Giancarlo Guideri

Myocyte cell loss and myocyte hypertrophy in the aging rat heart

To determine the effects of age on the myocardium, the functional and structural characteristics of the heart were studied in rats at 3, 10 to 12 and 19 to 21 months of age. Systemic arterial pressure, left ventricular pressure and its first derivative (dP/dt) and heart rate were comparable in the three animal groups. In the interval between 3 and 10 to 12 months, mean myocyte cell volume per nucleus increased 53 and 26% in the left and the right ventricle, respectively. The total number of myocyte nuclei remained constant in either ventricle. In the following period, between 10 to 12 and 19 to 21 months, a 39% further cellular hypertrophy on the left side of the heart was found in association with an 18% loss of cells in the ventricle. Cell loss was accompanied by discrete areas of interstitial and replacement fibrosis in the subendocardium. In contrast, no myocardial damage was observed in the right ventricle, and the measured 35% additional enlargement of myocytes occurred without a change in cell number. Thus, the aging left ventricle is composed of a smaller number of hypertrophied cells. Cellular hypertrophy may explain the unaltered cardiac function of the aged myocardium.

Distribution and function of the branchial nerve in the mussel.

1. Using standard dissecting and histological techniques, branchial nerve fibers have been traced from the visceral ganglion to the ciliated epithelium of the gill in the mussel, Mytilus edulis.2. The pattern of activation of cilia obtained by electrical stimulation of the visceral ganglion and branchial nerve indicates that individual filaments or small groups of adjacent filaments are independently innervated, allowing for discrete control of ciliary activity on different parts of the gill.3. The relationship of this innervation to the known functions of the gill is discussed.

NERVOUS CONTROL OF CILIARY ACTIVITY.

Electrical stimulation of the visceral ganglion of the mussel Mytilus edulis caused cilia on the lateral epithelium of the gill to beat faster. This effect was blocked by cocaine, physostigmine, hyoscyamine, and acetylcholine but not by tubocurarine. These agents did not block the cilioexcitatory effect of serotonin.

Single‐Dose Pharmacokinetics of Oral Ciprofloxacin in Patients With Cystic Fibrosis

The singie‐dose pharmacokinetics of oral ciprofloxacin were studied in ten patients with cystic fibrosis aged 18 to 34 years. Each patient received three different drug doses (500 mg, 750 mg, and 1,000 mg) at successive one‐week intervals. Dosing and drug assays were double blinded. Blood and urine were assayed over the 48 hours following each dose. Ciprofloxacin was absorbed from the gastrointestinal tract. Peak serum concentrations averaged 2.8, 4.5, and 4.6 μg/mL respectively at the three doses, well above the mean inhibitory concentrations of most isolates of Pseudomonas aeruginosa. Time to peak concentration was approximately two hours. The range of sputum levels in three patients was 1.1–2.1 μg/mL at four hours after the three doses. The serum elimination half‐life was 3.7 hours and was independent of dose. Urinary recovery was 26%; greater than 90% of urinary excretion occurred within the first 12 hours. The results of this study indicate that ciprofloxacin has potential for use in the treatment of P aeruginosa infections in patients with cystic fibrosis.

Effects of alcohol on isoproterenol-induced ventricular fibrillation in adult rats

To determine whether the pattern of alcohol consumption, intake, and withdrawal modulates the incidence of malignant ventricular arrhythmias and sudden cardiac death due to β-adrenergic stimulation in a species susceptible to administration of isoproterenol alone, a regimen was formulated in which both continuous and interrupted alcohol ingestion was obtained. After alcohol treatment of fully mature, adult rats for 7 weeks, a single subcutaneous injection of 150 μ/kg of isoproterenol was given to control (non-alcohol-treated), alcoholic (continuous consumption), and alcohol withdrawal (interrupted) rats. The incidences of malignant ventricular arrhythmias and related deaths were compared. The results revealed that arrhythmias and arrhythmic deaths were highest in the “alcohol withdrawal group,” 92% and 54%, respectively. As judged from baseline studies, withdrawal of alcohol produced a 16% decrease in serum K+ concentration compared with controls, whereas continuous alcohol ingestion resulted in a 20% elevation in magnesium concentration. These electrolyte changes were further affected by isoproterenol and may have contributed to the differential response to β-adrenergic stimulation as a result of the pattern of alcohol intake.

Death in ventricular fibrillation induced by isoproterenol in doca-salt pretreated rats preceded by changes in myocardial electrolytes

Serum and tissue content of sodium, potassium, magnesium and calcium was determined in controls and desoxycorticosterone acetate (DOCA)-salt treated rats to determine whether electrolyte changes preceded the development of isoproterenol-induced death in ventricular fibrillation. Control Sprague Dawley, male rats, were injected subcutaneously (s.c.) with either saline (Group A) or actinomycin D (0.1 mg/kg; Group B) once daily for 4 days. Other rats received 20 mg of DOCA by implantation, drank normal saline and were injected with either saline (Group C) or actinomycin D (Group D) once daily for 4 days. In the first part of the experiment, it was determined that none of 15 rats from Group C died when challenged with isoproterenol (150 micrograms/kg, s.c.) six days later: however, 13 out of 15 rats from Group D died within 29.1 +/- 15.0 minutes (mean +/- S.D.) from isoproterenol injection. Myocardial sodium was elevated (48.8 +/- 3.8 versus 36.3 +/- 1.9) and potassium decreased (60.4 +/- 3.4 versus 70.6 +/- 3.3, meq/kg wet weight, mean +/- S.D.) in rats that had succumbed to isoproterenol. In the second part of the experiment serum and tissues were removed from control and DOCA-saline pretreated rats before they died in ventricular fibrillation, 20 minutes after isoproterenol. DOCA-saline pretreated rats were hypernatremic and hypokalemic and exhibited higher sodium and lower potassium in skeletal muscle than control rats. Isoproterenol elicited hypokalemia in all rats, but it only elevated sodium and decreased potassium content in the myocardium of rats of Group D, that were more prone to die in ventricular fibrillation. It is concluded that myocardial electrolyte changes precede the onset of ventricular fibrillation and may be associated with the development of this dysrhythmia.

