oxadiazoles and Arteriosclerosis

A generalized accumulation of cholesterol, calcium and matrix materials (collagen, elastin and proteoglycans) occurs in an age-dependent manner in major arteries. Human atherogenesis is a disease of arteries characterized by a focal accumulation of fibrous matrix elements, lipids and calcium at lesion sites. Studies in cholesterol-fed animal models have indicated that calcium competitors and chelating agents can reduce calcium, lipid and matrix accumulation in arterial lesions and reduce the extent of lesion formation. These agents generally alter soft and hard tissue calcium pools or have deleterious side-effect profiles. Antiatherogenic studies with calcium antagonists (which have been shown to be safe in human clinical studies) have created confusion because of conflicting results. It is apparent, however, that high doses of calcium antagonists can significantly decrease atherogenic lesion development in cholesterol-fed rabbits. The antiatherogenic effects of calcium antagonists may be the result of changes in intracellular calcium pools within smooth muscle cells, which may lead to alterations in cellular metabolic activity or may be due to activities not related to calcium channel effects. Several mechanisms involving regulation of lipoprotein receptor synthesis, lipoprotein uptake or degradation, cholesterol ester hydrolytic activity and arterial matrix synthesis are discussed as potential sites of activity for calcium antagonists. A dihydropyridine channel antagonist, PN 200-110 (isradipine), has been shown to be a very potent antiatherogenic agent in the rabbit and also to be a potent inhibitor of smooth muscle cell matrix synthesis.

Topics: Animals; Arteriosclerosis; Calcinosis; Calcium; Calcium Channel Blockers; Humans; Ion Channels; Isradipine; Muscle, Smooth, Vascular; Oxadiazoles

Peripheral atherosclerosis was treated in 178 patients: 90 were given pyridinol carbamate for 2--4 months, 40 pentoxyphylline, 30 cetedil, and 18 received butalamine. in intermittent claudication pyridinol carbamate and trental proved most effective, cetedil (straten) was less effective. The favourable effect of pyridinol carbamate is associated with its action both on the state of microcirculation and on the content of lipids. A significant decrease in the level of blood triglycerides was observed during treatment with pyridinol carbamate. Pentoxyphylline reduced blood viscosity and platelet aggregation in patients with peripheral atherosclerosis but had no effect on the blood lipid content. Cetedil did not reduce blood viscosity although it decreased the aggregation of erythrocytes and inhibited the second phase of platelet aggregation. The objective criterion for the improvement of circulation in the affected extremities was increased tolerance to load, particularly in medication with pyridinol carbamate and trental.

Topics: Aged; Arteriosclerosis; Arteriosclerosis Obliterans; Azepines; Clinical Trials as Topic; Drug Evaluation; Female; Humans; Leg; Male; Microcirculation; Middle Aged; Oxadiazoles; Pentoxifylline; Plethysmography, Impedance; Pyridinolcarbamate; Thiophenes; Vasodilator Agents

Augmented vasoconstriction to serotonin (5-hydroxytryptamine [5-HT]) in atherosclerotic vessels plays a crucial role in the development of myocardial ischemia. We investigated mechanisms for serotonin-evoked hypercontraction in atherosclerotic rabbit coronary arteries.. Contractile responses to serotonergic agents of endothelium-denuded coronary arteries from control and Watanabe heritable hyperlipidemic rabbits (WHHL) were examined. WHHL coronary arteries exhibited hypercontraction to 5-HT(1)-receptor agonists; the constrictor threshold concentrations and E:D(50) to serotonin, 5-carboxamidotryptamine, and sumatriptan in WHHL were significantly lower, and the E:(max) in WHHL to these agents were increased 55% to 59% above those of the control. Serotonin-evoked contractions in both groups were inhibited by GR127935 (5-HT(1B/1D) antagonist; 0.1 to 1 nmol/L) and pertussis toxin but not by ketanserin (5-HT(2) antagonist; 0.01 to 1 micromol/L), suggesting that the hypercontraction is most likely mediated by 5-HT(1B/1D) receptors through a pertussis toxin-sensitive pathway. Furthermore, simultaneous measurements of [Ca(2+)](i) and isometric tension of fura-2-loaded arteries revealed that the hypercontraction was concomitant with the augmented elevation of [Ca(2+)](i) in the smooth muscle. The 5-HT(1B) mRNA levels in WHHL coronary arteries increased to 2.5-fold over those in control arteries, whereas neither 5-HT(1D) nor 5-HT(2A) mRNA was detected in either group.. Atherosclerotic rabbit coronary arteries exhibited the enhancement in contraction and Ca(2+) mobilization in response to serotonin. The 5-HT(1B) receptor, which is upregulated by atherosclerosis, most likely mediates the augmenting effects of serotonin.

