can eventually occlude arteries leading to myocardial infarction (MI), stroke and peripheral vascular damage. Both elevated blood pressure and high plasma cholesterol can now be controlled with anti-hypertensives and medicines such as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, but no treatments are available that act specifically to reduce or reverse the progression of plaque. Calcium entry blockers (CEBs) are potent anti-hypertensives. However, the rationale for the use of a CEB to interfere with the mechanisms of plaque formation is also strong. It can be hypothesised that CEBs should potentially be able to reduce cholesterol deposition, cellular proliferation and migration and increased cellular matrix, since all of these processes involve calcium. However, CEBs are a heterogeneous class, differing in terms of structure, potency, vascular selectivity and duration of action. In addition, some possess additional properties such as anti-oxidant activity. The newer, third generation dihydropyridines, such as lacidipine, which combine potent CEB activity with long duration of action and anti-oxidant activity, offer the best hope of demonstrating anti-atherosclerotic effects in man. Animal data have confirmed that CEBs are able to reduce plaque progression, though to differing extents. Few so far have been assessed in man. Of those tested, results have not been encouraging. However, the ongoing trials with longer-acting compounds, such as lacidipine (ELSA), are of longer duration and are using B-mode ultrasonography monitoring to afford more precise measurements of atherosclerotic plaque progression. Thus, more consistent daily cover by the CEB should be expected, and the longer monitoring period and the more sensitive measurement should afford an improved chance of demonstrating clinical efficacy.

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Vascular Protection of Lacidipine in Salt-Loaded Dahl-S Rats at Nonsustained Antihypertensive Doses

Cited by 11 publications

References 0 publications

Marked reduction of mortality in salt-loaded Dahl salt- sensitive rats by the new, selective endothelin ETA receptor antagonist, J-105859

Marked reduction of mortality in salt-loaded Dahl salt- sensitive rats by the new, selective endothelin ETA receptor antagonist, J-105859

Dihydropyridines, Nitric Oxide and Vascular Protection

Calcium antagonists as anti-atherosclerotic agents

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