Bioconjugation strategies to couple supramolecular exo-functionalized palladium cages to peptides for biomedical applications.

Supramolecular Pd2L4 cages (L = ligand) hold promise as drug delivery systems. With the idea of achieving targeted delivery of the metallacages to tumor cells, the bioconjugation of exo-functionalized self-assembled Pd2L4 cages to peptides following two different approaches is reported for the first time. The obtained bioconjugates were analyzed and identified by high-resolution mass spectrometry.

Bidentate Lewis base adducts of methyltrioxorhenium(VII) and their application in catalytic epoxidation.

Methyltrioxorhenium(VII) (MTO) forms octahedral adducts with bidentate Lewis bases. These complexes were isolated and fully characterized, including X-ray crystallography. The compounds display distorted octahedral geometry in the solid state with a tendency of disorder concerning the Re central atom. At elevated temperatures, they undergo rapid ligand-exchange reactions in solution. The ease of this ligand exchange depends mainly on the Lewis basicity of the ligand. The more Lewis basic the ligand is, the stronger the metal-ligand interaction is, as can be shown by NMR spectroscopy. All examined complexes are temperature stable but quite sensitive to light and moisture. In the presence of H(2)O(2), the complexes form very active and highly selective epoxidation catalysts. Peroxo complexes are generated, and at least one of the Re-N interactions is cleaved during this process. Total ligand dissociation only occurs in the case of very weakly coordinating bidentate ligands. The peroxo complexes of the MTO Lewis base adducts are, in general, more sensitive to water than MTO itself.

Cocaine-induced cardiovascular effects: lack of evidence for a central nervous system site of action based on hemodynamic studies with cocaine methiodide.

It has been suggested that cocaine acts directly in the brain to enhance central sympathetic outflow. However, some studies suggested that the cardiovascular effects of cocaine are related to a peripheral action. To characterize further the site of cocaine's cardiovascular effect, we compared the hemodynamic effects of cocaine (2 mg/kg, i.v. bolus) with those observed after administration of an equimolar dose (2.62 mg/kg, i.v. bolus) of cocaine methiodide, a quaternary derivative of cocaine that does not penetrate the blood-brain barrier, by using sufentanil-sedated dogs. Cocaine produced significant (p < 0.05) increases in heart rate (+37+/-11 beats/min), mean arterial pressure (+55+/-11 mm Hg), left ventricular end-diastolic pressure (+5.3+/-1.0 mm Hg), and cardiac output (+2.4+/-0.9 L/min). Cocaine methiodide produced increases in heart rate (+57+/-11 beats/min), mean arterial pressure (+45+/-11 mm Hg), left ventricular end-diastolic pressure (+3.4+/-1.0 mm Hg), and cardiac output (1.1+/-0.9 L/min), which were not significantly different from those observed with cocaine. Because opiate sedation potentially might have attenuated central sympathetic outflow, we further confirmed the qualitative similarity of the actions of cocaine and cocaine methiodide on heart rate and blood pressure in unsedated, conscious dogs. Our data suggest that the cardiovascular effects of cocaine result primarily from a peripheral site of action.

Stimulation of dog RVLM and A5 area changes sympathetic outflow to vascular beds without effect on the heart.

Studies were conducted in anesthetized, vagotomized dogs while blood pressure; blood flows in femoral, renal, mesenteric, and left circumflex coronary arteries; electrocardiogram; and regional cardiac contractile force were monitored. The ventral surface of the medulla was exposed, and pressor sites in the rostral ventrolateral medulla (RVLM) were mapped by microinjections of L-glutamate. L-Glutamate activation of the RVLM evoked selective effects on different components of the cardiovascular system. Increases of 20-130 mmHg in blood pressure were accompanied by vascular conductance decreases in the femoral (-48 +/- 4%), renal (-30 +/- 4%), and mesenteric (-38 +/- 3%) arterial beds. These effects were without any obvious topography within the RVLM. There were only small or negligible changes in heart rate (HR), cardiac contractile force, and coronary vascular conductance. Thus stimulation of the canine RVLM increased sympathetic tone selectively to structures other than the heart. Stimulation of the ventral medulla in a region that lay rostral to the RVLM and ventromedial to the facial nucleus selectively increased femoral vascular conductance by 103 +/- 33% and decreased vascular conductance in the renal (-20 +/- 5%) and mesenteric (-15 +/- 4%) arterial beds. There was no increase in HR, and the increases in blood pressure were relatively small. Immunohistochemical data led us, tentatively, to identify this rostral area as overlapping part of the A5 area.