Topics: Animals; Arteriosclerosis; Calcium; Coronary Vessels; Dose-Response Relationship, Drug; Female; In Vitro Techniques; Ketanserin; Male; Oxadiazoles; Phenylephrine; Piperazines; Rabbits; Receptor, Serotonin, 5-HT1B; Receptors, Serotonin; RNA, Messenger; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Sumatriptan; Vasoconstriction

We tested the effects of low doses of a dihydropyridine calcium antagonist, PN 200110, on endothelium-dependent vascular relaxation in rabbits fed a 1% cholesterol diet. The drug was given orally, 1 mg/day, and control rabbits received placebo. Plasma total cholesterol after 10 weeks, was similar in the placebo- and PN 200110-treated groups. The respective values averaged 2140 +/- 116 (n = 14; mean +/- SEM) and 2012 +/- 115 mg/dl (n = 13). In placebo-treated rabbits, sudanophilic aortic lesions covered 52 +/- 5% of the intimal surface, and the aortic cholesterol concentration was 72 +/- 6 mg/g protein. Corresponding values in aortas from PN 200110-treated rabbits were significantly lower [36 +/- 5% (P less than 0.03) and 52 +/- 3 mg/g protein (P less than 0.03)]. Maximal endothelium-dependent cholinergic relaxation of aortic strips in untreated (n = 14) and treated cholesterol-fed rabbits (n = 13) differed significantly (P less than 0.01) and averaged 31 +/- 4% and 61 +/- 7% of the value in normocholesterolemic controls (n = 13). We conclude that cholesterol feeding suppresses endothelium-dependent relaxation evoked by acetylcholine, and that PN 200110 reduces the severity of atherosclerosis and impairment of endothelium-dependent relaxation.

Topics: Animals; Aorta; Arteriosclerosis; Calcium Channel Blockers; Cholesterol, Dietary; Endothelium; Hemodynamics; Isradipine; Male; Microscopy, Electron, Scanning; Oxadiazoles; Parasympathetic Nervous System; Rabbits

Balloon catheter damage of the rat carotid artery endothelium results in an extensive and reproducible neointimal lesion composed of smooth muscle cells and connective matrix. The authors have examined two calcium channel blockers, PN 200-110 and PY 108-068, for their ability to inhibit neointimal lesion development in the rat carotid model. When given subcutaneously (1.0 mg/kg day) both compounds produced rapidly acting and long-lasting hypotension, reducing blood pressure 25-29%. At this dose given daily, PN 200-110 reduced lesion cross-sectional area by 44%, compared with only 25% seen by PY 108-068, which suggests that the antiatherosclerotic effect may not be related to lowering of blood pressure. Furthermore, PN 200-110 did not reduce the extent of platelet deposition (compared with controls) occurring at the denuded vessel surface 1 hour or 24 hours after balloon catheterization, which indicates that the inhibition of lesion development may not reflect an antiplatelet mechanism. The observed inhibition by PN 200-110 may relate to mitogen responses of the smooth muscle cell in the vessel wall (migration and proliferation) involved in lesion progression after endothelial damage.

Topics: Angioplasty, Balloon; Animals; Arteriosclerosis; Blood Platelets; Blood Pressure; Carotid Arteries; Hypotension; Isradipine; Male; Muscle, Smooth, Vascular; Nifedipine; Oxadiazoles; Rats; Rats, Inbred Strains