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Biomedical subjects

A Gulati

Publications and source records attributed to A Gulati.

At least 55 records · Page 3Linked to original sources
PubMed1996

Effect of corticosterone on serotonin and catecholamine receptors and uptake sites in rat frontal cortex.

The effects of corticosterone (1 mg/kg per day for 7 days) on serotonin 5-HT1A, 5-HT2A, 5-HT uptake sites, and alpha 2-adrenergic receptor sites were measured. Corticosterone treatment significantly decreased the number of 5-HT1A receptor sites (Bmax = 108 +/- 8.20 fmol/mg protein and 152.31 +/- 13.36 fmol/mg protein in corticosterone- and vehicle-treated rats, respectively). No significant differences were found in other measures. It is possible that corticosteroids exert some of their behavioral effects via regulation of 5-HT1A sites in frontal cortex.

Animals↗
PubMed1996

Cardiovascular effects of centrally administered endothelin-1 and its relationship to changes in cerebral blood flow.

Intracerebroventricular (i.c.v.) injection of endothelin-1 (ET-1; 100 ng. i.c.v.) produced an initial pressor (24%) (peak at 3 min following ET-1 administration) and a delayed depressor (-40%) (30 and 60 min following ET-1 administration) effects in urethane anesthetized rats. The pressor effect of ET-1 was due to an increase (21%) in cardiac output, while the depressor effect of ET-1 was associated with a marked decrease (-46%) in cardiac output. Stroke volume significantly decreased at 30 and 60 min after the administration of ET-1. No change in total peripheral vascular resistance and heart rate was observed following central administration of ET-1. The effects of ET-1 on Blood pressure, cardiac output and stroke volume were not observed in BQ123 (10 micrograms, i.c.v.) treated rats. Blood flow to the cerebral hemispheres, cerebellum, midbrain and brain stem was not affected at 3 min, but a significant decrease in blood flow to all the regions of the brain was observed at 30 and 60 min following central administration of ET-1. BQ123 pretreatment completely blocked the central ET-1 induced decrease in blood flow to the brain regions. It is concluded that the pressor effect of centrally administered ET-1 is not accompanied by a severe decrease in brain blood flow, however, a subsequent decrease in blood pressure is associated with a decrease in blood flow to the brain. The cardiovascular effects of ET-1 including decrease in brain blood flow are mediated through central ET receptors.

Animals↗
PubMed1996

Modification of systemic and regional circulatory effects of intracerebroventricular administration of endothelin-1 by propranolol in anesthetized rats.

1. Cardiovascular effects of centrally administered endothelin-1 (ET-1) were studied in control and propranolol-treated anesthetized rats using a radioactive microsphere technique. 2. In the control group, blood pressure, cardiac output, and stroke volume were decreased, and heart rate was not altered after the administration of ET-1.ET-1 produced a reduction in blood flow to the brain, heart, kidneys, gastrointestinal tract, portal system, musculoskeletal system, and skin. 3. Propranolol significantly attenuated the decrease in blood pressure, cardiac output and stroke volume induced by centrally administered ET-1. The reduction in blood flow to the brain, heart, kidneys, gastrointestinal tract, portal system, musculoskeletal system and skin induced by centrally administered ET-1 was blocked by propranolol. 4. It is concluded that centrally administered ET produces significant cardiovascular effects which are mediated through the sympathetic nervous system and could be antagonized by propranolol. These findings can also be helpful in explaining some of the beneficial effects of propranolol in various cardiovascular disorders involving central ET mechanisms.

Adrenergic beta-Antagonists↗
PubMed1996

Role of endothelin in the cardiovascular effects of diaspirin crosslinked and stroma reduced hemoglobin.

