Effects of taprostene, a chemically stable prostacyclin analogue, in patients with ischaemic peripheral vascular disease: a placebo controlled double-blind trial

Thirty patients with ischaemic peripheral vascular disease and intermittent claudication were randomly allocated to receive either placebo or taprostene, a chemically stable prostacyclin analogue, intravenously at a rate of 25 ng/kg/min for 6 hours daily on 5 consecutive days. Taprostene produced a significant (p less than 0.05) increase in absolute walking time compared to placebo on one day after infusion and at 1, 4 and 8 weeks (14% vs 2.8%) later. Taprostene also produced a significant (p less than 0.05) increase in the pain-free walking time compared to placebo in the follow-up period (8 weeks after infusion: 23% vs 3.8%). During the infusion period systolic and diastolic blood pressure decreased (p less than 0.05) and heart rate was accelerated (p less than 0.05) in the taprostene treated group whereas no change was monitored in the placebo group. The ankle/brachial Doppler index was unaffected by taprostene. The platelet half-life was significantly (p less than 0.05) prolonged following taprostene-infusion (72.6 +/- 9.35 vs 77.9 +/- 7.44 hours). However, no change on platelet half-life was found in the placebo group (p less than 0.05). Various measures of platelet function parameters followed in vitro (ADP-induced aggregation, platelet sensitivity to PGI2, PGE1, PGD1 and taprostene, concentrations of platelet factor 4 and beta-thromboglobulin) showed no change with taprostene. Measures of circulating platelet aggregates and endothelial cells count showed no changes during the 2 months follow-up period too. It is assumed that taprostene may be of clinical benefit in patients with ischaemic peripheral vascular disease. However, future investigations have to be carried out to assess the optimal dose regime.     

Small weight gain is not associated with development of insulin resistance in healthy, physically active individuals.

We investigated whether weight gain alters insulin sensitivity and leptin levels in physically active individuals. Six (5 males and 1 female; age 26.6+/-1.0 years; BMI 21.5+/-0.9, body fat 17.4+/-2.2%) healthy individuals were enrolled in an overfeeding study (caloric surplus 22.5-26.5 kcal/kg/day) to achieve up to 10% weight gain over 4-6 week period with subsequent weight maintenance over additional 2 weeks. The participants were requested to maintain their previous physical activity which in all of them included 45-60 min training sessions at the gym 2-3 times/week. RESULTS: BMI increased to 23.4+/-0.9 (4.4 kg weight gain; p<0.05) and body fat to 21.0+/-2.8% (p < 0.05) over the period of active weight gain and remained stable over the two week period of weight maintenance; fasting plasma glucose and serum insulin remained unchanged; serum leptin nearly doubled (3.8+/-1.0 vs 6.4+/-1.9 ng/ mL; p < 0.05); insulin sensitivity, when expressed per kg of the total body (11.1+/-1.6 vs 12.4+/-2.1 mg/kg/min; p = NS), and lean body mass (13.4+/-1.9 vs 15.7+/-2.6 mg/kgLBM/min; p = NS), did not decrease after weight gain. On the contrary, insulin action had improved in 5 out of 6 individuals. In conclusion, the data presented in this preliminary report indicate that a small weight gain due to overfeeding in lean, healthy, physically active individuals is associated with rise in circulating leptin levels but not with worsening of insulin action.     

Ciprostene, a stable prostacyclin analog, produces peripheral vasodilation, platelet inhibition and increased clot dissolution in the cat

The effect of the stable prostacyclin analog ciprostene on hemodynamic parameters, platelet aggregation and clot dissolution was examined in the sodium pentobarbital anesthetized cat. Hemodynamic and platelet aggregation effects were measured in 5 cats following infusion of 5, 10, 20, 40 and 80 micrograms/kg/min of ciprostene. Drug was dissolved in Tyrode's buffer (pH 7.4) and all doses were infused for 20 minute intervals in ascending order. The hemodynamic data were consistent with peripheral vasodilation. The total peripheral resistance and mean aortic pressure decreased with increasing dose. No change in heart rate, cardiac index, or left ventricle dP/dt (contractility) was observed. All doses infused produced inhibition of ADP induced platelet aggregation. In vivo fibrinolytic activity was assessed with an aortic thrombus positioned at the bifurcation of the aorta. Five cats were infused with vehicle and 5 cats each were infused with 8 and 20 micrograms/kg/min ciprostene respectively. All infusions were via a 4F catheter positioned in the aorta proximal to the thrombus. Infusion time was 3 hours. Infusion of 8 micrograms/kg/min did not enhance dissolution of the aortic thrombus. However, the 20 micrograms/kg/min infusion significantly reduced the thrombus weight (mean = 13.2 mg) compared to vehicle (mean = 38.7 mg) (p less than 0.03). The results suggest that ciprostene is a potent vasodilator and platelet inhibitor with clot dissolution properties.     

