Peroxynitrite reduces vasodilatory responses to reduced intravascular pressure, calcitonin gene-related peptide, and cromakalim in isolated middle cerebral arteries.

Vasodilatory responses to progressive reductions in intravascular pressure or to calcitonin gene-related peptide (CGRP) or cromakalim were determined in rodent middle cerebral arteries (MCAs) before and after treatment with peroxynitrite (ONOO-). Middle cerebral artery diameters in isolated, pressurized MCAs were measured as intravascular pressure was reduced from 100 to 20 mm Hg in 20-mm Hg increments before and after inactive ONOO-, pH-adjusted ONOO-, or 10, 20, or 40 micromol/L ONOO- was added to the bath. In other MCAs, responses to CGRP (1 x 10-9 - 5 x 10-8) or cromakalim (3 x 10-8 - 8 x 10-7) were measured before and after the addition of 25 micromol/L ONOO-. Inactive ONOO- (n = 6, P = 0.40), pH-adjusted ONOO- (n = 6, P = 0.29), and 10 micromol/L ONOO- (n = 6, P = 0.88) did not reduce vasodilatory responses to reduced intravascular pressure. Middle cerebral arteries treated with 20 (n = 6, P < 0.0001) and 40 (n = 6, P > 0.0001) micromol/L ONOO- constricted significantly when intravascular pressure was reduced. Vasodilatory responses to CGRP or cromakalim were reduced by ONOO- (P > 0.02, n = 6 and P > 0.01, n = 7, respectively). ONOO- had no effect on vasoconstriction in response to serotonin or vasodilation in response to KCl. These studies demonstrate that ONOO- reduces multiple cerebral vasodilatory responses.

Traumatic brain injury reduces myogenic responses in pressurized rodent middle cerebral arteries.

Traumatic brain injury (TBI) reduces cerebral vascular pressure autoregulation in experimental animals and in patients. In order to understand better the mechanisms of impaired autoregulation, we measured myogenic responses to changes in intraluminal pressure in vitro in pressurized, rodent middle cerebral arteries (MCAs) harvested after TBI. In an approved study, male Sprague-Dawley rats (275-400 g) were anesthetized, intubated, ventilated with 2.0% isoflurane in O2/air, and prepared for fluid percussion TBI. The isoflurane concentration was reduced to 1.5%, and rats (n = 6 per group) were randomly assigned to receive sham TBI followed by decapitation 5 or 30 min later or moderate TBI (2.0 atm) followed by decapitation 5 or 30 min later. After decapitation, MCA segments were removed, mounted on an arteriograph, and pressurized. MCA diameters were measured as transmural pressure was sequentially reduced. MCA diameters remained constant or increased in the sham groups as intraluminal pressure was reduced from 100 to 40 mm Hg. In both TBI groups, diameter decreased with each reduction in pressure. In summary, MCAs removed from uninjured, isoflurane-anesthetized rats had normal vasodilatory responses to decreased intraluminal pressure. In contrast, after TBI, myogenic vasodilatory responses were significantly reduced within 5 min of TBI and the impaired myogenic responses persisted for at least 30 min after TBI.

Resuscitation with hypertonic saline dextran improves cardiac function in vivo and ex vivo after burn injury in sheep.

In a 24 h, double-blind, prospective trial, we tested the hypothesis that two 4 mL/kg doses of hypertonic saline dextran (HSD; 7.5% NaCl/6% dextran 70) given in addition to isotonic fluid treatment would produce both immediate and sustained benefit for the heart after large burn injury. 12 instrumented sheep were subjected to a 40% total body surface area full-thickness flame burn under halothane anesthesia. 1 h after burn, when the animals had recovered from anesthesia, the first dose of either HSD (n=6) or normal saline (NaCl .9%; n=6) was infused over 30 min. The test solution was immediately followed by lactated Ringer's solution infused to maintain a urine output of 1-2 mL/kg x h throughout the study. The second dose of test solution was started at 12 h and was infused over 5 h. The initial dose of HSD corrected the burn-induced reduction in cardiac output, cardiac work, an index of myocardial contractility, and restored myocardial blood flow, as measured by the colored microsphere technique, to preburn values. Plasma concentrations of troponin I, creatine kinase (CK), and CK isoenzyme CKMB were increased 1 h after burn, but were not altered after HSD treatment. After euthanasia at 24 h, myocardial glutathione concentrations were higher in HSD-treated animals, whereas other markers of oxidative injury in heart or in plasma did not show systematic differences. The maximum contraction force measured in isolated right papillary muscles ex vivo was significantly greater in HSD-treated than normal saline-treated animals. In conclusion, the first dose of 4 mL/kg HSD infused 1 h after burn improved cardiac function, whereas the second dose of HSD infused at 12 h was without apparent effect on dynamic variables. An overall effect of the HSD treatments was a lasting increase in papillary muscle contraction force.