OBJECTIVES: Diaspirin crosslinked hemoglobin is a resuscitative solution with excellent oxygen-carrying capacity. Diaspirin crosslinked hemoglobin produces an immediate increase in blood pressure and marked regional circulatory changes in rats and pigs. Our objective was to determine the role of endothelin in the cardiovascular actions of diaspirin crosslinked hemoglobin (modified) and (unmodified) stroma reduced hemoglobin solutions. DESIGN: Prospective, randomized comparison of cardiovascular effects of diaspirin crosslinked and stroma reduced hemoglobin in control rats and in rats pretreated with cyclo(D-Asp-Pro-D-Val-Leu-D-Trp) (BQ-123), an endothelin-A receptor antagonist. SETTING: Research laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Modified, highly purified, and heat pasteurized (diaspirin crosslinked) and unmodified (stroma reduced) hemoglobin in control (untreated) and BQ-123 (5 mg/kg/hr iv)-treated rats. MEASUREMENTS AND MAIN RESULTS: Infusion of stroma reduced hemoglobin (400 mg/kg iv) in control rats produced an increase in blood pressure (43%) and total peripheral resistance (65%) without any change in heart rate, cardiac output, and stroke volume. Stroma reduced hemoglobin decreased blood flow to the kidneys and liver, increased blood flow to the heart, and had no effect on blood flow to the brain, gastrointestinal tract, spleen, musculoskeletal system, skin, and mesentery and pancreas. Infusion of stroma reduced hemoglobin in rats treated with BQ-123 (5 mg/kg/hr iv) increased the blood pressure to a similar degree when compared with control rats, but the increase in total peripheral resistance was significantly attenuated. The stroma reduced hemoglobin-induced decrease in blood flow to the kidneys and liver was significantly attenuated in BQ-123-treated rats as compared with control rats. However, the stroma reduced hemoglobin-induced increase in blood flow to the heart of BQ-123-treated rats was similar to the increase in control rats. Infusion of diaspirin crosslinked hemoglobin (400 mg/kg iv) produced increases in blood pressure (81%), cardiac output (36%), stroke volume (30%), and total peripheral vascular resistance (45%), along with increases in blood flow to the heart, spleen, gastrointestinal tract, and skin of control rats. The blood flows to the brain, kidneys, liver, musculoskeletal system, and mesentery and pancreas were not altered by diaspirin crosslinked hemoglobin in control rats. The increases in blood pressure, cardiac output, stroke volume, and total peripheral vascular resistance by diaspirin crosslinked hemoglobin were significantly blocked in BQ-123-treated rats as compared with control rats. The increases in blood flow to the heart, spleen, and skin by diaspirin crosslinked hemoglobin were significantly blocked in BQ-123-treated rats as compared with control rats. Diaspirin crosslinked hemoglobin produced an increase in the blood flow to the brain and a decrease in blood flow to the kidney and musculoskeletal system of BQ-123-treated rats as compared with control rats. Blood plasma endothelin-1-like immunoreactivity was found to be significantly increased after treatment with diaspirin crosslinked hemoglobin or stroma reduced hemoglobin. CONCLUSIONS: The endothelin-A receptor antagonist, BQ-123, could attenuate the systemic hemodynamic and regional circulatory effects of diaspirin crosslinked hemoglobin and stroma reduced hemoglobin. However, the increase in blood flow to the heart induced by stroma reduced hemoglobin could not be attenuated by BQ-123.

Animals↗
PubMed1995

Endothelin-1 stimulates proliferation of normal airway epithelial cells.

To investigate the influence of endothelins on airway epithelial cell growth, we measured [3H]thymidine incorporation and cell numbers of cultured porcine tracheal epithelial cells in the presence or absence of endothelin-1 or -3 with or without PD-145065 (a combined endothelin-A and -B receptor antagonist), BQ-123 (an antagonist specific for endothelin-A receptors) or phosphoramidon (an inhibitor, in part, of endothelin converting enzymes). We found that endothelin-1 stimulated the proliferation of airway epithelial cells and this response was progressively inhibited by increasing concentrations of either PD-145065 or BQ-123. In contrast to endothelin-1, airway epithelial cells were not responsive to endothelin-3. They also appeared to be producing endothelin-1 endogenously. Phosphoramidon significantly decreased basal growth of cells incubated in the absence of exogenous endothelin, and was associated with a significant diminution in their endothelin production. We conclude that endothelin-1 is mitogenic for porcine airway epithelial cells and may be involved in both autocrine and paracrine control of them.

Amino Acid Sequence↗
PubMed1995

Systemic hemodynamic and regional circulatory effects of centrally administered endothelin-1 are mediated through ETA receptors.

