Altered calcium regulation in the cardiac plasma membrane in experimental renal hypertension

The factors regulating calcium homeostasis in the cardiac plasma membrane of renal hypertension in the rat (two kidney-one clip, Goldblatt model) have been studied. Comparison of the cardiac sarcolemma from control (C) and hypertensive (H) rats indicates similar protein yield and purity. Study of longer term hypertension (4 to 12 weeks) shows a decrease in the number of calcium channel receptor binding sites (Bmax C: 549 +/- 122 fmol/mg; H: 334 +/- 74 fmol/mg) as well as a depressed calcium pumping ATPase activity (C: 7.6 +/- 2.5 nmol/mg/min; H: 3.8 +/- 1.5 nmol/mg/min). Furthermore, there is a decreased rate of Na+-Ca2+ exchange (C: 5.4 +/- 1.9 nmol/mg/5 s; H: 2.3 +/- 0.9 nmol/mg/5 s). Study of short-term hypertension (1 to 4 weeks) indicates that the earliest change occurs at 1 week with decreased calcium pumping ATPase due to a change of the Vmax of Ca2+ transport (C: 9.7 +/- 1.6 nmol/mg/min; H: 5.4 +/- 1.4 nmol/mg/min). This is then followed by the decreased calcium channel receptor binding. However, the rate and the extent of depression in Ca2+-ATPase activity are much greater than that of Ca2+ channel receptor binding. Since alteration of Ca2+-ATPase is accompanied by an increase in intracellular Ca2+ concentration and there is a temporal association with the onset of myocardial lesions in the hypertensive rats, it is suggested that elevated intracellular calcium concentration as a result of altered Ca2+-ATPase activity may play a significant role in the development of hypertensive cardiomyopathy.     

Cellular proliferation in atherosclerosis and hypertension

We have tried to compare the proliferative responses seen in two vascular diseases: atherosclerosis and hypertension. Both diseases involve endothelial injury and proliferation, but our knowledge of this phenomenon is just beginning to emerge. In atherosclerosis the best evidence is that denudation does not occur in the normal young animal. Man, however, ages over a much longer time than our usual animal models, and the study of denudation during the chronic progression of atherosclerotic lesions remains to be done. We need to consider the possibility that repetitive, small lesions may occur at sites of endothelial turnover. We also need to know more about the possible role of nondenuding injuries, including death of endothelial cells in situ and the apparent increased stickiness of endothelial cells and monocytes during the early stages of hypercholesterolemia. The role of endothelial injury in hypertension also needs more study. We know that extensive denudation and thrombosis occur in small vessels subjected to high blood pressure. It is highly probable that release of PDGF occurs at these sites, possibly accounting for the characteristic hyperplasia seen in malignant hypertension. Whether this process is related to the more subtle changes in vessel wall mass seen in chronic hypertension remains unknown. Finally, there are remarkable differences in the proliferative behavior of the smooth muscle cells themselves in these two diseases. Hypertensive vascular disease is, in large part, a disease of the media. Atherosclerosis is characterized by intimal hyperplasia. Injury results in migration of smooth muscle cells from the media and cell division in the intima. It is possible to identify chemotactic factors using putative atherosclerosis risk factors or normal components of serum. This has already been done for one component of lesion formation, PDGF, and there is a report of a monocyte chemotactic factor released by smooth muscle cells. Factors released by other components of lesions may be of considerable interest. In contrast, changes in hypertension occur within a more orderly preservation of vessel wall structure. The wall thickens, but this occurs by increased synthesis of cell mass in the media. The cells themselves do not even divide, but they undergo a form of amitotic replication of their DNA.(ABSTRACT TRUNCATED AT 400 WORDS)     

The role of calcium in the regulation of normal vascular tone and in arterial hypertension

The vascular tone depends on periarterial neurogenic nerve stimulus and endothelial substances release. The most evident biochemical cause of the vascular smooth muscle contraction-relaxation process lies in the changing concentration of cytosolic Ca2+. Intracellular free calcium is the major determinant of vascular tone. The depolarization wave opens the slow calcium channels, which permit Ca2+ to enter in small quantities into the interior of the cell triggering the release of much larger quantities of calcium from the sarcoplasmic reticulum. The flux of Ca2+ to and from the cytosol is regulated by three principle mechanisms. The calcium voltage sensitive Ca2+ channel that are opened by the depolarization wave. The potassium channels (CK+) and the Na+/K(+)-ATPase pump. The CK+ opening permits the exit of potassium from the interior of the cell which tends to hyperpolarize the smooth muscle cell membrane and closes the calcium channel avoiding the entry of Ca2+. The activity of the sodium pump also produces membrane hyperpolarization. Thus, the activity of these two mechanisms counter-regulates the voltage dependent calcium channel. The massive release of Ca2+ from intracellular stores of the sarcoplasmic reticulum is done through two classes of channels. One is ryanodine sensitive, the other is the inositol 1,4,5-trisphosphate receptor. The endothelial cell dysfunction is accompanied by a decrease in the production and/or the release of nitric oxide and the increase of contracting factors. That induce a Ca2+ mobilization of extracellular and intracellular stores. Contraction of smooth muscle to hypoxia is mediated by an accumulation of intracellular Ca2+. The relaxant substances of vascular smooth muscle inhibit activation of the phospholipase C and open Ca2+ channels, or produce a stimulus to the exit of the Ca2+ through the plasmatic membrane, with a decrease of intracellular calcium. An endothelial dysfunction with decrease of nitric oxide release exists in different types of hypertension. Pregnancy-induced hypertension is associated with low calcium levels in the diet, improving with the treatment of calcium supplements.     