In vitro myocardial depression by ketamine or thiopental is dependent on the underlying beta-adrenergic tone.

BACKGROUND: Depression of myocardial contractility by muscarinic stimulation is dependent on the underlying beta-adrenergic tone. Prior beta-adrenergic stimulation enhances muscarinic negative inotropic responses, an effect that has been termed accentuated antagonism. The purpose of this study was to determine whether accentuated antagonism occurs with myocardial depression caused by thiopental or ketamine. METHODS: Using an isolated, electrically stimulated rat left afrium model, the dose-response curves to the muscarinic agonist carbachol and the anesthetics ketamine and thiopental were compared under conditions of high (10(-6)M isoproterenol bath concentration) or low (10(-6)M propranolol) beta-adrenergic tone. RESULTS: As expected, depression by carbachol was accentuated in preparations stimulated with isoproterenol compared with atria treated with propranolol. The decrease in tension by high doses (> 400 muM thiopental, > 200 muM ketamine) of thiopental or ketamine was attenuated in isoproterenol-stimulated tissue when compared with beta-adrenergic blocked muscle. Low concentrations (200 muM thiopental, 100 muM ketamine) of anesthetic caused either no change in contractility (thiopental) or small positive inotropic responses (ketamine) in pro-pranolol-treated but not isoproterenol-stimulated tissue. CONCLUSIONS. In contrast to muscarinic agonists, myocardial depression by high concentrations of ketamine or thiopental is attenuated by prior beta-adrenergic stimulation. Positive inotropic responses may be seen with low concentrations of ketamine in muscle with low beta-adrenergic tone. The results of this study demonstrate that the underlying beta-adrenergic tone greatly influences the in vitro response of cardiac tissue to ketamine or thiopental.

Myocardial depression by isoflurane is dependent on the underlying beta-adrenergic tone.

Depression of myocardial contractility by muscarinic agonists is dependent on underlying beta-adrenergic tone. The negative inotropic effect of muscarinic agonists is enhanced by previous beta-adrenergic stimulation, an action that has been termed accentuated antagonism. We wished to determine whether accentuated antagonism occurs with isoflurane-induced myocardial depression. We used an isolated, electrically stimulated rat left atrium model to compare the dose-response curves to the muscarinic agonist carbachol and isoflurane under conditions of high (10(-6)M isoproterenol added to the bath) or low (10(-6)M propranolol) beta-adrenergic tone. As expected, myocardial depression by carbachol was accentuated in preparations stimulated with isoproterenol as compared with atria treated with propranolol. The decrease in contractility induced by isoflurane was attenuated in isoproterenol-stimulated preparations as compared with beta-blocked atria. The increased sensitivity to isoflurane observed in propranolol-treated muscles was reversed by increasing the concentration of calcium in the bath from 2.5 to 5.0 mM. In contrast to muscarinic agonists, isoflurane-induced myocardial depression is attenuated by previous beta-adrenergic stimulation. Isoproterenol most likely attenuates isoflurane's negative inotropic action by increasing the availability of external calcium. The results of this study demonstrate that the underlying beta-adrenergic tone greatly influences the negative inotropic response of cardiac tissue of isoflurane.

Thiopentone inhibits beta-adrenergic responses in myocardial tissue.