Central endothelin (ET) has been implicated in the regulation of the cardiovascular system. The effect of intracerebroventricular (i.c.v.) administration of ET-1 or IRL 1620 (5, 15 and 45 ng) on the systemic hemodynamics and regional circulation was studied in anesthetized rats using a radioactive microsphere technique. Systemic hemodynamics and regional blood circulation were determined before (baseline) and at 30 min after the injection of each dose of ET-1 or IRL 1620. Administration of saline (5 microliters, i.c.v.) did not produce any significant cardiovascular effects. The lower doses of ET-1 (5 and 15 ng) did not produce any significant effect on blood pressure (BP), heart rate (HR), cardiac output (CO), stroke volume (SV), total peripheral resistance (TPR) and regional blood circulation. However, the higher dose (45 ng) produced a transient rise (26%) followed by a sustained fall (48%) in BP. The decrease in BP was accompanied by significant decreases in CO (44%) and SV (39%), while HR and TPR were not affected. ET-1 (45 ng, i.c.v.) also produced a significant reduction in blood flow to the brain (75%), heart (49%), kidneys (66%), GIT (40%), portal system (52%) and musculo-skeletal system (38%), while blood flow to the skin was not affected. To determine pharmacological specificity of the central effects of ET-1, studies were performed in rats pretreated with BQ-123, a specific ETA receptor antagonist. Pretreatment with BQ-123 (10 micrograms, i.c.v.), 15 min prior to the administration of ET-1, completely antagonized the systemic hemodynamic as well as the regional circulatory effects of ET-1 (45 ng, i.c.v.). In order to determine whether stimulation of central ETB receptors produces any cardiovascular effects, studies were performed using IRL 1620, a specific ETB receptor agonist. Administration of IRL 1620 (5, 15 and 45 ng, i.c.v.) did not produce any effect on systemic hemodynamics and regional blood circulation in rats. It is concluded that ETA but not ETB receptors are involved in the central cardiovascular actions of ET.

Animals↗
PubMed1995

Effect of diaspirin crosslinked and stroma-reduced hemoglobin on mean arterial pressure and endothelin-1 concentration in rats.

The effect of unmodified stroma reduced (SRHb) and modified diaspirin crosslinked (DCLHb) hemoglobin solutions on the mean arterial pressure and endothelin-1 (ET-1) concentration in blood plasma and various tissues was studied. Infusion of DCLHb or SRHb increased mean arterial blood pressure by 96% and 39%, respectively. Heart rate was not significantly affected by DCLHb or SRHb. A significant increase (P < 0.003) in the ET-1 levels in blood plasma after DCLHb and SRHb infusion was observed. The increase in plasma ET-1 concentration was significantly more marked with SRHb (141%) as compared to DCLHb (78%) treated rats. The concentration of ET-1 in the heart and brain regions was not altered in DCLHb or SRHb treated rats as compared to control. However, ET-1 concentration was significantly increased in the thoracic aorta (151%) and renal medulla (272%) of DCLHb treated rats. SRHb treated rats also showed a significant increase in ET-1 concentration in the thoracic aorta (141%) and renal medulla (429%). The effect of SRHb on the renal medulla was found to be significantly greater than that of DCLHb. ET may be one of the factors responsible for the cardiovascular effects of hemoglobin solutions.

Animals↗
PubMed1995

Endothelin ETA receptor antagonist, BQ-123, blocks the vasoconstriction induced by sarafotoxin 6b in the heart but not in other vascular beds.

1. The cardiovascular effects of SRT6b in control and BQ-123, a specific ETA receptor antagonist, pretreated rats were determined in anesthetized rats using a radioactive microsphere technique. 2. Infusion of SRT6b produced an increase in blood pressure and total peripheral resistance, decrease in cardiac output and stroke volume, and no change in heart rate of control or BQ-123 treated rats. 3. SRT6b induced a decrease in blood flow to the heart which was completely blocked by BQ-123 pretreatment. The decrease in blood flow to other organs by SRT6b was not affected by BQ-123 pretreatment. 4. This study indicates that ET receptors in the coronary blood vessels are of a different type (neither ETA nor ETB) to those in other vascular beds.

Animals↗
PubMed1995

Yohimbine modulates diaspirin crosslinked hemoglobin-induced systemic hemodynamics and regional circulatory effects.

