Effects of SM-9018, a Potential Atypical Neuroleptic, on the Central Monoaminergic System in Rats

Abstract

ABSTRACT-This investigation was undertaken to characterize the vasoconstrictor responsiveness in aortas isolated from a rat model of arteriosclerosis induced by vitamin D2 (VD) administration followed by feeding with a high-cholesterol diet. Cumulative contractile responses to KC1, noradrenaline and serotonin in thoracic aortic strips isolated from arteriosclerotic rats were slightly augmented in concentrations lower than the EC50 value of each agent and rather attenuated in their higher concentrations as compared with those from normal rats. Maximum contractions to the agonists were markedly attenuated in arteriosclerotic aortas; the degree of attenuation was greater in rats treated with a combination of VD and cholesterol than in those treated with VD alone. There was a significant negative correlation between the maximum contrac tion to KCI, noradrenaline or serotonin and the content of calcium or cholesterol ester in aortas. Removal of endothelium markedly enhanced sensitivity and contractility to the agonists in aortic strips from normal rats, whereas the same procedure only slightly enhanced them in aortic strips from arteriosclerotic rats. These results indicate that in arteriosclerotic rat aortas, contractile responsiveness to agonists of vascular smooth muscle cells is impaired with deposition of calcium and cholesterol, and they suggest that augmenta tion of contractile responses to the agonists in lower concentrations is due to impairment of endothelial func tion.Keywords: Arteriosclerosis, Vitamin D, High-cholesterol diet, Calcification, Contractile response Atherosclerosis accompanied with hypercholesterol emia results in altered responsiveness of blood vessels to vasoactive substances in parallel with smooth muscle cell proliferation and lipid deposition. A number of studies have shown augmented responses to serotonin, histamine or ergonovine (1-6), and impaired endothelium-depend ent relaxation to a variety of vasodilator agents (7 -12) in various regions of arteries with experimental or human atherosclerosis. These changes may predispose athero sclerotic arteries to vasospasm. On the other hand, only a limited number of studies have been carried out on the vascular reactivity of arteriosclerotic vessels without depo sition of lipids (13,14). Henrion et al. (14) have reported that in the aorta from a rat model of vascular calcium overload produced by treatment with vitamin D3 and nicotine, not only endothelium-dependent relaxation to carbachol but also the vasoconstrictive response to noradrenaline is attenuated, while the relaxing responses to sodium nitroprusside is unchanged. Studies in our laboratory have also shown attenuation of vasorelaxation to acetylcholine or the calcium ionophore A23187 in aortas from rats with arteriosclerosis produced by four consecutive doses of vitamin D2 (VD) (15). We also dem onstrated that such impairment of endothelium-depend ent relaxations to acetylcholine and A23187 was propor tional to the degree of calcium deposition and facilitated by cholesterol feeding ...

Warfarin-Induced Artery Calcification Is Accelerated by Growth and Vitamin D

“…In the second set of experiments, we examined the effect of concurrent Warfarin treatment in an animal model in which some degree of artery calcification had been induced by high doses of vitamin D. Treatment with high doses of vitamin D has been known for many years to induce artery calcification in humans, rats, and other animals. [32][33][34][35][36][37] This vitamin D-induced calcification is confined to the media of arteries and closely resembles the pattern of calcification seen in Monckeberg's syndrome in humans. 24,25 In the vitamin D treatment regime used for the current studies, vitamin D induced marked artery calcification within 4 days of treatment.…”

Vitamin D and the Cardiovascular System

“…Similarly, this was attributed to calcium deposition in the vascular wall [19]. A negative correlation between maximal contraction and calcium content was also found in aorta from vitamin-D-treated rats fed with a normal or high-cholesterol diet [38]. On the other hand, some studies have shown that vitamin D treatment increases blood vessel response to vasoconstrictors.…”

Effects of a High-Cholesterol Diet on Vascular and Endothelial Function in Rat Aorta

“…This is not entirely surprising, since the rat is relatively resistant to atherosclerosis [3], so that most rat models of diet induced cardiovascular disease employ susceptible strains of rat [4][5][6][7] or vitamin D [8,9]. We wished to develop a simple model of vascular dysfunction, based only on a highcholesterol diet.…”

“…The rat is relatively resistant to atherosclerosis [3], so that consistent morphological changes in the vascular wall are reported only when combining a high cholesterol diet with vitamin E deficiency [5], excess vitamin D [8], excess total fat [7] or with models of hypertension [6]. In a study of normal rats fed a 2% cholesterol and 5% fat diet for 6 months, structural changes in the aorta were only found in aged (24 month old) rats [11].…”

“…Hence, various studies have examined the effects of a high-cholesterol diet on vascular and endothelial function, employing animals genetically or experimentally predisposed to atherosclerosis [4][5][6][7], or employing vitamin D treatment [8,9]. In this study, we have examined the effects of high cholesterol (1%) diet for 8 weeks on vascular and endothelial responsiveness of normal rats, and related responses to plasma cholesterol levels.…”