Sympathetic nervous system mediated cardiovascular effects of cocaine are primarily due to a peripheral site of action of the drug.

Currently, augmentation of sympathetic nervous system function produced by cocaine is thought to be due primarily to stimulation of sympathetic centers in the brain (central effect) and to inhibition of catecholamine uptake into postganglionic sympathetic nerve terminals (peripheral effect). In this review of our work, we present the following evidence that cocaine-induced changes in cardiovascular function, particularly those that peak within 1 to 5 min after an i.v. bolus injection of the drug, are due to a peripheral effect of the drug: (1) In both dogs and cats, cocaine potentiates the tachycardiac effect of neurally-released and injected norepinephrine (NE). The time course of action and dosage range of cocaine that produces potentiation follows that which increases blood pressure (BP), heart rate (HR), rate-pressure product and coronary vasoconstriction. (2) Cocaine given in i.v. doses that increase BP in decerebrate cats (0.25-1.0 mg/kg) has no significant effect on directly monitored spontaneous cardiac sympathetic nerve activity (SNA). In fact, higher doses of cocaine (2-4 mg/kg, i.v.) consistently inhibit preganglionic cardiac and splanchnic nerve activity. (3) Cocaine (0.1-1.0 mg) administered directly into the blood supply of the hindbrain via the vertebral artery produces no increase in BP, HR or SNA in cats; instead, decreases in BP and sympathetic activity occur. The same dose (1 mg), injected i.v., does not depress BP or SNA. In addition, cocaine injected into the forebrain via the carotid artery or into the cerebral ventricles (0.1-1.0 mg) has very little effect on BP. Our results indicate that there is no significant excitatory effect of cocaine on CNS sympathetic centers, and that the sympathomimetic effects of cocaine on the cardiovascular system are likely to be mediated at peripheral sites.

Coronary artery disease in women. Risk factors, evaluation, treatment, and prevention.

Cardiovascular disease is the leading cause of death in women. Unfortunately, the problem of cardiovascular disease in women has been largely ignored as women have been enrolled in limited numbers or excluded entirely from many of the major trials on which treatment of cardiovascular disease have been based. Furthermore, recent evidence suggests that a gender bias against aggressive intervention and treatment of cardiovascular disease in women may exist. This article reviews the risk factors, methods of identification, and treatment of coronary artery disease in women, as well as the potential benefits of postmenopausal estrogen.

Cholesterol and lipoproteins: beyond atherogenesis.

Although much emphasis has been placed on the role of cholesterol and lipoproteins in atherosclerotic plaque formation, recent studies suggest that lipids have other vascular actions which may contribute to the pathogenesis of myocardial ischemia. These include deleterious effects of lipids on platelet and endothelial cell function, coagulation, fibrinolysis, and prostacyclin metabolism. The purpose of this report is to review recent data regarding the nonatherogenic effects of lipids and provide insight as to how lipid lowering might contribute to clinically important improvements in vascular biology.

Additive myocardial depressant effects of cocaine and ethanol.