OBJECTIVE: Diaspirin crosslinked hemoglobin, a hemoglobin-based blood substitute, is proposed to be an effective resuscitative solution. It produces an immediate, but limited increase in blood pressure when administered to conscious or anesthetized rats. This vasoactivity is associated with an increase in blood flow to several major organs. It has been shown that alpha-adrenergic receptors in the peripheral vascular system are sensitized by diaspirin crosslinked hemoglobin in rats. The present study was conducted to determine the effect of yohimbine, an alpha 2-adrenergic receptor antagonist on systemic hemodynamics and regional circulatory effects of diaspirin crosslinked hemoglobin. DESIGN: Prospective, randomized comparison of cardiovascular effects of diaspirin crosslinked hemoglobin in control and yohimbine-pretreated rats. SETTING: Laboratory of experimental medicine. SUBJECTS: Male Sprague-Dawley rats weighing 300 to 350 g. INTERVENTIONS: Modified, highly purified, and heat-pasteurized hemoglobin (diaspirin crosslinked hemoglobin) in control and yohimbine-treated (2 mg/kg i.v.) rats. MEASUREMENTS AND MAIN RESULTS: The systemic hemodynamics and regional circulation were measured using a radioactive microsphere technique. Diaspirin crosslinked hemoglobin (400 mg/kg i.v.) produced an increase in blood pressure and total peripheral resistance, while heart rate, cardiac output, and stroke volume were not significantly altered in control rats. In yohimbine-pretreated (2 mg/kg i.v.) animals, diaspirin crosslinked hemoglobin did not produce any change in heart rate, stroke volume, cardiac output, and total peripheral resistance, but a slight increase in blood pressure was observed compared with baseline values obtained after the administration of yohimbine. The increase in blood pressure induced by diaspirin crosslinked hemoglobin was significantly blocked by pretreatment with yohimbine. Yohimbine (2 mg/kg i.v.) per se decreased blood pressure, while other systemic hemodynamic parameters were not affected. Diaspirin crosslinked hemoglobin increased blood flow to the heart, gastrointestinal tract (stomach, small intestine, cecum, and large intestine), portal (spleen, mesentery, and pancreas) and skin, while blood flow to the brain (cerebral hemispheres, diencephalon, cerebellum, and brain stem), liver, kidneys, and musculoskeletal system was not affected in control rats. In yohimbine-pretreated animals, diaspirin crosslinked hemoglobin produced an increase in blood flow to the heart, brain (cerebellum and brain stem), liver, small intestine, cecum, spleen, mesentery and pancreas, kidneys, skin and musculoskeletal system, while blood flow to the stomach and large intestine was not affected. Yohimbine pretreatment significantly attenuated the diaspirin crosslinked hemoglobin-induced increase in blood flow to the large intestine, mesentery, and pancreas. CONCLUSIONS: The cardiovascular actions of diaspirin crosslinked hemoglobin are partially mediated through alpha 2-adrenergic receptors. Adrenergic receptor antagonists may be useful in attenuating the pressor effect of diaspirin crosslinked hemoglobin while maintaining the regional perfusion.

Animals↗
PubMed1995

Role of NO mechanism in cardiovascular effects of diaspirin cross-linked hemoglobin in anesthetized rats.

The role of nitric oxide (NO) in the cardiovascular actions of diaspirin cross-linked hemoglobin (DCLHb) was studied in anesthetized rats. The regional circulatory and systemic hemodynamic effects of DCLHb (400 mg/kg iv) were studied using a radioactive microsphere technique in control (untreated) and L-arginine (a NO precursor) pretreated rats. DCLHb produced a significant increase in blood pressure (75%), cardiac output (42%), stroke volume (36%), and total peripheral resistance (45%), without affecting heart rate, when administered to control rats. L-Arginine pretreatment significantly attenuated DCLHb-induced systemic hemodynamic effects. DCLHb-induced increase in blood flow to the skin and spleen was completely blocked, and that to the heart was partially blocked, by L-arginine pretreatment, suggesting that cardiovascular actions induced by DCLHb could be antagonized by the NO precursor L-arginine. The NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) produced significant increases in regional vascular resistance, leading to a decrease in blood flow to all the organs except the heart, where an increase in blood flow and a decrease in vascular resistance was observed. DCLHb, when administered in L-NAME-pretreated rats, accentuated the decrease in blood flow to the gastrointestinal system, spleen, mesentery and pancreas, skin, and musculoskeletal system. These studies provide evidence that the NO precursor L-arginine can attenuate the effects of DCLHb and that DCLHb can potentiate the effect of the NOS inhibitor L-NAME. The role of NO in the mechanism of action of DCLHb was further studied by estimating plasma guanosine 3',5'-cyclic monophosphate (cGMP) in control, DCLHb-treated, L-NAME-treated, and L-NAME followed by DCLHb-treated rats. DCLHb and L-NAME significantly decreased the concentration of circulating cGMP in blood plasma. L-NAME pretreatment potentiated DCLHb-induced decrease in cGMP levels. Because the formation of cGMP is stimulated by NO, these studies provide additional evidence for the involvement of NO in the mechanism of action of DCLHb. It is concluded that NO plays an important role in the cardiovascular effects of DCLHb.

