Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bisoprolol, (+/-)1-(4-[(2-isopropoxyethoxy)-methyl]-phenoxy)-3-isopropyl-amino -2- propanol-hemifumarate, is a new, highly selective beta 1-adrenoceptor blocking agent without intrinsic sympathomimetic activity and low to moderate local anaesthetic activity. As demonstrated in binding experiments, and in classical pharmacological studies using rats, guinea pigs, cats, and dogs, bisoprolol markedly differentiated between beta 1-adrenoceptors of the heart, or the renal juxtaglomerular apparatus, and the beta 2-subtype in arterial blood vessels, bronchi, liver, or skeletal muscle. Up to concentrations nearly 100-fold higher than the therapeutic plasma levels in humans, bisoprolol did not affect the functional refractory period of the heart, and was devoid of a direct suppressive effect on myocardial contractility and of calcium antagonistic properties in heart and vascular muscle. The pattern of haemodynamic effects of bisoprolol was typical of beta-blockers and included decreases in blood pressure (BP), heart rate (HR), and cardiac output, concomitant with an increase in calculated total peripheral resistance. In contrast to other beta-blockers, bisoprolol increased renal blood flow in anaesthetized dogs. Bisoprolol lowered BP in hypertensive dogs and rats, attenuated the development of spontaneous hypertension in rats, decreased plasma renin activity and protected the heart from the sequelae of transient ischemia. It did not block presynaptic beta-adrenoceptors in blood vessels. Serum lipids and the serum lipoprotein profile remained unaltered after bisoprolol. Bisoprolol was devoid of affinity for autonomic receptors other than beta-adrenoceptors or for autacoid receptors. This is probably one of the reasons why bisoprolol did not affect the function of the central nervous, respiratory, and gastrointestinal systems in an obvious way. The high beta 1-selectivity of bisoprolol is linked with extremely favourable pharmacokinetic properties. These include nearly complete enteral absorption and virtual absence of liver first-pass metabolism, both resulting in high bioavailability, long plasma half-life, pharmacokinetics that are linear over a wide dose range and independent of age, food intake and hydroxylator status, low plasma protein binding, and a 1:1 ratio of hepatic metabolization to renal elimination of the unaltered substance. This sum of favourable pharmacological and pharmacokinetic properties characterize bisoprolol as an optimized beta-blocker.
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PMID:High beta 1-selectivity and favourable pharmacokinetics as the outstanding properties of bisoprolol. 243 93

The effects of angiotensin II (AII) and captopril (C) on the inducibility of ventricular tachyarrhythmias were investigated 14 days after infarction in pigs. In 27 pigs, ischemia was induced by 60-min occlusion of the left coronary artery. Four pigs died of ventricular fibrillation during ischemia, and six others died within 24 h due to pump failure. Of the 17 survivors, eight pigs developed a sustained (greater than 30 s) monomorphic ventricular tachycardia (sVT) after programmed electrical stimulation. In nine noninducible pigs, an AII infusion (0.6 microgram/kg/min) caused inducible sVT in three animals and nonsustained VT in two animals (greater than 10 reentrant beats). In two of the remaining four animals, spontaneous premature ventricular beats appeared during the infusion. In a group of five healthy pigs, the electrophysiological effects of AII were evaluated. Infusion of AII caused a rapid and sustained increase in arterial blood pressure to 161 +/- 6.4% (p less than 0.001). The sinus cycle length decreased to 74 +/- 5.2% (p less than 0.02). The effective refractory period of the right ventricle decreased significantly to 82 +/- 5.5% (p less than 0.05). These results show that modulation of the renin-angiotensin system after myocardial infarction influences the inducibility of malignant ventricular tachyarrhythmias, as shown by the increased inducibility of sustained ventricular tachycardia. This may be related to a decreased ventricular refractoriness. Therefore, it is suggested that C can reduce malignant ventricular tachycardia late after myocardial infarction by preventing the deleterious arrhythmogenic effects of AII.
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PMID:Effects of angiotensin II and captopril on inducible sustained ventricular tachycardia two weeks after myocardial infarction in the pig. 246 44

Biochemical, pharmacological, and molecular biological data provide evidence for the presence of a cardiac renin-angiotensin system. Tissue angiotensins were demonstrated in all regions of the mammalian heart. Reduction of cardiac angiotensin II formation after oral administration of converting enzyme (CE) inhibitors in nephrectomized animals points to local generation of these peptides. Functional studies in isolated working rat hearts subjected to transient regional ischemia and reperfusion showed that there is aggravation of arrhythmias as well as exhaustion of energy status by angiotensins. This was prevented by CE inhibition and/or perfusion with bradykinin (BK), which in turn could be competitively antagonized with a BK antagonist. Intracoronary infusion of low-dose bradykinin attenuated ischemia-reperfusion injuries and reduced enzyme and lactate release in anesthetized dogs. Oral pretreatment with the CE inhibitor ramipril in rats, in doses that did not affect the elevation of blood pressure caused by aortic constriction, could prevent induction of as well as cause regression of established cardiac hypertrophy. In contrast, pure vasodilation was without effect on cardiac enlargement despite lowering blood pressure, pointing to a possible trophic influence of angiotensin II. Thus, apart from afterload reduction and euvolumia produced by CE inhibition, the outstanding efficacy of this therapeutic approach in congestive heart failure and cardiac hypertrophy and its potential usefulness in myocardial ischemia may also be explained by intracardiac suppression of angiotensin II generation and bradykinin degradation.
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PMID:Pharmacological interference with the cardiac renin-angiotensin system. 248 22