Although significant morbidity and mortality have been associated with the combined use of cocaine and ethanol, the cardiovascular effects of this combination are unknown. In this study, the effect of ethanol on cocaine-induced cardiovascular alterations was examined in two groups (n = 8 each) of dogs, which were randomized to receive either ethanol (1.68 gm/kg intravenously) or saline solution and cocaine (2 mg/kg intravenously). Ethanol had no effect on heart rate, mean arterial pressure, or rate-pressure product; but it increased ventricular end-diastolic pressure (p < 0.05), reduced coronary diameter (p < 0.02), and decreased ejection fraction by 16% +/- 4% (p < 0.005) from baseline. Cocaine produced increases in mean arterial pressure, rate-pressure product, and left ventricular end-diastolic pressure that were similar in both groups. After administration of cocaine, left ventricular ejection fraction decreased 16% +/- 2% (p < 0.001) from the baseline value in controls and 32% +/- 5% (p < 0.0002 vs baseline; p < 0.01 vs controls) in the ethanol group. Coronary diameter decreased (p < 0.05) in both groups after administration of cocaine; however, there was no difference between groups in the response of coronary circulation to cocaine. Cocaine and ethanol depress myocardial function, and their effects are additive. Failure of ethanol to enhance cocaine-induced coronary vasoconstriction suggests that the additive myocardial depressant effect of this combination is not related to ischemia but rather to a direct toxic effect of these drugs. Individuals who combine ethanol and cocaine may be at increased risk of hemodynamic compromise.

Cocaine produces coronary artery vasoconstriction independent of an intact endothelium.

Studies have demonstrated that cocaine causes coronary vasoconstriction, but this has been unassociated with myocardial ischemia. Therefore, cocaine seems unlikely to precipitate myocardial infarction in the absence of potentiating factors. We hypothesized that injury to coronary endothelium could potentiate cocaine-induced coronary vasoconstriction by decreasing EDRF. The effect of cocaine on LAD diameter was measured in dogs subjected to coronary endothelial denudation and compared with that in a non-denuded control group. Endothelial denudation was accomplished by abrasion with an inflated angioplasty balloon and confirmed in vivo by demonstrating a vasoconstrictive response to infused acetylcholine and by postmortem scanning electron microscopy. Cocaine produced a similar maximal reduction in LAD diameter in both groups. Thus, cocaine induces endothelium-independent coronary artery vasoconstriction. Failure of endothelial injury to potentiate the coronary vasoconstrictive effect by cocaine suggests that factors other than endothelial dysfunction may be important in pathogenesis of cocaine-associated myocardial infarction.

Effects of high-density lipoprotein on acetylcholine-induced coronary vasoreactivity.

Recent evidence suggests that high-density lipoprotein (HDL) cholesterol has important vasoactive properties which may contribute to its beneficial effects on atherosclerotic coronary artery disease. The endothelium-dependent vasodilator acetylcholine has been used in a number of experimental studies to assess endothelial function. The relation between serum lipoproteins and acetylcholine-induced coronary vasoreactivity was investigated in patients (n = 27) undergoing elective coronary arteriography. Mean serum cholesterol, low-density lipoprotein cholesterol, HDL cholesterol and triglyceride levels were 189 +/- 7 (4.84 +/- 0.18 mmol/liter), 134 +/- 6 (3.47 +/- 0.15 mmol/liter), 41 +/- 3 (1.06 +/- 0.08 mmol/liter) and 106 +/- 30 mg/dl (1.20 +/- 0.03 mmol/liter), respectively. After a baseline arteriogram, acetylcholine was infused into the left main coronary artery and percent change from baseline dimension was determined in 27 angiographically smooth coronary artery segments and in 14 arterial segments with evidence of mild atherosclerotic disease. Intact vascular smooth muscle function was then confirmed in all segments by dilation to intracoronary nitroglycerin. Acetylcholine produced significant vasoconstriction of both angiographically smooth (13 +/- 4%, p less than 0.05 vs baseline) and diseased (19 +/- 4%, p less than 0.05 vs baseline) coronary segments. A positive correlation was observed between HDL cholesterol and normal acetylcholine-induced coronary vasoreactivity in both angiographically smooth (r = 0.59, p less than 0.001) and diseased (r = 0.62, p less than 0.02) coronary segments. No significant correlation was observed, however, between total and low-density lipoprotein cholesterol, or between total cholesterol to HDL ratio and the response of coronary artery diameter to acetylcholine infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence that cocaine slows cardiac conduction by an action on both AV nodal and His-Purkinje tissue in the dog.