Animals↗
PubMed1995

Changes in the concentration of endothelin-1 during development of hypertensive rats.

The concentration of endothelin-1 (ET-1) in the brain regions, heart, and throacic aorta of 1-, 4-, 6- and 8-week-old spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats was determined using radioimmunoassay. ET-1-like immunoreactivity in the brain regions of 1-week-old WKY and SHR rats was lower compared to older (6 and 8 weeks) rats. ET-1 levels in the central nervous system gradually increased with age in both SHR and WKY rats. However, the concentration of ET-1 in 8-week-old rats was lower in the brain regions of SHR compared to WKY rats. The concentration of ET-1 in the thoracic aorta of SHR (224 +/- 43 pg/g tissue) rats was lower than that of WKY (452 +/- 11 pg/g tissue) rats at 1 week of age. However, ET-1 levels gradually increased with age in SHR rats. By 8 weeks of age, levels of ET-1 in SHR (623 +/- 33 pg/g tissue) rats were higher compared to WKY (439 +/- 62 pg/g tissue) rats. In the heart, ET-1 levels were similar in WKY and SHR rats at 4 weeks of age, but at 8 weeks of age ET-1 levels were higher in SHR rats (364 +/- 33 pg/g tissue) compared to WKY rats (260 +/- 31 pg/g tissue). It appears that at 8 weeks of age when hypertension is fully expressed in rats, ET-1 levels are lower in the central nervous system and are higher in the thoracic aorta and heart of SHR compared to WKY rats.

Animals↗
PubMed1995

Role of endothelin-converting enzyme in the systemic hemodynamics and regional circulatory effects of proendothelin-1 (1-38) and diaspirin cross-linked hemoglobin in rats.

Diaspirin cross-linked hemoglobin (DCLHb) is a promising hemoglobin-based, oxygen-carrying resuscitative solution. DCLHb (400 mg/kg, iv) produces significant cardiovascular effects, along with an increase in plasma endothelin-1 (ET-1) level, when administered to conscious or anesthetized rats. Present studies were performed to determine whether the cardiovascular effects of DCLHb are due to an increase in the conversion of proendothelin-1 (1-38) (proET-1) to ET-1 by endothelin-converting enzyme (ECE). The regional circulatory and systemic hemodynamic effects of proET-1 (20 micrograms/kg, iv) and DCLHb (400 mg/kg, iv) were determined by using a radioactive microsphere technique in control rats and rats pretreated with phosphoramidon (ECE inhibitor). Administration of proET-1 produced an immediate increase in mean arterial pressure (MAP)(52%) and total peripheral resistance (TPR) (55%); stroke volume (SV) and cardiac output were not affected in the initial phase but were decreased subsequently. Heart rate (HR) was not affected after administration of proET-1. A significant increase in blood flow to the heart (39%), brain (46%), kidneys (74%), portal system (40%), and gastrointestinal tract (GIT) (42%) was also observed after administration of proET-1. Vascular resistance was found to be significantly increased in the mesentery and pancreas (168%) and in the musculoskeletal system (147%) and decreased in the kidneys (-11%) after administration of proET-1. Phosphoramidon (4 mg/kg, iv) pretreatment attenuated the increase in MAP and TPR induced by proET-1. Phosphoramidon pretreatment significantly attenuated the proET-1-induced increase in blood flow to the heart, brain, kidneys, portal system, and GIT. The increase in vascular resistance induced by proET-1 in the mesentery and pancreas and in the musculoskeletal system was also attenuated by phosphoramidon. DCLHb increased MAP (63%) and TPR (54%) without affecting HR. DCLHb increased blood flow to the heart (95%), GIT (45%), portal system (43%), and skin (79%) and increased vascular resistance in the musculoskeletal system (58%). In phosphoramidon-treated rats, DCLHb increased MAP (99%), HR (25%), cardiac output (37%), and TPR (60%). DCLHb increased blood flow to the heart (104%), brain (66%), kidneys (49%), GIT (59%), portal system (63%), and skin (100%) when administered to phosphoramidon-treated rats. Phosphoramidon did not attenuate any of the DCLHb-induced cardiovascular effects. It is concluded that proET-1 increases blood flow to various organs and that phosphoramidon, an ECE inhibitor, could block the proET-1-induced increases in regional blood flow.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Renal actions of endothelin-1 in newborn piglets: dose-effect relation and the effects of receptor antagonist (BQ-123) and cyclooxygenase inhibitor (indomethacin).