Age differences in renal response to atrial natriuretic peptide in rabbits

Plasma levels of atrial natriuretic peptide (ANP) and the effect of exogenous ANP on renal function have been studied in newborn and adult rabbits. In order to investigate an age difference in responsiveness to ANP, we studied the renal effects of alpha-human ANP (1-28) administered at the same dose per kg body weight in adult and neonatal rabbits. Plasma basal ANP levels were similar in 18 newborn (4- to 11-day-old) compared to 7 adult rabbits (150 +/- 16 and 151 +/- 28 pg/ml, resp.). Eleven newborn and 11 adult rabbits were anesthetized and mechanically ventilated. After a control period, each animal received an hANP loading dose (3 micrograms/kg i.v.), followed by an infusion of 0.3 micrograms/kg/min. Blood gases remained stable throughout the experiment in both groups. Mean blood pressure decreased in newborn (28.5 +/- 0.8 to 26.2 +/- 1.0 mmHg) and adult (92 +/- 3 to 84 +/- 3 mmHg) animals. Percent hANP-induced changes in renal functions in newborn and adult rabbits were, respectively: urine flow rate: -21 +/- 4% and +57 +/- 8%; urinary sodium excretion: +4 +/- 7% and +81 +/- 11%; glomerular filtration rate (GFR): -19 +/- 4% and -4 +/- 6%; renal blood flow (RBF): -22 +/- 4% and -11 +/- 5%. As expected, diuresis and natriuresis increased in adult rabbits. Failure of hANP to increase natriuresis and diuresis in newborn rabbits could be related to the marked decrease in GFR, receptor immaturity and/or interactions with other hormonal systems.     

Effects of atrial natriuretic factor on urinary concentration of catecholamines and renin secretion in dogs

This study evaluated the effects of synthetic atrial natriuretic factor (ANF) on renal hemodynamics, urinary excretion of electrolytes, norepinephrine (NE), and dopamine (DA); and renal production of renin in anesthetized dogs. Following a bolus (1 micrograms/kg body weight) and infusion (0.1 microgram/kg/min) for 30 min, there was significant increase in urine flow (220 +/- 41%), glomerular filtration rate (72 +/- 14%), and urinary sodium excretion (170 +/- 34%). There was a decrease in renin secretory rate and the concentration ratio of urine NE to DA following ANF was decreased (p less than 0.05). These data suggest that ANF decreases renal production of NE and renin.     

Role of antidiuretic activity in the inhibition of renin secretion by vasopressin in anesthetized dogs

The nature of the activity of vasopressin which is responsible for the inhibition of renin secretion was studied by comparing the effects of vasopressin (AVP) and analogs of AVP in anesthetized water-loaded dogs. Infusion of AVP (1.0 ng/kg/min) increased mean arterial pressure (MAP) and decreased heart rate (HR) and free water clearance (CH2O). Plasma renin activity (PRA) decreased from 11.9 +/- 4.7 to 3.8 +/- 1.7 ng/ml/3 hr (p less than 0.05). A selective antidiuretic agonist, 1-deamino-8-D-arginine vasopressin (1.0 ng/kg/min), which had no effect on MAP or HR but was effective as AVP in decreasing CH2O, decreased PRA from 13.5 +/- 4.6 to 7.0 +/- 2.9 ng/ml/3 hr (p less than 0.05). Infusion of a selective vasoconstrictor agonist, 2-phenylalanine-8-ornithine oxytocin (1.0 ng/kg/min), increased MAP and decreased HR but did not decrease CH2O or PRA. A vasoconstrictor antagonist, d(CH2)5Tyr(Me)AVP (10 micrograms/kg), completely blocked the MAP and HR responses to AVP but did not block the decrease in CH2O or PRA (5.9 +/- 1.8 to 2.9 +/- 1.6 ng/ml/3 hr) (p less than 0.001). Infusion of the 0.45% saline vehicle had no significant effect on MAP, HR, CH2O or PRA. These results indicate that the inhibition of renin secretion by vasopressin in anesthetized water-loaded dogs is due to its antidiuretic activity.     

