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J A Bauer

Publications and source records attributed to J A Bauer.

At least 55 records · Page 3Linked to original sources
PubMed1997

Application of pharmacodynamic modeling for designing time-variant dosing regimens to overcome nitroglycerin tolerance in experimental heart failure.

PURPOSE: Prolonged continuous administration of nitroglycerin (NTG) leads to hemodynamic tolerance. We used a previously developed pharmacokinetic-pharmacodynamic (PK/PD) model of NTG tolerance in experimental heart failure to test whether dosage regimens, designed from this model, may allow avoidance of tolerance development upon continuous NTG infusion. METHODS: Simulation experiments (using ADAPT II) were performed to evolve a time-variant infusion regimen that would theoretically provide sustained hemodynamic effect (30% reduction in left ventricular end-diastolic pressure, LVEDP) throughout 10 hours of drug dosing. A computer controlled infusion pump was utilized to deliver this time-variant input. Infusion experiments were then conducted in CHF rats to challenge the predictability of the applied PK/PD model. RESULTS: Simulations showed that exponentially increasing input functions provided more sustained LVEDP effects when compared to linear or hyperbolic input functions delivering the same total NTG dose. A computer-selected infusion regimen of 6.56e0.00156 x minutes micrograms/min was anticipated to provide the desired hemodynamic profile in our animal model. Experiments conducted in rats with congestive heart failure (n = 4) confirmed the prediction of sustained hemodynamic effect without tolerance (28 +/- 4% reduction in LVEDP at 10 hrs). CONCLUSIONS: These findings support the utility of our PK/PD model of NTG tolerance in predicting NTG action, and serve as an example of therapeutic optimization through PK/PD considerations.

Animals↗
PubMed1997

Vascular and hemodynamic differences between organic nitrates and nitrites.

Because nitroglycerin (NTG, an organic nitrate) and isoamyl nitrite have similar chemical structures and a common mechanism of vascular relaxation (i.e., conversion to nitric oxide in vascular tissues and activation of guanylyl cyclase), it has often been assumed that organic nitrates and nitrites have identical pharmacologic actions. Because recent studies have shown that the vascular enzymes responsible for nitric oxide generation from organic nitrates and nitrites are distinct, we hypothesized that the in vitro vascular actions, in vivo hemodynamic effects and tolerance properties (both in vitro and in vivo) would be different as well. Isolated blood vessel studies showed that NTG provided more stable relaxation effects than ISAN, was more potent and caused greater in vitro vascular tolerance. Because the mechanism(s) of vascular tolerance in vitro may not be the same as those occurring in vivo, we also compared the left ventricular hemodynamic effects and tolerance properties of NTG vs. isoamyl nitrite and in congestive heart failure rats. Constant NTG infusion (10 micrograms/min) caused initial reductions in left ventricular end-diastolic pressure of 45 to 55%, which returned to baseline within 10 hr (tolerance development). In contrast, isobutyl nitrite and isoamyl nitrite (45 micrograms/min) caused initial reductions in left ventricular end-diastolic pressure similar to NTG (42-58%), but these hemodynamic effects of organic nitrites were maintained even when infusions were carried out to 22 hr. These results show that organic nitrites and organic nitrates are not pharmacologically identical (in vitro or in vivo), and may suggest a therapeutic advantage for organic nitrites in the treatment of some cardiovascular diseases.

Amyl Nitrite↗
PubMed1996

Specific binding of nitroglycerin to coronary artery microsomes. Evidence of a vascular nitrate binding site.

The vasodilating action of organic nitrates, such as nitroglycerin (NTG), is thought to be mediated through metabolic conversion to nitric oxide (NO) in vascular smooth muscle. Although the pertinent enzyme(s) that carries out this crucial step has not been identified, previous studies have shown that the primary enzymatic site is located within cellular membrane fractions. In these studies, we examined the binding of [14C]NTG to microsomal fractions from bovine coronary arteries. Specific binding was linearly related to protein concentration, and binding equilibrium was reversible, reached equilibrium within 1 hr, and remained stable for 4 hr at 25 degrees. Competition experiments with unlabeled NTG demonstrated the presence of two binding sites of differing affinities (high-affinity site: Bmax 24.1 +/- 0.9 pmol/mg protein, Kd 554 +/- 22 pM; low-affinity site: Bmax 79.0 +/- 2.9 pmol/mg protein, Kd 151 +/- 3 microM). Both of the thiol alkylators 1-chloro-2,4-dinitrobenzene and N-ethylmaleimide were found to inhibit [14C]NTG binding, as well as enzymatic generation of NO from NTG, in a concentration-dependent manner. Competition of [14C]NTG was also observed with five other organic nitrate vasodilators, and the degree of competition was linearly related to the in vitro vaso-relaxing potencies of these agents. Parallel experiments also showed that in the absence of thiol cofactor, the enzymatic production of NO from NTG was antagonized competitively by less potent organic nitrates. Intact blood vessel experiments using rat aorta also showed that the presence of isosorbide dinitrate (ISDN), at concentrations that did not induce relaxation alone, caused a slight but significant shift in the relaxation potency of NTG (EC25 9 +/- 2 versus 28 +/- 7 nM, in the presence and absence of 0.3 microM ISDN, respectively; P < 0.05). These results demonstrate the presence of specific binding of organic nitrates to microsomal proteins in vascular smooth muscle, and the observed binding is apparently related to enzymatic conversion to NO and the vasodilating properties of these compounds.