The purpose of this study was to determine the importance of inhibition of beta-adrenergic function in thiopentone-induced myocardial depression. Using an isolated, electrically stimulated rat left atria model, contractile dose-response curves to thiopentone (200 microM, 400 microM, 600 microM, 800 microM) were shifted to the right in preparations treated with 10(-3)M dibutyryl cyclic adenosine monophosphate (cAMP) compared with atria stimulated with 10(-6) M dibutyryl cyclic isoprenaline, demonstrating that inhibition of beta-adrenergic mechanisms by thiopentone is physiologically important. Depression by thiopentone was similar in atria treated with 10(-5) M forskolin compared with preparations stimulated with 10(-6) M isoprenaline, indicating that thiopentone does not block beta-adrenergic receptors. It is concluded that thiopentone depresses myocardial function by several mechanisms, one of which involves inhibition of the adenyl cyclase cascade. The adenyl cyclase enzyme is a likely site where thiopentone inhibits the system; however, other components of the cascade may also be involved.

Comparison of the in vitro myocardial depressant effects of isoflurane and halothane anesthesia.

The myocardial depressant effects of isoflurane and halothane were compared using feline right ventricular papillary muscles bathed in Krebs-bicarbonate solution. In experiment 1 muscles were stimulated by field electrodes (0.2 Hz) to obtain control measurements of developed tension (dt) and maximal rate of tension development (dF/dt) prior to exposing the papillary muscles to four concentrations of either isoflurane (4.0%, 2.0%, 1.0%, 0.5%) or halothane (2.0%, 1.0%, 0.5%, 0.25%). Repeat measurements of dt and dF/dt were recorded after 20 min at each concentration. Isoflurane and halothane both caused dose-dependent depression of dt and dF/dt, but at 0.5%, 1.0%, and 2.0%, halothane was significantly more depressant than isoflurane (P less than 0.01 for dt and dF/dt). Quadratic equations were fitted to the dose-response data by least squares analysis (R2 greater than .985 for both anesthetics), and the isoflurane and halothane concentrations that decreased dt to 90%, 70%, 50%, and 30% of control were determined to compare the relative myocardial depressant potency of isoflurane and halothane by linear regression analysis. This potency relationship is described by the equation: isoflurane concentration = -0.005 + 1.445 (halothane concentration). In experiment 2 papillary muscle responses at two similar cardiodepressant concentrations of isoflurane (1.25% and 2.0%) or halothane (0.80% and 1.35%) were compared at stimulus frequencies of 0.05, 0.1, 0.2, 0.4, 0.8, 1.0, and 2.0 Hz. The concentrations of isoflurane and halothane were selected from the data obtained in experiment 1 and represent the anesthetic concentrations that diminish muscle function to approximately 70% and 50% of control.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship of cardiac muscle tension to Na+,K+-adenosine triphosphatase activity after chronic digitoxin administration in cats.

To obtain a better understanding of the mechanism of action of the cardiac glycosides, we examined inotropic and biochemical effects of digitoxin in myocardium from cats chronically exposed to the drug. The mechanical function of papillary muscles was tested isometrically and left ventricular tissue was analyzed for Na+,K+-dependent adenosine triphosphatase ATPase activity. Muscles from control cat hearts developed tension at 2.5 +/- 0.7 g/mm2; muscles from cats that received subcutaneous digitoxin--100 micrograms/kg on day 1, followed by 40 micrograms/kg/day for 4 days (group A), and 75 micrograms/kg on day 1, followed by 25 micrograms/kg/day for 9 days (group B)--developed significantly greater (p less than 0.05) tension of 4.8 +/- 0.3 and 3.6 +/- 0.6 g/mm2, respectively. Further, in vitro maximal responsiveness to digitoxin was greater in the muscles from digitalized groups than in controls (p less than 0.05): Muscles from control cats had a maximal response to in vitro addition of digitoxin of 3.5 +/- 0.1 g/mm2; muscles from cats in group A reached 4.9 +/- 0.3 g/mm2, and those from group B, 4.5 +/- 0.7 g/mm2. Specific activity of microsomal Na+,K+-ATPase from hearts of digitalized groups A and B was inhibited by 50-70% (p less than 0.01). Developed tension, specific Na+,K+-ATPase activity, and in vitro maximal responsiveness to digitoxin in a third group (C) of cats receiving the least daily digitoxin (75 micrograms/kg on day 1, followed by 15 micrograms/kg/day for 29 days) were not different from controls. Mean plasma digitoxin concentrations were 33, 16, and 3 ng/ml in groups A, B, and C, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular manifestations of acute antibiotic toxicity during E coli endotoxin shock in anesthetized dogs.