Time course of development and cessation of myocardial sensitization to isoproterenol by DCA-saline in the albino rat the role of protein synthesis

Abstract The time course the development of myocardial sensitization to isoproterenol induced by desoxycorticosterone acetate (DCA) was determined in albino rats implanted subcutaneously with various doses of DCA and maintained on 1% saline as drinking fluid. The animals were challenged at predetermined intervals following DCA implantation with a single, subcutaneous dose of isoproterenol (150 ug/kg body weight). The onset of myocardial sensitization, as determined by the incidence of mortality (due to ventricular fibrillation) was not dependent on the dose of DCA used and was noted within one or two days from the beginning of exposure to DCA. Removal of the steroid pellet after 6 days of pretreatment resulted in rapid decline of sensitization. Removal of DCA after 33 or 90 days of pretreatment, on the other hand, did not completely abolish sensitization. Treatment with the protein synthesis inhibitors cycloheximide and actinomycin D prevented the development of myocardial sensitization.

Enhanced Incidence of Isoproterenol-Induced Ventricular Fibrillation in the Magnesium-Deficient Rat

The electrocardiogram was recorded and serum and bulk myocardial electrolytes were determined in male Sprague Dawley rats, subjected to dietary magnesium deficiency for various periods, to assess the time course of development and cessation of the enhanced arrhythmogenic action of isoproterenol (150 micrograms/kg, subcutaneously) and to establish possible relationships between electrolyte changes and severe ventricular dysrhythmias. Ventricular fibrillation occurred within 60 min following isoproterenol injection in 25, 25, 62.5, 50, and 62.5% of rats on magnesium deficient diet for 4, 7, 11, 15, and 19 days (N = 8), respectively, and resulted in death in most animals (83%). Reintroduction of normal chow following a 30-day period on magnesium-deficient diet normalized serum magnesium (from 1.42 +/- 0.23 to 1.90 +/- 0.08 mEq/liter, mean +/- SD) but did not significantly reduce the incidence of ventricular fibrillation. Magnesium deficiency did not produce statistically significant alterations in bulk myocardial content of sodium, potassium, magnesium, and calcium. However, sodium was elevated and potassium diminished in hearts from rats that died in ventricular fibrillation, but not in those that had recovered. Magnesium-deficient rats sacrificed 30 min after isoproterenol injection, that is before the occurrence of ventricular fibrillation, exhibited hypomagnesemia and hypokalemia as well as elevated sodium and diminished potassium and magnesium in the myocardium. In contrast, rats on Purina Chow exhibited hypermagnesemia, but also showed hypokalemia and diminished cardiac potassium. The results indicate that magnesium deficiency enhances the arrhythmogenic propensity of isoproterenol and that the development of ventricular fibrillation is preceded by serum and myocardial electrolyte alterations.

Effects of a negative quaternary ion-sodium tetraphenylboron (TPB) on the rat phrenic nerve-diaphragm preparation

Abstract The effects of the negatively charged quaternary ion tetraphenylboron (TPB) on the rat hemidiaphragm resembled those of acetylcholine (ACh), including relief of curare block. They appeared to be on the post-synaptic membrane since TPB affected neither nerve conduction nor the systems for synthesis and destruction of ACh. Pretreatment with TPB enhanced blocking by choline (Ch), d-tubocurarine (TC) and decamethonium, but decreased the blocking potency of ACh to that of Ch. Enhancement of block depended on pretreatment concentrations of TPB. Regardless of initial tissue sensitivity, the same concentration of TPB induced constant degrees of block by TC and Ch. We conclude that its negative charge and electron donating properties cause TPB to react with electrophilic sites (ES). We suggest that cholinergic receptors are activated by disruption of an equilibrium that exists between ES and anionic sites (AS) by reaction at either site.

Enhanced Arrhythmogenic Activity of β-Adrenoceptor Stimulants in Desoxycorticosterone-Pretreated Rats

The arrhythmogenic activity of four beta-adrenoceptor stimulants, metaproterenol, salbutamol, isoetharine, and dobutamine, was determined in adult, Wistar rats pretreated for 3-4 weeks with desoxycorticosterone (DOCA) and 1% saline as drinking fluid. Doses (SC) of these stimulants which were well tolerated in untreated animals elicited severe ventricular dysrhythmias, often leading to death in ventricular fibrillation. The LD50 in mg/kg was as follows: metaproterenol, 0.28; salbutamol, 0.60; isoetharine, 2.3; and dobutamine, 4.8. The relative potency of metaproterenol, salbutamol, and isoetharine correlates well with their ability to stimulate beta 1-adrenoceptors. It is suggested that DOCA-saline pretreatment in rats may be used as a model for the rapid screening of drugs affecting beta-adrenoceptors.