The effects of intravenous cocaine (2 mg/kg) were tested on several indices of cardiac electrical activity in sedated dogs. These included sinus rate, PR, AH, and HV intervals; AV nodal effective refractory period (AVNERP); ventricular effective refractory period; QRS duration; and the QT interval. Cocaine induced significant changes in six control animals with an intact-functioning autonomic nervous systems. After pharmacologic autonomic blockade with propranolol plus propantheline, cocaine increased the PR interval (+ 11 +/- 4.0 ms, p less than 0.05), primarily by slowing conduction at the AV nodal level. However, with constant atrial pacing at a rate above the sinus cycle length, prolongation of both the AH and the HV intervals (+ 15 +/- 2.5 and 6.7 +/- 1.7 ms, respectively) occurred. There was also a significant increase in the AVNERP (+ 29 +/- 5.9 ms, p less than 0.05). Consistent with the observed rate-dependent HV prolongation, cocaine decreased the rate of rise of phase 0 of the transmembrane action potential of Purkinje fibers. These data indicate that cocaine impairs cardiac conduction by direct actions on AV nodal and His-Purkinje cells.

Effect of cocaine on the coronary circulation and systemic hemodynamics in dogs.

This study investigated the effect of intravenous cocaine (0.5 to 2 mg/kg body weight) on the coronary circulation and systemic hemodynamics in closed chest sedated dogs. The role of alpha- and beta-adrenoceptor stimulation in mediating these effects was also investigated. Cocaine produced dose-dependent increases in mean arterial pressure and rate-pressure product. Although the lower doses of cocaine had no significant effect on the coronary circulation, the 2 mg/kg dose produced a 55 +/- 14% increase in coronary vascular resistance (p less than 0.05 versus baseline) and a 19 +/- 3% reduction in diameter of the left anterior descending coronary artery (p less than 0.05 versus baseline). Despite these potentially deleterious effects on the coronary circulation (occurring at a time of markedly increased myocardial oxygen demand), the electrocardiogram did not demonstrate ischemic changes and there was no myocardial lactate production. Cocaine-induced coronary vasoconstriction was abolished by pretreatment with the alpha-adrenoceptor antagonist phentolamine, but not by pretreatment with the beta-adrenoceptor antagonist propranolol. The findings that cocaine did not change systemic vascular resistance in dogs without adrenergic blockade, reduced systemic vascular resistance in dogs after alpha-blockade (p less than 0.05) and increased systemic vascular resistance in dogs after beta-blockade (p = 0.06) suggest that epinephrine (rather than norepinephrine) is primarily responsible for the peripheral vascular actions of cocaine. Thus, in this canine preparation with normal coronary arteries, cocaine produced vasoconstriction of both epicardial and coronary resistance vessels that was not associated with evidence of myocardial ischemia. The pharmacologic mechanism for the effect of cocaine on the coronary circulation is alpha-adrenoceptor stimulation, whereas systemic hemodynamic effects are mediated by combined alpha- and beta-adrenoceptor stimulation.

Testosterone and muscle hypertrophy in female rats.

The effects of chronic treatment with testosterone propionate on compensatory muscle hypertrophy secondary to synergist removal were studied in female rats. Synergist removal resulted in a significant (2-fold) increase in muscle wet weight, with no changes in protein concentration. As reported previously, oxidation of [2-14C]pyruvate to 14CO2 was significantly decreased in hypertrophic muscles. In addition, malate dehydrogenase and lactate dehydrogenase activities were significantly decreased in overloaded muscles on a wet weight basis but not on the basis of noncollagen protein. These data suggest that specific metabolic adaptations may occur in response to overload of muscle. Administration of testosterone propionate in subcutaneously implanted Silastic capsules resulted in a 20-fold increase in serum testosterone levels. This treatment had no effect on body weight, muscle weight, pyruvate oxidation, or malate and lactate dehydrogenase activities in both control and hypertrophic muscles, although there was an effect on the noncollagen protein content of overloaded muscles. These results do not support the hypothesis that androgens, in conjunction with weight-bearing exercise in female subjects, are effective in increasing muscle mass or function in female subjects.