Although the effects of endothelin-1 (ET-1) on intact or perfused adult kidney are well understood, its effects in the fetus and the newborn have not been well studied. We examined the effects of infusions of 25, 50, and 100 ng/kg of ET-1 per minute on mean blood pressure (MBP), cardiac index (CI), renal blood flow (RBF), glomerular filtration rate (GFR), and urine volume (UV) in 7- to 10-day-old piglets (n = 24). In addition, the effects of pretreatment with a receptor antagonist (BQ-123) and with a cyclooxygenase inhibitor (indomethacin) were studied in 12 separate piglets. ET-1 produced a dose- and level-dependent decrease in CI (60%), RBF (50% to 75%), GFR (66% to 80%) and MBP 15% to 17%. These changes returned to 75% to 80% of baseline 60 minutes after discontinuation of ET-1. Low-dose infusion (25 ng/kg) did not result in any changes in systemic or renal hemodynamics. Plasma half-life of ET-1 in piglets was 2.1 +/- 0.4 minutes. Pretreatment with the specific ETA receptor antagonist BQ-123 completely blocked the ET-1-induced systemic and renal hemodynamic changes. Indomethacin blocked the ET-1-induced rise in MBP but failed to block any renal changes. In fact, indomethacin accentuated the changes induced by ET-1, especially the changes in RBF, RVR, and GFR. Studies of receptor binding in the renal cortex and medulla showed that, in the cortex, the Ki value for ET-1 was 6.32 +/- 1.57, and for ET-3 it was 20.05 +/- 4.38 (p < 0.05); in the medulla, the Ki values were similar for both ET-1 and ET-3. These results indicate that in piglets the renal vascular bed is highly sensitive to ET-1, and its effects are predominantly mediated through ETA receptors.

Animals↗
PubMed1995

Cardiovascular effects of centrally administered endothelin-1 in rats.

The effect of centrally administered endothelin-1 (ET-1) or IRL 1620 (5, 15, and 45 ng) on systemic hemodynamics was studied in anesthetized rats using a radioactive microsphere technique. Administration of saline (5 microliters, i.c.v.) did not product any significant cardiovascular effects. The lower doses of ET-1 (5 and 15 ng) did not produce any significant effect on blood pressure (BP), heart rate (HR), cardiac output (CO), stroke volume (SV), and total peripheral resistance (TPR). However, the highest dose (45 ng) produced a transient rise followed by a sustained fall in BP. The CO and SV decreased significantly, whereas HR and TPR were not affected. Pretreatment with BQ-123 (10 micrograms, i.c.v.) 15 min before administration of ET-1, completely antagonized the systemic hemodynamic effects of ET-1. Centrally administered IRL 1620, a specific ETB receptor agonist, did not produce any effect on BP, HR, CO, SV, and TPR in rats. It is concluded that ETA but not ETB receptors are involved in the central cardiovascular actions of ET.

Amino Acid Sequence↗
PubMed1995

Cocaine hydrochloride in poly(L-lactide) microspheres potentiates effects on the locomotion of rats+.

Stress-related effects can often interfere with studies of behavioral pharmacology in animals. This is known to occur where frequent dosing is required as in the study of drugs of abuse. A depot system capable of eliciting a pharmacodynamic response over an extended period would circumvent the need for frequent dosing. Cocaine hydrochloride was incorporated in 4.2 microns median diameter (geometric standard deviation 1.7) poly(L-lactide) microspheres at a concentration of 20% w/w. Seventy percent of the drug load was released in the period from 1-8 h. Studies of the locomotion of rats (n = 10/group) in an open field demonstrated a baseline movement of approximately 0.1 m/h after the intraperitoneal administration of microspheres in saline, or saline alone. Ten milligram of cocaine in saline increased the movement of rats to > 3 m/h for a period of 1 h following injection. The distance travelled by rats after administration of 10 mg of cocaine in microspheres was > 3 m/h for a period up to 6 h. Cocaine delivered in microspheres significantly increased the drug action (0.022 < p < 0.032). Particulate carriers were used to deliver small quantities of drug that overcame the need for multiple dosing of experimental animals to achieve extended behavioral effects.