The prostacyclin analogue taprostene and recombinant human superoxide dismutase increase the permanent survival rate of endotoxemic rats

The permanent survival rate of endotoxemic rats was studied. In 40 untreated control rats the survival rate 7 days after the endotoxin administration was 33%. The survival rate was increased to 40% with recombinant human superoxide dismutase (r-HSOD), to 55% (p less than 0.05) with the prostacyclin analogue Taprostene and to 70% (p less than 0.01) with the combination of r-HSOD and Taprostene (20 rats for each treatment group). r-HSOD and Taprostene provide significant and permanent protection in rat endotoxic shock.     

Renal effects of dopamine and dopexamine in the newborn anesthetized rabbit.

The renal effects of dopexamine, a new dopaminergic agonist with marked beta 2-adrenergic agonist properties, but no alpha-adrenergic effect, has been studied in 8 newborn New Zealand rabbits, whose renal functional characteristics show close similarities with those of premature infants. Six animals were used as controls. After a control period, dopexamine was infused intravenously at a rate of 4 micrograms/kg per min and after a wash-out period, at 10 micrograms/kg per min. The renal effects of dopamine were studied in similar conditions. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were determined by inulin and para-aminohippuric acid clearances, respectively. Dopexamine, 4 micrograms/kg per min, did not induce changes in cardiovascular and renal hemodynamics or in renal functions. At 10 micrograms/kg per min, a significant increase in urine flow rate (25 +/- 5%; p less than 0.01), urine sodium excretion (77 +/- 17%; p less than 0.01) and fractional sodium excretion (69 +/- 25%; p less than 0.05) was observed. The GFR, RPF and renal vascular resistance (RVR) were not affected. Heart rate increased slightly but significantly (8 +/- 3%; p less than 0.05), without change in mean blood pressure (MBP). Dopamine, 4 micrograms/kg per min, decreased slightly albeit significantly MBP (3 +/- 1%; p less than 0.05). At 10 micrograms/kg per min the only renal effect was a significant increase in RVR (19 +/- 6%; p less than 0.02). The different actions of these two dopaminergic agonists in this immature model could be explained by their respective ability to activate electively the adrenergic and dopaminergic peripheral receptors. The natriuretic and diuretic effect of dopexamine in normal immature rabbits, in the absence of changes in RPF or GFR is probably mediated by a direct action of this agent on dopaminergic tubular receptors. Failure of these two drugs to increase RPF may be related to an immaturity of the dopaminergic vascular receptors.     

Galanin inhibits rat pancreatic amylase release via cholinergic suppression.

The effects of galanin on pancreatic exocrine function were examined using rat pancreatic tissues. In anesthetized rats, galanin (40 micrograms/kg/h) decreased amylase secretion stimulated by 2-deoxy glucose (5.8 +/- 0.1 vs. 3.1 +/- 0.1 times basal) and cholecystokinin octapeptide (21.5 +/- 0.6 vs. 16.8 +/- 0.5), while not inhibiting bethanechol-stimulated secretion. In dispersed acini, there was no effect of galanin alone (10(-8) to 10(-13) M) on amylase release, nor did galanin (10(-6) or 10(-8) M) coincubation affect amylase release stimulated by bethanechol (10(-3) to 10(-7) M) or CCK-8 (10(-8) to 10(-13) M). Using pancreatic lobules, coincubation with galanin (10(-6) M) suppressed 75 mM KCl-stimulated amylase secretion and ACh release (10.1 +/- 0.6% vs. 7.3 +/- 0.4%). Veratridine-stimulated (10(-4) M) amylase secretion and ACh release (12.4 +/- 1.7% vs. 8.5 +/- 0.7%) were similarly diminished.     