Regulation of calcium metabolism in hypertension

In patients with hypertensive disease, the intravenous calcium tolerance test revealed a delayed elimination of loading hypercalcemia, which totally reflects the effectiveness mechanisms aimed at removing excessive calcium from the extracellular space. In hypertensives, renal calcium excretion was also delayed due to a lower suppression of calcium channel reabsorption. The patients showed a greater background concentration of parathyroid hormone (PTH) and during the calcium tolerance test a much lower PTH levels and higher calcitonin concentrations, though their homeostatic effects remained inadequate due to their diminished sensitivity of target organs. Thus, there was an increase in the activity of parathyroidal glands in patients with hypertensive disease.     

Cellular phenotypes and the genetics of hypertension

Cellular phenotypes have been used in the search for genes or loci harboring genes in control of blood pressure in animals and humans. Preliminary findings using cellular phenotypes confirm that multiple genes contribute to the development of essential hypertension, consistent with the polygenic nature of this disorder. Although these results are promising, no loci have been unequivocally identified as causative for human hypertension. Cellular phenotypes, if combined with large-scale studies and evolving methodologies and databases for the human genome, could play an integral role in the search for genes causing essential hypertension.     

门静脉高压症形成的细胞分子机制

门静脉高压症是一组由门静脉压力增高引起的症候群,绝大多数患者由肝硬化引起。近10年来门脉高压症的发病机制研究在病理生理学、病理学以及细胞分子理论方面取得了很大进展,其中门静脉高压症的细胞分子机制是当今研究的热点。     

Role of calcium antagonists in systemic hypertension

Despite the physiologic rationale of their use in hypertension, traditional vasodilators such as hydralazine and minoxidil are often relegated to the second and, more often, to the third and fourth steps of step-care programs. Although they are powerful blood pressure-lowering agents, they cause tachycardia, excessive renin stimulation and sodium retention, and cannot be used as the only antihypertensive agent. The characteristics of the antihypertensive action of calcium antagonists make them suitable for monotherapy. Indeed, all calcium antagonists, while effectively lowering blood pressure through vasodilation, either do not affect heart rate (verapamil and its analogs) or cause a moderate and transient heart rate increase (dihydropyridine compounds). Dihydropyridines also possess a natriuretic effect, probably due to inhibition of tubular sodium transport. The natriuretic effect is evident during the first 2 days of administration, but a small negative sodium balance persists for at least 1 week. There is no increase in body weight or fluid volumes with long-term administration of calcium antagonists with a marked acute natriuretic response, such as dihydropyridines, and those antagonists with a very moderate immediate natriuretic response, such as verapamil. All calcium antagonists, therefore, appear capable of preventing the sodium and water retention that vasodilatation would otherwise entail. More liberal step-care guidelines are now possible to find the agent most suitable for the individual patient. In these guidelines, calcium antagonists, as well as angiotensin converting enzyme inhibitors, are considered as possible first-choice agents along with diuretics and beta blockers.     

Developmental changes in cardiac myocyte calcium regulation

Developmental changes in the contributions of transsarcolemmal Ca2+ influx and Ca2+ release from intracellular storage sites to myocardial contraction were evaluated in isolated ventricular myocytes from neonatal (aged 1-7 days) and adult (aged 8-10 weeks) New Zealand White rabbits. Contractions ceased in one beat when extracellular Ca2+ was decreased from 1mM to micromolar levels using a rapid perfusion technique. On reperfusion with 1 mM Ca2+, recovery of control contraction amplitude occurred after significantly fewer beats in neonatal myocytes compared with adult myocytes, and after 1 minute compared with 5 minutes of reduced Ca2+. After 15 minutes of perfusion with either 1 or 10 microM ryanodine, contraction amplitude decreased in both age groups, but the decrease was significantly greater in adults than in neonates. These experiments indicate that isolated ventricular myocytes may be used in the study of developmental changes in intracellular Ca2+ regulation. Results suggest that cardiac contraction in neonates is relatively more dependent on transsarcolemmal Ca2+ influx. Furthermore, although Ca2+ release from intracellular storage sites is present in both neonates and adults, its role in cardiac contraction is more significant in adults.