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OBJECTIVE: Cilazapril, a long-acting angiotensin converting enzyme (ACE) inhibitor, was evaluated against captopril for safety and efficacy in the treatment of mild to moderate essential hypertension. METHODS: One hundred thirty-two patients were randomly assigned to receive cilazapril, 2.5 mg once daily; 62 patients were randomly assigned to receive captopril, 25 mg twice daily. If necessary, dosage was increased to 5.0 mg cilazapril, once daily or 50 mg captopril, twice daily. Adjunctive hydrochlorothiazide (12.5 mg once daily) was later added to this higher dosage, if required. RESULTS: After eight weeks of monotherapy, sitting diastolic blood pressure (SDBP) had decreased 7.5 mm Hg from baseline for cilazapril-treated patients, versus 5.6 mm Hg for captopril-treated patients. These decreases were 7.6 mm Hg and 6.8 mm Hg for cilazapril and captopril, respectively, at Week 12. At Week 8, 36.5% of patients receiving cilazapril had achieved a SDBP of 90 mm Hg or less, versus 26.0% of captopril-treated patients. The overall responder rate at Week 8 was 47.1% for cilazapril and 34.0% for captopril. None of these differences between the two treatment groups were statistically significant. Both drugs alone or in combination with hydrochlorothiazide were well tolerated during the 12-week treatment period. CONCLUSION: The results of this study indicate that cilazapril, alone or with adjunctive hydrochlorothiazide, is effective and well tolerated as treatment for mild to moderate hypertension.

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High concentrations of methylxanthines induce contraction in many smooth muscle types, but relax guinea-pig trachealis. We examined this discrepancy by studying the interaction of caffeine and spasmogens in the isolated guinea-pig trachealis. We extended our observations to the isolated human trachealis. In the guinea-pig trachealis, 25 mM but not 2.5 mM caffeine totally blocked any contractile effect of methacholine or histamine, but not of KCl, whose contractile effect relies on extracellular Ca++. The beta-adrenergic agent isoprenaline (10(-3)M) only partially blocked the spasmodic effect of methacholine and histamine. In the human trachealis, 25 mM but not 2.5 mM caffeine induced an initial contraction followed by a relaxation. After this latter relaxation, methacholine (10(-5) M) and histamine (10(-5) M) were without effect, while KCl caused a contraction. In the guinea-pig, a contractile effect of 25 mM but not 2.5 mM caffeine was uncovered by switching to a high K+, Ca(++)-free solution prior to adding the caffeine. The source of the Ca++ promoting the contraction thus must be intracellular stores. Accordingly, ryanodine, an inhibitor of Ca++ storage, blocked this contraction. Similarly histamine (10(-5) M) and methacholine (10(-5) M) in the Ca(++)-free solution induced a contraction. The histamine contraction was completely blocked by ryanodine, the methacholine contraction, 79% blocked. We conclude that caffeine appears to surpass the antispasmodic effects of beta-adrenergic stimulation, at least in part, by depleting intracellular stores of Ca++.

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In solutions containing Mg2+ and Ca2+, ATP is in equilibrium between the tetrabasic form (ATP4-) and its bidentate coordination complexes, i.e., MgATP2- and CaATP2-. We sought evidence to determine whether contractions of the smooth muscle of the guinea pig vas deferens to ATP are in response to ATP4- or its bidentate complexes. Contractions to ATP were elicited in seven modified Krebs-Henseleit solutions containing varied concentrations of free and total Mg2+ and Ca2+ to alter the concentration of ATP4- at given ATPtotal concentrations. As the concentration of Mg2+ increased the concentration of ATP required to stimulate contraction to an equivalent degree also increased. Regardless of the free or total Mg2+ and Ca2+ concentrations, response magnitude was generally correlated with [ATP4-]. This suggests that ATP4- is the agonist at the P2x purinoceptor of the guinea pig vas deferens. The potency of ATP4- is high; the threshold, occurring at approximately 1 nM ATP4-, is 1000-fold less than that for norepinephrine. The implications of ATP4- as agonist are discussed in relation to adenine nucleotide potency, metabolism and P2 purinoceptor classification.

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It is known that after exposure to (3 mM) tetraethylammonium (TEA), guinea-pig isolated trachealis generates tonic spasm followed by phasic tension changes. We found that 8-Br-cAMP or 8-Br-cGMP (10(-6)-5 x 10(-4) M) suppressed tonic spasm secondary to TEA and induced rapid mechanical oscillations. NaN3, forskolin, aminophylline, and isoprenaline had effects similar to those of the cyclic nucleotides. Tetrodotoxin, atropine, diphenhydramine, and cimetidine were without effect on the rapid oscillations. KCl (16 mM) stimulated the oscillations in tissue treated with TEA or TEA plus 8-Br-cGMP. Diltiazem abolished all rhythmic activity in TEA plus 8-Br-cGMP-treated tissues. We conclude: (A) The rapid oscillations are a result of increased cytoplasmic calcium flux with K+ affecting the contractile arm by increasing Ca2+ entry and cyclic nucleotides affecting the relaxant arm by reducing cytosolic free Ca2+. (B) The cyclic nucleotide effect is direct. (C) Cyclic nucleotides may enhance the rate of contraction and relaxation in the presence of some forms of phasic activity.