Animals↗
PubMed1996

A comparative and ultrastructural study of synaptic contacts established by primary sensory fibers in the spinal trigeminal nucleus of the rat.

A quantitative evaluation of the types of afferent synaptic contacts in the pars oralis, using transganglionic degeneration and a comparison of previous data obtained from the pars interpolaris (Lapa & Bauer, 1992), of the rat was performed. Following left inferior alveolar nerve transection or partial pulpectomy of the first and second left lower molar teeth well-defined degenerating terminals appeared bilaterally. In both experiments, the majority of these afferent synapses formed single asymmetric contacts with intermediate and distal dendritic segments in the pars oralis. Fewer contacts were observed with dendritic spines, proximal dendritic segments, perikarya, and other terminals. Double and multiple synaptic contacts, preferentially with small dendritic profiles, were also found. Pars oralis showed higher density of degenerating terminals and higher proportion of the contralateral contacts than pars interpolaris suggesting that it is a prime input area and that it may play a role in the bilateral management of sensory information. Pars oralis showed a higher density of contacts with intermediate and distal dendritic segment and a lower density of double contacts in comparison to the pars interpolaris. Partial pulpectomy revealed a distribution in synaptic types similar to that following IAN transection suggesting that sensory fibers conveying pain-related stimuli are not distinguished from fibers of other sensory modalities as to preference of synaptic contacts. The overall pattern demonstrates a structural organization of the sensory inputs to the spinal trigeminal nucleus regarding the bilateral handling of sensory information.

Afferent Pathways↗
PubMed1996

Arterial versus venous metabolism of nitroglycerin to nitric oxide: a possible explanation of organic nitrate venoselectivity.

Nitroglycerin (NTG) and other organic nitrates are predominant venodilators in vivo and in vitro. This selectivity is an important determinant of their ability to relieve angina and congestive heart failure symptoms, but the mechanism of this phenomenon is unknown. Because organic nitrate vasodilation occurs through metabolism to nitric oxide (NO), we tested the hypothesis that their venoselectivity is related to an enrichment of the pertinent enzyme in venous tissue. Enzymatic conversion of NTG to NO was examined in microsomal fractions from bovine aorta as compared with vena cava tissues. NTG (150, 450, or 900 microM) was incubated with 1 mg microsomal protein and glutathione (13 microM), and cumulative NO production was measured for 5 h. When enzyme velocities were normalized to microsomal protein, statistical significance was not observed between fractions from aorta and those from vena cava. However, when enzyme activity was normalized to tissue weight or total homogenate protein, statistically higher activity was observed in the venous tissue (p < 0.05). These differences were greatest (two- to three-fold higher in vena cava at all three NTG concentrations, p < 0.01) when enzyme velocity was normalized to the initial cellular content of the homogenates (i.e., homogenate DNA concentrations). These results suggest that organic nitrate venoselectivity may be at least partly explained by enrichment of the bioactivating enzyme in venous smooth muscle cells.

Animals↗
PubMed1996

Sustained antiplatelet properties of nitroglycerin during hemodynamic tolerance in rats.

