dihydropyridines and Vascular-Diseases

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.

Topics: Animals; Aorta, Thoracic; Blotting, Western; Dihydropyridines; Electrochemistry; Humans; Mice; Nitric Oxide; Rats; Rats, Inbred Dahl; Rats, Inbred SHR; Vascular Diseases

Ca antagonists of the dihydropyridine class (DHPs) are a heterogeneous group of drugs that interfere with Ca entry into vascular smooth muscle cells of resistance arterioles through type-L calcium channels producing arteriolar vasodilation. This leads to a reduction of vascular tone and, therefore, they have been successfully used in the treatment of systemic hypertension, myocardial ischemia (stable, variant, and unstable angina and silent ischemia), and Raynaud's phenomenon. Furthermore, recent clinical trials have indicated that DHPs may induce regression or slowing the progression of atheroma in coronary arteries. The results obtained with DHPs in the prophylaxis of migraine headache and in treating ischemic stroke and cerebral artery vasospasm are encouraging. However, more carefully designed, double-blind, large-scale, long-term studies are needed to better define the therapeutic value of DHPs in these disorders, the severity of adverse effects, and the mechanism responsible for their therapeutic effects.

Topics: Calcium Channel Blockers; Dihydropyridines; Humans; Muscle, Smooth, Vascular; Vascular Diseases

We compared the levels of microparticles, platelet activation markers, soluble cell adhesion molecules, and soluble selectins between hypertensive patients with and without type 2 diabetes and control subjects. Binding of anti-glycoprotein IIb/IIIa and anti-glycoprotein Ib monoclonal antibodies to platelets did not differ significantly between the hypertensive patients and controls, but platelet expression of activation markers (CD62P, CD63, PAC-1, and annexin V) was higher in the hypertensive patients. Platelet-derived microparticle (PDMP) and monocyte-derived microparticle (MDMP) levels were significantly higher in the hypertensive patients than in the controls. Soluble ICAM-1, VCAM-1, P-selectin, and E-selectin levels were also higher in the hypertensive patients, and they were significantly higher in the hypertensive patients with diabetes. After treatment with efonidipine, the levels of PDMPs, CD62P-, CD63-, PAC-1-, and annexin V-positive platelets, sICAM-1, sVCAM-1, sP-selectin, and sE-selectin all decreased significantly. The MDMP levels decreased, and the decrease was significant in the hypertensive patients with diabetes. These findings suggest that administration of efonidipine to hypertension patients with diabetes may prevent the development of cardiovascular complications caused by cell adhesion molecules or activated platelets and monocytes.

Topics: Aged; Antihypertensive Agents; Blood Cell Count; Cell Adhesion Molecules; Diabetes Mellitus, Type 2; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Monocytes; Nitrophenols; Organophosphorus Compounds; Platelet Activation; Vascular Diseases

The aim of this study was to evaluate the macrocirculatory and microcirculatory effects of treatment with lercanidipine, a new antihypertensive agent acting both on blood pressure and microcirculation in patients with moderate essential hypertension and without vascular disease and in patient with hypertension and vascular disease. In hypertensive subjects target-organ damage associated with high blood pressure may now be objectively documented by noninvasive tests. These alterations constitute a model to evaluate not only the pressure effects of antihypertensive treatment but also the normalization of the peripheral microcirculatory network. With color duplex scanning, flow velocity in the central retinal artery and retinal flow velocity can be measured and with use of laser-Doppler-flowmetry, it is also possible to evaluate microcirculation alterations in hypertensive subjects. These evaluation methods are completely noninvasive and may be used to assess the microcirculatory effects of antihypertensive drugs.

Topics: Adult; Aged; Antihypertensive Agents; Dihydropyridines; Female; Humans; Hypertension; Laser-Doppler Flowmetry; Male; Microcirculation; Middle Aged; Retinal Artery; Treatment Outcome; Ultrasonography; Vascular Diseases

Cilnidipine is an L- and N-type calcium channel blocker (CCB), and amlodipine is an L-type CCB. Valsartan (10 mg kg(-1)), valsartan (10 mg kg(-1)) and amlodipine (1 mg kg(-1)), and valsartan (10 mg kg(-1)) and cilnidipine (1 mg kg(-1)) were administered once daily for 2 weeks to stroke-prone, spontaneously hypertensive rats (SHR-SPs). Blood pressure was significantly reduced by valsartan, and it was further reduced by the combination therapies. Vascular endothelial dysfunction was significantly attenuated in all therapeutic groups, and further significant attenuation was observed in the valsartan+cilnidipine-treated group, but not in the valsartan+amlodipine-treated group. Vascular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit NOX1 gene expression was significantly attenuated in all therapeutic groups, and significantly greater attenuation was observed in the valsartan+cilnidipine-treated group than in the valsartan-treated group. Compared with the valsartan-treated group, the positive areas for 4-hydroxy-2-nonenal were significantly lower only in the valsartan+cilnidipine-treated group. Plasma renin activity was significantly augmented in the valsartan-treated group, and it was significantly attenuated in the valsartan+cilnidipine-treated group. A significant increase in the ratio of plasma angiotensin-(1-7) to angiotensin II was observed only in the valsartan+cilnidipine-treated group. Vascular angiotensin-converting enzyme (ACE) gene expression was significantly attenuated only in the valsartan+cilnidipine-treated group, but ACE2 gene expression was significantly higher in all of the therapeutic groups. Thus, valsartan and cilnidipine combination therapy might have a powerful protective effect in the vascular tissues via increases in the angiotensin-(1-7)/angiotensin II ratio in plasma.