Surgically instrumented, pentobarbital-anesthetized dogs were used to examine the acute cardiovascular activities of gentamicin, tobramycin, sodium penicillin-G, and sodium cephalothin during a control state and during experimental circulatory shock induced by E coli endotoxin. Intravenous administration of 2.5, 5, 10, and 20 mg/kg gentamicin or tobramycin resulted in a transient (5--20-minute) state of cardiovascular depression, as reflected by dose-related decreases of systemic blood pressure, cardiac output, left ventricular pressure, dP/dt max, left ventricular contractile force, and dF/dt max; heart rate was affected little. Endotoxin produced a persistent state of circulatory depression characterized by hypotension, decreased cardiac output, arterial acidemia, and reduced indices of cardiac function. During endotoxin shock, the cardiovascular effects of gentamicin and tobramycin were relatively more pronounced (sometimes more than doubled) than effects observed during the control state. Equally large doses of penicillin or cephalothin, however, had no discernible circulatory effects in either control dogs or dogs subjected to endotoxin shock. Present data indicate that the cardiovascular toxicities of the aminoglycoside antibiotics gentamicin and tobramycin were augmented during experimental circulatory shock, and suggest the need for specific hemodynamic surveillance when intravenous administration of cardioactive antibiotics is required in patients with pre-existing circulatory dysfunction.

The influence of ketamine on inotropic and chronotropic responsiveness of heart muscle.

The influence of ketamine on the inotropic and chronotropic responsiveness of heart muscle was examined in spontaneously beating right atrial preparations and in electrically driven left atrial preparations of guinea pigs. Ketamine (2.63 X 10(-5) to 4.2 X 10(-4) M) decreased heart rate of right atria and decreased contractile tension and its maximum rate of increase in both right and left atrial preparations (right atria greater than left atria). Ketamine did not prevent the heart rate increase produced by norepinephrine (NE; 1 X 10(-8) to 1 X 10(-4) M) in right atria; however, the maximum heart rate was consistently lower in ketamine-treated than in control muscles even after exposure to NE. Although contractile tension was decreased by ketamine, the maximum inotropic response to NE was consistently greater in ketamine-treated atria than in control atria. An inhibitor of the slow Ca++ current in heart muscle, D600, depressed the contractile effects of NE but did not prevent the positive inotropic interaction of ketamine and NE. Ketamine similarly enhanced the inotropic responses to norepinephrine (1 X 10(-6) M), epinephrine (1 X 10(-6) M), isoproterenol (1 X 10(-7) M) and dibutyryl cyclic adenosine 3':5'-monophosphate (AMP; 4 X 10(-3) M) in left atria electrically paced at a constant frequency of contraction of 1 Hz; however, ketamine inhibited the positive inotropic response to increased frequency of stimulation (0.1-3.0 Hz) and to ouabain (3 X 10(-7) M). These findings demonstrate that ketamine can exert a selective positive inotropic influence in heart muscle independent of heart rate or direct or reflexogenic autonomic nervous system changes, and suggest that this activity could in some way be associated with an alteration of the intracellular disposition of cyclic AMP.

Neuromuscular blocking effects of aminoglycoside antibiotics on fast- and slow-contracting muscles of the cat.

The neuromuscular-blocking effects of neomycin, streptomycin, and gentamicin were examined in fast- and slow-twitch muscles of pentobarbital-anesthetized cats. These antibiotics were more effective in reducing indirectly stimulated contractions of the gastrocnemius muscle than of the ipsilateral soleus muscle in adult cats. Respiratory-depressant effects of these antibiotics were more closely associated temporally with effects on soleus than on gastrocnemius twitch. Neomycin was a more potent neuromuscular blocking agent in kittens greater than 7 weeks old than in kittens less than 6 weeks old. Calcium ions were more effective in antagonizing the effects of neomycin on gastrocnemius than on soleus twitch; however, neostigmine was more effective in antagonizing the effects of neomycin on soleus than on gastrocnemius twitch. These data indicate a difference in responsiveness of fast- and slow-twitch muscles (fast greater than slow) to the neuromuscular-blocking effects of aminoglycoside antibiotics, and suggest that this may be related to a difference in the predominance of pre- and postjunctional inhibitory actions of these agents in the 2 muscle types.