Organic nitrates possess important antiplatelet actions that are useful in the treatment of unstable angina and myocardial infarction, but the susceptibility of platelets to nitrate tolerance has not been extensively studied. In normal conscious rats, we showed that continuous infusion of nitroglycerin (NTG) at 10 micrograms/min had no significant effect on mean arterial pressure (MAP) as compared with control, but hemodynamic tolerance could be demonstrated by MAP response to a bolus intravenous (i.v.) NTG challenge. By this criterion, continuous 8-h NTG infusion produced hemodynamic tolerance (a decrease in MAP response of 45.7 +/- 19.9%, p < 0.05), whereas D5W control and S-nitroso-N-acetylpenicillamine (SNAP) infusions did not. During NTG infusion, platelet-rich plasma (PRP) cyclic GMP was increased by 41.4 +/- 13.6% as compared with control and remained increased throughout the infusion (p < 0.05). Bleeding time during a 2-h infusion of NTG was 8.9 +/- 1.2 min as compared to 3.8 +/- 0.4 min in controls (p < 0.05). After 8-h of NTG infusion, the bleeding time was 10.2 +/- 1.4 min versus 4.4 +/- 0.4 min in controls (p < 0.05). NTG also decreased the PRP platelet concentration by 30% in 8 h, whereas D5W had no effect. In vitro experiments showed that platelets in themselves do not produce significant amounts of cyclic GMP. These data indicate that the biochemical and antiaggregation effects of NTG on platelets are not diminished during hemodynamic tolerance and that these effects may be dependent on extraplatelet production of nitric oxide (NO).

Animals↗
PubMed1995

Nitric oxide donors: biochemical pharmacology and therapeutics.

The NO donors are a diverse group of agents with unique chemical structures and biochemical requirements for generation of NO. The differences in biochemistry and metabolism may, in turn, cause differences in their pharmacology and therapeutic actions. A thorough understanding of the biochemical pharmacology of NO donors and factors controlling their therapeutic activity would facilitate the optimal use of these agents as chemical carriers of NO, and the development of newer agents than can selectively modulate the many physiological actions of NO.

Animals↗
PubMed1994

Effects of morphine withdrawal syndrome on endo-oligopeptidase (EC 3.4.22.19) activity.

Endo-oligopeptidase (EC 3.4.22.19), an enzyme capable of generating enkephalin by single cleavage from enkephalin-containing peptides, was examined in several areas of the central nervous system (CNS) as well as in the immune and endocrine tissues of rats chronically treated with morphine and submitted to naloxone-induced withdrawal. A specific fluorogenic substrate was used to determine the endopeptidase 22.19 activity. A non-uniform increase in endopeptidase 22.19 activity was detected in the CNS. The highest increase in endopeptidase 22.19 specific activity was found in the dorsal hippocampus (about 3.5-fold higher than control), followed by occipital and frontal cortex, substantia nigra, thalamus and hypothalamus. In peripheral tissues, a significant decrease of endopeptidase 22.19 was observed in the pineal gland, whereas the morphine withdrawal syndrome caused a slight but significant increase in lymphoid tissues such as lymph nodes and thymus. These findings are indicative of a possible participation of endopeptidase 22.19 in naloxone-induced withdrawal.

Animals↗
PubMed1994

Mechanisms of nitrate tolerance.

There is now little dispute that clinical tolerance of organic nitrates occurs, particularly when these drugs are used by themselves to treat patients with stable angina pectoris and congestive heart failure. Classical hypotheses of nitrate tolerance suggest the phenomenon to result from vascular depletion of critical sulfhydryl groups, which are necessary to bring about vasorelaxation from nitrates. While this mechanism of nitrate tolerance probably operates when isolated blood vessels are exposed to high concentrations of nitrate in vitro, there is little evidence to suggest that it contributes to clinical nitrate tolerance. Instead, emerging data suggest that nitrates can cause significant shifts in fluid distribution and secretion of neurohormonal factors that can modulate their vasorelaxant effects. Use of angiotensin converting enzyme inhibitors and diuretics in conjunction with nitrates may alleviate the development of tolerance, but the experience has not been universally favorable. Other receptor-effector systems that affect cardiovascular function, such as the adrenergic system, may also be affected by nitrate tolerance. The mechanisms of nitrate tolerance are therefore likely to be multifactorial, involving vascular biochemical changes, physiologic compensation, and possibly receptor regulation.

Angina Pectoris↗
PubMed1994

Endogenous nitric oxide in expired air: effects of acute exercise in humans.

Nitric oxide (NO) is present in the exhaled breath of humans and experimental animals, but its physiologic role and cellular source(s) remain to be determined. Possible sites of origin are pulmonary endothelial cells and/or resident macrophages. Here we have tested the hypothesis that changes in cardiovascular status can alter the apparent pulmonary excretion of NO. Exercise on a stationary bicycle produced rapid and reversible increases in pulmonary NO excretion rate, and changes in NO excretion rate during exercise were well correlated with observed changes in heart rate. These results suggest that changes in expired NO during exercise are related to corresponding cardiovascular responses.

Adult↗
PubMed1994

Photochemical generation of nitric oxide from nitro-containing compounds: possible relation to vascular photorelaxation phenomena.