The oxygenation of arachidonic acid by lipoxygenases results in the formation of HPETEs (hydroperoxyeicosatetraenoic acids), the first products of the LOX pathway. These compounds are short lived and are catabolised into various families of more stable compounds of which the HETEs, hepoxilins, lipoxins and leukotrienes have been identified so far. The development of new techniques have helped to identify and understand the structures of various HPETEs and only recently the biological effects of HPETEs and their various catabolites are being unraveled. Although lipoxygenases are ubiquitous, not all tissues possess the same spectrum of lipoxygenase enzymes. Hence different HPETEs can be formed in different tissues. Recent studies have revealed that HPETEs or products derived from them possess a diversity of important biological properties including the regulation of electrolyte flux and eicosanoid and corticosterone syntheses, release of histamine, regulation of oocyte maturation and release of various reproductive hormones. HPETEs appear to be involved in some pathological conditions viz, skin psoriasis, Clarkson's disease, nerve injury and spinal cord ischemia. These novel eicosanoids are associated with the release of insulin as well as renin. Recently HPETEs have been suggested to act as second messengers in the Aplysia sensory neurons and its catabolite, hepoxilin, has been demonstrated to have effects on mammalian hippocampal neurons. The purpose of this review is to provide a brief summary of the formation of the HPETEs and the various families of compounds derived from them as well as the various types of biological activities for these products described so far.
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PMID:Biosynthesis, catabolism, and biological properties of HPETEs, hydroperoxide derivatives of arachidonic acid. 251 25

Following vascular occlusion, development of collateral circulation occurs in at least two time-related phases: (1) the fast enhancement of the function of preexisting channels and (2) the slow formation of new vessels. Inasmuch as the renin-angiotensin system can act as a protective mechanism against local ischemia by activating preexisting collateral vessels, it is of interest to establish whether angiotensin II also produces stimulation of new vessel formation. Angiotensin II or cholecystokinin, an unrelated peptide, was incorporated in a slow-release formulation polyacrylamide gel and implanted in a pocket made in the rabbit cornea. Periodic examinations revealed that angiotensin II significantly stimulates new vessel formation; maximum values were attained in approximately 2 to 3 weeks. In contrast, cholecystokinin or polyacrylamide gel alone failed to stimulate any significant new vessel formation. Positive neovascularization was present in 85% of the total number of corneas implanted with angiotensin II, whereas 14% and 8% positive results were seen in the corneas implanted with either cholecystokinin or polyacrylamide gel alone, respectively. It is concluded that angiotensin II not only facilitates the activation of preexisting collateral vascular pathways but also has angiogenic properties and therefore could play an active role not only in the fast but also in the slow phase of the development of collateral circulation.
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PMID:Neovascularization produced by angiotensin II. 257 74

Utero-placental ischemia is known to cause systemic hypertension in various species, but the mechanisms are unknown. These studies were designed to test the hypothesis that the increased systemic arterial pressure that occurs during reduced utero-placental perfusion pressure is mediated by the renin-angiotensin system, possibly due to release of renin or angiotensin from the ischemic gravid uterus. In trained, chronically instrumented pregnant dogs (gestational age 47 +/- 2 days, term = 60 days) maintained on a normal Na+ intake (approximately 80 meq/day), uterine perfusion pressure was reduced to 60 mmHg with an inflatable aortic occluder positioned distal to the renal arteries but proximal to the uterine arteries and was servo-controlled at this level for 1 h. Systemic arterial pressure rose by 14 +/- 2 mmHg, from 96 +/- 7 to 110 +/- 8 mmHg. Plasma renin activity and angiotensin II levels did not change significantly. On another day in the same animals, the activity of the renin-angiotensin system was fixed by infusing captopril and sufficient angiotensin II to restore arterial pressure to normal (2-5 ng.kg-1.min-1 iv). Reduction of uterine artery pressure to 60 mmHg caused systemic arterial pressure to increase by 10 +/- 2 mmHg with the renin-angiotensin system fixed, a response not different from that in the control experiments. These data suggest that the increase in systemic arterial pressure during reduced uteroplacental perfusion pressure is independent of the renin-angiotensin system.
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PMID:Role of the renin-angiotensin system in hypertension during reduced uteroplacental perfusion pressure. 266 22