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1. The Na+,K+-pump has been implicated in animal models of airway hyperreactivity. We examined the effects of inhibiting the Na+,K+-pump and Na+,Ca2+-exchange on isometric tone of isolated trachealis from humans and other species. 2. In preparations from 5 out of 9 humans, strong spontaneous contractions (36-48 h-1; up to 1.8 g) developed within 25 min. 3. Ouabain (10(-7)-10(-5) M) caused an immediate and sustained contraction. This response was not blocked by atropine, diphenhydramine, or cimetidine. 4. Contractions were also elicited when the normal physiological solution was changed to a K+-free solution, a procedure which inhibits the Na+,K+-pump, and in reduced (15 mM) Na+ solution, which inhibits Na+,Ca2+ exchange. 5. In preparations of dog and guinea-pig isolated trachea, ouabain (10(-5) M) caused a multiphasic response; in the rabbit, ouabain was without effect. K+-free solution was without effect in the dog preparations and produced relaxation of the guinea-pig trachea. Guinea-pig tracheae responded to a low Na+ solution with a strong contraction. 6. Our findings indicate that: (a) human airway smooth muscle may be a spontaneously contracting muscle, at least in vitro, (b) a prolonged contraction to ouabain is unique for the human airway smooth muscle among the animals tested, as is the contraction in a K+-free medium, and (c) the contractile response does not involve acetylcholine or histamine release, but may involve a Na+,Ca2+-exchange mechanism. These results suggest that the level of Na+,K+-pump activity could play a role in determining the degree of bronchomotor tone in humans.

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Polyamines, found in all nucleated cells, have been shown to relax uterine, gastrointestinal, and respiratory tract smooth muscle. When parenterally administered to the rat or dog they cause hypotension. To determine the range of the relaxing effect of polyamines on smooth muscle and the mechanism of the hypotensive effect anaesthetised dogs were infused with increasing intravenous bolus doses of spermine while cardiovascular measurements were made. At doses of greater than or equal to 2 mg X kg-1 spermine a reversible hypotensive effect was produced that is accounted for by changes in peripheral vascular resistance. It is unlikely that this effect was due to the known propensity of polyamines to release histamine because the hypotensive action of 2 mg X kg-1 spermine was unaltered by pretreatment with the H1 and H2 blockers, diphenhydramine and cimetidine. Evidence that the spermine effect is not mediated by circulating agents was shown by the ability of spermine to relax the precontracted guinea pig isolated aorta. These results in vascular smooth muscle may be added to those in other types of smooth muscle shown to be relaxed by polyamines; the polyamine effect on smooth muscle may be ubiquitous. These data also raise the possibility that changing concentrations of tissue polyamines may play a role in the regulation of tissue blood flow.

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We have previously observed a paradoxical relaxant effect of K+ on guinea-pig isolated trachealis after exposure to polyamines. The purpose of the present study was to evaluate whether the relaxation involved a reduction in the entry of extracellular Ca2+. We therefore investigated the effect of K+ in the presence of Ca2+-entry blocking drugs and in the presence of Ca2+-free solution. In the presence of nifedipine (10(-5) M), verapamil (10(-5) M) or diltiazem (10(-5) M), K+ (30 mM) induced relaxation of the trachealis muscle. The relaxation to K+ was not blocked by ouabain (10(-6) M), propranolol (10(-6) M), or indomethacin (10(-6) M). A relaxation in response to K+ was also observed in Ca2+-free solution, (with tone induced by methacholine), an effect not blocked by propranolol or ouabain. Tetraethylammonium (30 mM) (TEA), which ordinarily evokes contractile responses, induced trachealis relaxation in the presence of verapamil or nifedipine. The relaxation was unaltered by ouabain or propranolol. Tetrodotoxin (10(-6) M) (TTX) blocked 65% of the K+-induced relaxation in the presence of nifedipine and 100% of K+-induced relaxation either in a Ca2+-free solution or after polyamine exposure. TTX was without effect on TEA-induced relaxation after Ca2+-entry blocking drugs. Atropine (10(-6) M) or hexamethonium (10(-6) M) did not affect K+-induced relaxation after polyamine exposure. The concentration-response curve for K+-induced contraction in normal modified Krebs-Henseleit solution was shifted to the left by TTX. 8 It is concluded: (a) K+ has a direct effect on the trachealis causing contraction and an indirect effect, mediated by neurotransmitter release, causing relaxation. This latter effect is exposed when the direct effect is inhibited by Ca2+-entry blocking drugs, Ca2+-free solution or polyamine exposure; the indirect effect is non-adrenergic, non-cholinergic and not via ganglionic transmission; (b) the TEAinduced relaxation and a component of the K+-induced relaxation after Ca2+ blocking drugs cannot be explained by neurotransmitter release; (c) polyamines may act as naturally occurring Ca2+ antagonists.