We examined the production of nitric oxide (NO) from various nitro-containing compounds (500 microM and 100 microM solutions in Krebs buffer, pH 7.4). Sealed vials containing solutions of NaNO2, N-nitro-L-arginine, 4-nitrophenol, BAY K 8644, or N-nitro-L-arginine methyl ester were stored in the dark, under normal room light, or were exposed to ultraviolet light (365 nm), for 30 min (24 degrees C). NO was measured in the vial headspace after 30 min, using a sensitive assay previously established in our laboratory. Production of NO was found to be dependent on the intensity of light exposure for all compounds, and the highest degree of light-induced production of NO was found for NaNO2 and BAY K 8644 solutions. Since NO is a relaxant of smooth muscle, these results help explain the increased sensitivity to relaxation by UV light of vascular and other types of smooth muscle in the presence of NaNO2, BAY K 8644 and N-nitro-L-arginine, as observed by other investigators.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1994

Pharmacodynamic models of nitroglycerin-induced hemodynamic tolerance in experimental heart failure.

Pharmacodynamic tolerance during continuous nitroglycerin (NTG) infusion is a significant limitation of nitrate therapy. The mechanism of this phenomenon is not well-understood but may involve physiologic compensation which involves vasoconstriction. We have obtained pharmacodynamic data on NTG-induced hemodynamic tolerance in a rat model of congestive heart failure (CHF), which we have shown to mimic human behavior toward NTG in vivo. In this report, we developed two mechanism-based pharmacokinetic/pharmacodynamic models to describe the time-dependent effects of NTG infusion on left ventricular end-diastolic pressures (LVEDP) in CHF rats and compared their abilities to describe the observed hemodynamic data. Both mathematical models introduced a counter-regulatory vasoconstrictive effect as a result of NTG-induced vasodilation and assumed the magnitude of this effect to be driven by the extent of the initial hemodynamic effect produced by NTG. The decay of this counter-regulatory effect was described by a first-order process in both models. A model that assumed vasoconstriction to develop via two sequential first-order processes was statistically superior in describing the data, when compared to one that assumed a single first-order process and a lag phase. Both models provided similar estimates of the half-life for the disappearance of the vasoconstriction (t1/2 of vasoconstriction: 128min vs. 182min, respectively), and both predicted rebound elevation of LVEDP after abrupt NTG withdrawal. These results are consistent with a counter-regulatory mechanism of NTG-induced hemodynamic tolerance and suggest that such an approach may be useful for modeling other tolerance phenomena as well.

Animals↗
PubMed1994

The development of eye alignment, convergence, and sensory binocularity in young infants.

PURPOSE: To measure and compare the development of ocular alignment, sensory binocularity, and convergence in infants during the first 5 months of life. METHODS: Healthy infants were tested between 2 and 21 weeks of age. Ocular alignment was measured by the Hirschberg test; convergence was determined by visual examination as an illuminated toy approached an infant's face; and sensory binocularity was measured by preferential looking for fusible versus rivalrous gratings. In experiment 1 we compared the proportion of infants at different ages demonstrating orthotropic ocular alignment with those showing convergence. In experiment 2, we compared the age of onset of convergence to that of sensory binocularity. RESULTS: Experiment 1: Most infants were orthotropic during the first month, and almost all of the others showed small amounts of exotropia. None of the infants showed accurate convergence until 6 weeks of age. By 4 months of age virtually all were orthotropic and had good convergence. Experiment 2: The onset of sensory binocular fusion occurred at 12.8 +/- 3.3 weeks. Full convergence did not occur until 13.7 +/- 3.2 weeks, although the first signs of convergence occurred slightly earlier. For individual infants there was a high correlation between the age of onset of sensory binocularity and convergence, and both onsets occurred earlier in girls than in boys. CONCLUSIONS: Ocular alignment did not require the development of binocularity mechanisms, and the development of binocularity mechanisms did not await the onset of good ocular alignment. The relatively sudden onset of binocularity, both sensory (preference for fusion and stereopsis) and motor (convergence) at about 3 months of age and the high correlation between these measures indicate a common causal mechanism that probably involves refinements in striate cortex circuitry.

Child Development↗
PubMed1994

Morphologic study of tissue changes occurring in the apical third and periapex of rat molars after endodontic treatment performed under different occlusal conditions.