Topics: Aldehydes; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Carotid Arteries; Cysteine Proteinase Inhibitors; Dihydropyridines; Heart; Immunohistochemistry; Male; Muscle Relaxation; Muscle, Smooth, Vascular; NADH, NADPH Oxidoreductases; NADPH Oxidase 1; Nitric Oxide Synthase Type III; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Real-Time Polymerase Chain Reaction; Tetrazoles; Valine; Valsartan; Vascular Diseases

Although the recommended target blood pressure for patients with chronic kidney disease is <130/80 mm Hg, this is difficult to achieve by treatment with an angiotensin receptor blocker alone. Addition of either a calcium channel blocker or a diuretic is suggested as second-line medication; however, which combination is most beneficial for target-organ protection remains unknown.. SHR/NDmcr-cp rats were administered no medications (control) or low-dose olmesartan for 2 weeks and then either olmesartan at an increased dose, azelnidipine, or the hydrochlorothiazide for 3 weeks. We assessed oxidative stress in the kidney and aorta, and endothelial function.. Urinary protein excretion was lower in all treated rats than in control rats. Oxidative stress caused by activation of NAD(P)H oxidase was observed in the glomeruli and aorta of control rats and was significantly suppressed in the olmesartan/azelnidipine (Olm/Azl) groups. Combination therapy with olmesartan and hydrochlorothiazide (Olm/HCTZ) however failed to suppress oxidative stress. The Olm/Azl groups maintained the endothelial surface layer in the glomeruli and protected endothelial function in the aorta.. In an animal model of metabolic syndrome, a combination of Olm/Azl is superior to a combination of Olm/HCTZ in terms of prevention of glomerular and vascular injuries.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Azetidinecarboxylic Acid; Dihydropyridines; Drug Therapy, Combination; Hydrochlorothiazide; Imidazoles; Kidney Diseases; Oxidative Stress; Rats; Rats, Inbred SHR; Tetrazoles; Vascular Diseases

Dihydropyridines can inhibit gene expression in-vitro and may have a protective vascular effect independent of blood pressure reduction. We tested the hypothesis that lacidipine prevents induction of inducible NO synthase (iNOS), influences leukocyte adhesion and infiltration, inhibits nuclear factor (NF)-kappaB transcription factor activity, and ameliorates end-organ damage in a transgenic rat model of angiotensin (Ang) II--dependent organ sclerosis. We treated rats transgenic for human renin and angiotensinogen (dTGR) from week 4 to 7 with lacidipine (0.3 or 3 mg/kg by gavage). Blood pressure was measured by tail cuff. Organ damage was assessed by histology and immunohistochemistry. Adhesion molecules and cytokines were analyzed by immunohistochemistry. Transcription factors were analyzed by mobility shift assays. Untreated dTGR developed moderate hypertension, cardiac hypertrophy, and severe renal damage with albuminuria. Lacidipine decreased blood pressure slightly at the low dose and substantially at the higher dose. However, both treatments reduced albuminuria and plasma creatinine to the same degree (P<0.05). Intercellular adhesion molecule-1 (ICAM-1) was markedly reduced by lacidipine as well as renal neutrophil and monocyte infiltration. Lacidipine reduced mitogen-activated protein (MAP) kinase phosphorylation and iNOS expression in both cortex and medulla. NF-kappaB and AP-1 were activated in dTGR but reduced by lacidipine. Lacidipine ameliorates Ang II-induced end-organ damage independent of blood pressure lowering, perhaps by inhibiting the MAP kinase pathway and NF-kappaB activation.

Topics: Angiotensins; Animals; Blood Pressure; Cell Adhesion Molecules; Dihydropyridines; Disease Models, Animal; Oxidoreductases; Rats; Rats, Sprague-Dawley; Vascular Diseases

Lacidipine is a long-lasting 1,4-dihydropyridine calcium antagonist that has been reported to protect salt-loaded Dahl-S rats from vascular damage and accelerated mortality when it is administered prophylactically at 0.1 and 0.3 mg/kg p.o. once a day (equivalent to the recommended dose in humans). The aim of this study was to investigate the vasoprotective properties of lacidipine in Dahl-S rats that had already developed sustained hypertension after 4 weeks of a salt-rich diet. Although none of the dosages of lacidipine (0.3, 1, and 3 mg/kg) reduced the elevated values of blood pressure, an almost complete protection from mortality was obtained. Moreover, lacidipine dose-dependently inhibited the development of macroscopic and microscopic alterations in the distal branches of mesenteric arteries and in the brain. A clear regression of vascular damage and cardiac hypertrophy was observed at the highest dose tested (3 mg/kg). These findings further support the assumption that the protective properties of lacidipine are not restricted to a reduction in blood pressure.

Topics: Animals; Blood Pressure; Body Weight; Calcium Channel Blockers; Dihydropyridines; Heart; Heart Rate; Hypertension; Male; Organ Size; Rats; Rats, Inbred Strains; Retinal Diseases; Vascular Diseases