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A 49-year-old woman with virilization demonstrated biochemical features traditionally ascribed to virilizing ovarian tumors: marked elevation of serum testosterone level with normal urinary excretion of 17-ketosteroids and normal serum dehydroepiandrosterone level. An adrenal cortical adenoma containing neoplastic cells indistinguishable from Leydig cells, including the demonstration of characteristic crystalloids of Reinke, was shown to be the source of the elevated testosterone level. A review of the literature revealed 13 cases with a similar biochemical profile, and of these, two were reported to contain crystalloids of Reinke. Taking cognizance of the fact that these characteristic crystalloids are only found in 40 percent of Leydig cell tumors of the testis, it is concluded that Leydig cells may be present in, and may be active participants in, the pathophysiology of a number of testosterone-secreting adrenal tumors.

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Spermidine, spermine, and putreanine, a metabolite of spermidine, caused transient relaxation of the isolated guinea-pig trachealis. The spermidine effect was not blocked by ouabain, propranolol or indomethacin. Spermidine treatment was shown to desensitize the tissue to subsequent additions of spermidine. After exposure to spermidine and repeated washes with spermidine-free solution, trachealis responded to KCl (30 mM) with a paradoxical relaxation. This relaxation was not blocked by propranolol, ouabain or indomethacin.

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Pharmacologic doses of insulin stimulate hepatic ornithine decarboxylase activity. In an effort to see if changes of insulin levels in a physiologic range are also stimulatory, we tube fed 3-day fasted rats with pure carbohydrate, protein and fat meals. Only the protein meal was stimulatory in spite of the carbohydrate meal causing the largest increase in plasma insulin.

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The non-metabolizable amino acids alpha-aminoisobutyric acid (AIB) and cycloleucine and the poorly metabolizable amino acid D-alanine potently stimulated hepatic ornithine decarboxylase (ODC) activity in starved rats. The stimulation by AIB was shown to have several of the characteristics of stimulation by a protein meal and occurred in hypophysectomized animals. AIB also stimulated renal, but not brain or heart, ODC activity.

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Myocardial phosphorylase alpha activity responds to stimulation by catecholamines and thyroid hormone. In hyperthyroidism this enzyme is supersensitive to beta-adrenergic stimulation and blockade, indicating that its increased activity is an indirect effect of thyroid hormone. Myocardial ornithine decarboxylase (ODC) activity also responds to catecholamine and thyroid hormone stimulation. In the present studies, we sought to determine whether ODC shares the responses of phosphorylase alpha in hyperthyroidism. As opposed to euthyroid rats, isoproterenol acutely inhibited myocardial OCD activity in hyperthyroid rats. Timolol (60 mg/kg) injected immediately before the isoproterenol blocked this paradoxical inhibitory effect, defining it as beta-adrenergic. When timolol (100 mg/kg), distributed over a 24-h period, was administered during the 3 days of triiodothyronine (T3) administration, it blocked the T3 stimulation of myocardial OCD activity by 35%. However, timolol affected weight gain of the hyperthyroid rats. When fasted rats were used, timolol was without effect on T3-induced myocardial ODC stimulation. Timolol was also without effect on T3-induced stimulation of hepatic ODC or on T3-induced cardiomegaly. Timolol did decrease the T3-induced tachycardia. In summary, in the hyperthyroid heart, 1) isoproterenol paradoxically inhibits myocardial ODC activity and 2) timolol, when food intake is not a variable, is without effect. We conclude that the effect of thyroid hormone on myocardial ODC is not mediated by change in catecholamine sensitivity. Thus the behavior of phosphorylase alpha does not represent a general enzymatic phenomenon.

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We examined thyroidectomized, normal and hyperthyroid rats and found that ornithine decarboxylase activity was directly correlated with thyroid functional state in heart and liver and unaffected in brain, testes and spleen, phenomena that correlate with the known effect of thyroid hormone on protein synthesis.

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In order to separate direct effects of epinephrine on fuel metabolism from those mediated by glucagon, epinephrine (0.1 microng/kg-min) was infused for 120 min in 18- and 65-h fasted, nonanesthetized baboons with and without a concomitant somatostatin infusion. At both stages of fasting, epinephrine stimulated glucagon, secretion, and this was blocked by somatostatin. At 18 h, with epinephrine alone, glucose rose early and remained elevated throughout the infusion. In the glycogen-depleted 65-h fasted animals, there was attenuation of the early glucose rise, with glucose reaching a maximum level at 100-120 min. With somatostatin blockade of glucagon release in the 18-h fasted animals, a pattern of attenuated early glucose rise similar to that of the 65-h fasted animals occurred. Somatostatin also inhibited this early glycogenolytic response when the epinephrine dose was increased fivefold. The behavior of FFA, glycerol, and beta-hydroxybutyrate was unchanged by the addition of somatostatin to epinephrine at either stage of fasting. Thus, glucagon mediates the early glycogenolytic response to epinephrine, but not the delayed hyperglycemia and probably not the lipolysis.

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