The purpose of the present study was to carry out a histologic study of the periapical changes of the maxillary first molar of rats submitted to endodontic treatment under different occlusal conditions. The experiment was carried out under conditions analogous to those used in clinical practice. Pulpotomy, pulpectomy and chemomechanical preparation of the mesial root canal were carried out according to previously established techniques and the mesial root canal was filled with cement and gutta-percha. A glass ionomer cement was used as restorative material under conditions of subocclusion, normal occlusion and excessive occlusal forces. No inflammatory reaction of periapical tissue was observed under the three conditions used, and active closing of the root canal was observed 15 days after the procedure, with the formation of cementum replacing the pulpar remnant.

Animals↗
PubMed1993

Effect of apparent elimination half-life on nitroglycerin-induced hemodynamic rebound in experimental heart failure.

Hemodynamic rebound after abrupt withdrawal may be an important consideration associated with nitroglycerin (NTG) monotherapy. This phenomenon may arise from unopposed neurohormonal vasoconstriction because of rapid elimination of NTG. The role of NTG pharmacokinetics in the development of hemodynamic rebound was examined using a rat model of congestive heart failure. NTG was infused for 90 min, then the dose was either abruptly stopped (n = 8) or gradually reduced by 20% every 20 min (n = 7). Abrupt withdrawal caused rebound elevations of left ventricular end-diastolic pressure (LVEDP) to about 25% above baseline values, at 30-60 min after drug termination (P < 0.01), but this was completely avoided by graded NTG withdrawal. A positive correlation was observed (P < 0.05) between the percentage reduction in LVEDP during infusion and the maximum percentage rebound in rats after abrupt withdrawal but not after graded withdrawal. These results suggest that NTG-induced hemodynamic rebound is related to its short biological half-life and that this phenomenon is consistent with a mechanism of neurohormonal compensation.

Animals↗
PubMed1993

Continuous versus intermittent nitroglycerin administration in experimental heart failure: vascular relaxation and radioligand binding to adrenoceptors and ion channels.

Continuous nitroglycerin (NTG) administration causes pharmacologic tolerance in humans and animals, whereas intermittent dosing is capable of avoiding or reducing tolerance development. The mechanism of NTG-induced hemodynamic tolerance may involve specific vascular desensitization and/or neurohormonal compensation. We compared effects of long-term (10 days) NTG administration (continuous or intermittent 12 h on/12 h off transdermal dosing, 10 micrograms/min) to rats with congestive heart failure (CHF) on radioligand binding from selected tissues. Tension responses in isolated blood vessels, plasma renin activity (PRA), plasma Na+ and K+ concentrations were also determined. The maximal binding values (Bmax) for [3H]glyburide and [3H]PN 200 110 in homogenates of left ventricle, right ventricle, and brain were not significantly different after NTG administration (continuous or intermittent), as compared with control. Intermittent, but not continuous, NTG caused significant increases in beta-adrenoceptor densities in the left ventricle, as judged by [3H]dihydroalprenolol binding (Bmax values: intermittent NTG 34.5 +/- 4.8, continuous NTG 24.4 +/- 2.6, placebo control 20.9 +/- 2.9 fmol/mg protein); Kd values for all ligands were not significantly altered by NTG administration. Both intermittent and continuous NTG increased the vascular contractile response to phenylephrine in isolated rat thoracic aorta. Slight reductions (two- to four-fold shifts in EC50 values) in thoracic aorta relaxant response to NTG were observed in both treatment groups as compared with control. Intermittent and continuous NTG administration caused selective changes in beta-adrenoceptor density and vascular response. These changes may contribute partly to the phenomenon of pharmacologic tolerance after chronic nitrate administration.

Administration, Cutaneous↗
PubMed1992

Biochemical mechanism of organic nitrate action.

Increasing evidence suggests that organic nitrate action derives from their metabolic conversion to nitric oxide (NO) in the vascular smooth muscle cell. The primary catalytic activity of this process appears to reside at the cellular plasma membrane. There is no concrete evidence to indicate that NO formation is preceded by the production of inorganic nitrite ion or that the NO produced needs to form S-nitrosothiols before it can activate guanylate cyclase to produce cyclic guanosine 3',5'-monophosphate (cGMP). Although sulfhydryl donors can partially reverse nitroglycerin-induced tolerance in patients, this phenomenon (by itself) is not sufficient to implicate intracellular sulfhydryl depletion as an operating mechanism of clinical nitrate tolerance. This is because sulfhydryl donors can react with nitroglycerin extracellularly to form S-nitrosothiols, and nonsulfhydryl compounds, such as enalapril and hydralazine, can prevent the development of in vivo nitrate tolerance. In addition to the cellular biochemical reactions, organic nitrates also produce systemic biochemical effects through altering neurohormonal status. These systemic effects may contribute significantly to the development of nitrate tolerance in therapeutic situations.

Animals↗