Animals↗
PubMed1994

Effect of stroma-free hemoglobin and diaspirin cross-linked hemoglobin on the regional circulation and systemic hemodynamics.

The effects of unmodified stroma-free hemoglobin (SFHb) and diaspirin cross-linked hemoglobin (DCLHb) on the regional blood circulation and systemic hemodynamics were studied in rats using a radioactive microsphere technique. SFHb and DCLHb increased mean arterial blood pressure without affecting heart rate. SFHb produced a 24.9% decrease in the cardiac output while DCLHb produced an 44.8% increase in the cardiac output. Stroke volume was decreased (-27.3%) by SFHb and increased (+36.4%) by DCLHb. Total peripheral resistance increased with both SFHb and DCLHb. DCLHb increased blood flow to the heart, spleen, stomach, small intestine and skin, and had no effect on blood flow to the brain, kidneys, liver, mesentery, pancreas, caecum, large intestine and musculo-skeletal system. In contrast, in animals infused with SFHb, blood flow decreased to the kidneys, liver and spleen, increased to the heart, small intestine and skin, and had no effect to the brain, caecum, large intestine and musculo-skeletal system. DCLHb had no effect on vascular resistance in any organ except for an increase in the musculo-skeletal system. In contrast, SFHb increased vascular resistance in the kidneys, liver, spleen, skin, mesentery and pancreas, and had no effect on vascular resistance in the musculo-skeletal system, brain, heart, stomach, small intestine, caecum and large intestine. SFHb had no effect on distribution of cardiac output to the brain, gastrointestinal tract (GIT), kidneys, skin, musculo-skeletal and portal system, while DCLHb significantly decreased the percent cardiac output to the musculo-skeletal system. DCLHb did not affect the distribution of cardiac output to the brain, GIT, kidneys, skin and portal system. SFHb and DCLHb increased the percent cardiac output to the heart. It is concluded that similar concentrations and doses of DCLHb and SFHb produce different effects on the regional blood circulation and systemic hemodynamics.

Animals↗
PubMed1994

Prazosin blocks the pressor but not the regional circulatory effects of diaspirin crosslinked hemoglobin.

Diaspirin crosslinked hemoglobin (DCLHb) (400 mg/kg, i.v.) produces an increase in blood pressure and blood flow to the heart, spleen, stomach, small intestine, skin, mesentery and pancreas when administered to rats. The present study was conducted to determine (1) whether prazosin, an alpha 1-adrenergic antagonist, can block the pressor effect of DCLHb and (2) the effect of prazosin pretreatment on regional circulatory changes induced by DCLHb in rats. DCLHb (400 mg/kg, i.v.) produced an increase in blood pressure (64%), cardiac output (20%) and total peripheral resistance (65%) when administered to control rats. Infusion of DCLHb in prazosin (1 mg/kg, i.v.) treated rats did not show any significant pressor effect, but reversed the hypotensive effect of prazosin. Cardiac output and stroke volume were significantly increased and total peripheral resistance decreased in prazosin treated rats as compared to control (untreated) rats. DCLHb significantly increased blood flow to the heart, gastrointestinal tract, portal system (spleen), and skin of control rats. Blood flow to the brain, kidneys, and musculo-skeletal system was not altered following the infusion of DCLHb in controls rats. Infusion of DCLHb in prazosin treated rats produced a significant increase in blood flow to the brain, heart, kidneys, gastrointestinal tract, portal system, skin and musculoskeletal system. In summary, prazosin pretreatment blocked the pressor effect of DCLHb, however, blood flow to the heart, brain, gastrointestinal tract, portal system, kidneys, skin and musculoskeletal system was increased by DCLHb. It is concluded that blood flow to most of the organs is increased by DCLHb but the pressor effect of DCLHb is blocked by prazosin pretreatment.

Animals↗