The effects of combined alpha/beta-adrenoceptor blockade and of beta-receptor/slow channel calcium blockade on systemic and pulmonary hemodynamics and on adrenergic activity were compared in 2 matched groups of men suffering from ischemic heart disease. They were studied at rest supine and during ischemia-inducing exercise in the seated posture using invasive percutaneous techniques. Fourteen patients received 200 mg labetalol as a single oral dosis, 15 metoprolol (100 mg) plus nifedipine (10 mg). Both regimens reduced pressures in the systemic and pulmonary circulation under all conditions. At rest, stroke volume and cardiac output slightly decreased after labetalol and increased after metoprolol/nifedipine. During exercise the changes induced by the two regimens were virtually identical: heart rates and vascular resistances were reduced, stroke volume increased, cardiac output was not significantly changed. Plasma renin activity was lowered by labetalol, unchanged by metoprolol/nifedipine. Plasma adrenaline increased after metoprolol/nifedipine only, noradrenaline with both regimens. Both combinations significantly lowered stroke work and the rate pressure product and had similar beneficial effects on the onset and the duration of angina. It is concluded that both combinations attenuate or offset the potential adverse hemodynamic effects of beta-receptor blockade alone without loss but rather enhancement of symptomatic efficacy.
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PMID:Hemodynamic and adrenergic effects of combined alpha/beta-receptor blockade versus combined beta-receptor and slow channel calcium blockade in patients with ischemic heart disease. 279 65

The influence of the renin-angiotensin system on renal hemodynamics, tubular pressure and tubulo-glomerular feedback was investigated with the angiotensin converting enzyme inhibitor MK 421 (enalapril), in uninephrectomized rats with and without ischemia-induced acute renal failure. In animals with normal renal function proximal tubular pressure and tubulo-glomerular feedback response were lowered by enalapril long-term treatment, whereas glomerular filtration rate and renal blood flow were not influenced by the drug. After 45 and 70 minutes ischemia there was no difference between treated and untreated animals in the severely impaired glomerular filtration rate. Renal blood flow remained unaffected by the treatment. The histological damage due to ischemia (tubular casts, tubular necrosis and medullary capillary congestion) was not influenced by enalapril. As tubulo-glomerular feedback had been significantly inhibited during renin-angiotensin inhibition, its importance in mediating acute renal failure remains doubtful; other factors such as tubular obstruction and medullary congestion may be crucial.
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PMID:The angiotensin converting enzyme inhibitor enalapril in acute ischemic renal failure in rats. 283 Oct 78

Two infants with renal tumors and associated hypertension are presented. By using an antibody to purified human renal renin, the sites of renin production were localized immunohistochemically in each tumor. The first case was a 9-month-old girl with Beckwith-Wiedemann syndrome. She presented with bilateral renal masses and hypertension (140/90 mm Hg). Following a left nephrectomy and chemotherapy and radiotherapy, her BP returned to normal. Her tumor was a Wilms' tumor of favorable histology, composed predominantly of glomeruloid structures. Renin was localized within a part of these neoplastic glomeruloid bodies. We therefore designated this as a Wilms' tumor with glomeruloid differentiation having primary reninism. The second case was a 24-day-old girl with hypertension (140/70 mm Hg). A renal tumor was found and successfully removed. Her BP returned to normal. The tumor was histologically confirmed as a congenital mesoblastic nephroma. By indirect immunoperoxidase staining, renin was localized only in the hypertrophied juxtaglomerular cells adjacent to the residual glomeruli entrapped by the tumor. None was seen in the tumor cells. We concluded that this was a case of secondary reninism--a case of hypertension secondary to the local ischemia at the entrapped glomeruli.
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PMID:Demonstration of both primary and secondary reninism in renal tumors in children. 283 60

The renin-angiotensin system (RAS) has long been perceived as basically humoral. Since recent findings in molecular biology extended this view to local, possibly independent, tissue-RAS, both the RAS and the kallikrein-kinin cascade are understood as mixed local-systemic interacting systems, which explains local and systemic effects of converting enzyme (CE) inhibitors well. The key enzyme of both systems, CE, catalyzes the activation of the vasopressor and possibly trophic peptide, angiotensin II, and also inactivates the vasodilatory and, according to our observations, cardioprotective bradykinin. Thus, it is consistent that CE-inhibitors lower blood pressure, reduce cardiac hypertrophy, improve metabolic state and attenuate arrhythmias, particularly in ischemic hearts. It is evident from animal experiments that the tight binding favours new oral CE inhibitors, such as ramipril, not only for prevention but also for treatment of tissue injuries due to hypertension or ischemia.
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PMID:[Pharmacologic modification of the converting enzyme--local and systemic effects on the heart and blood vessels]. 285 Jun 85


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