Ciprostene, a stable prostacyclin analog, produces peripheral vasodilation, platelet inhibition and increased clot dissolution in the cat

The effect of the stable prostacyclin analog ciprostene on hemodynamic parameters, platelet aggregation and clot dissolution was examined in the sodium pentobarbital anesthetized cat. Hemodynamic and platelet aggregation effects were measured in 5 cats following infusion of 5, 10, 20, 40 and 80 μg/kg/min of ciprostene. Drug was dissolved in Tyrode's buffer (pH 7.4) and all doses were infused for 20 minute intervals in ascending order. The hemodynamic data were consistent with peripheral vasodilation. The total peripheral resistance and mean aortic pressure decreased with incresing dose. No change in heart rate, cardiac index, or left ventricle dP/dt (contractility) was observed. All doses infused produced inhibition of ADP induced platelet aggregation. In vivo fibrinolytic activity was assessed with an aortic thrombus positioned at the bifurcation of the aorta. Five cats were infused with vehicle and 5 cats each were infused with 8 and 20 μg/kg/min ciprostene respectively. All infusions were via a 4F catheter positioned in the aorta proximal to the thrombus. Infusion time was 3 hours. Infusion of 8 μg/kg/min did not enhance dissolution of the aortic thrombus. However, the 20 μg/kg/min infusion significantly reduced the thrombus weight (mean = 13.2 mg) compared to vehicle (mean = 38.7 mg) (p < 0.03). The results suggest that ciprostene is a potent vasodilator and platelet inhibitor with clot dissolution properties.     

Effect of the prostacyclin analogue iloprost in sodium-depleted rats pretreated with captopril.

Previous studies have shown that administration of captopril to sodium-depleted rats decreases the glomerular filtration rate (GFR) and blunts the increase in glomerular prostacyclin synthesis normally occurring in response to sodium depletion. To clarify the relationship between these two responses, iloprost, a stable analogue of prostacyclin, was administered to Na-depleted, captopril-treated (LNC) rats. At a dosage not affecting systemic blood pressure (12.5 ng/kg/min), iloprost increased GFR in LNC rats by 25% (from 0.26 +/- 0.03 to 0.35 +/- 0.03 ml/min/100 g body wt, P less than 0.01), without significant effects on renal plasma flow. No effect was observed in control rats. The results suggest that altered prostacyclin synthesis could contribute to the decrease of GFR in this model.     

Prostaglandins and control of breathing in newborn piglets

To investigate the possible role of prostaglandins in regulation of postnatal breathing, phrenic neural activity (PMO) was recorded as an index of breathing in 42 anesthetized, paralyzed piglets less than 30 days of age (weight 2.4 +/- 0.2 kg, age 9.9 +/- 1.5 days) who were mechanically ventilated with 100% O2 at a fixed tidal volume (8-10 ml/kg). End-tidal CO2 was held constant by an electronic servocontroller which adjusted ventilator rate; ventilator rate was monitored as an index of CO2 production. Rectal temperature was maintained at 39.0 +/- 0.2 degrees C. The effects on PMO of intravenous and brain ventricular injections of NaCl and agents active in the prostaglandin cascade were compared. Intravenous (0.25-1.0 mg/kg, n = 9) and brain (5-33 micrograms/kg, n = 6) indomethacin, a cyclooxygenase inhibitor, doubled PMO within 30 min. Intravenous (1-10 micrograms/kg, n = 6) and brain (1-40 micrograms/kg, n = 6) prostaglandin E1 inhibited PMO by one-half at 10 and 30 min.     

Effects of soman and its antidotes on tracheal mucociliary transport of ferrets

The purpose of this study was to examine the role of acetylcholinesterase on mucociliary transport by use of a potent anticholinesterase agent, soman, and potential antagonists, atropine (muscarinic antagonist) and pralidoxime (acetylcholinesterase reactivator). Initial measurements of mucociliary transport rate were obtained in anesthetized ferrets at 30-min intervals for 5.5 h. These rates remained constant at a mean of 18.2 +/- 1.0 (SE) mm/min. We studied the effects of intravenously administered soman (1-8 micrograms/kg) and observed a dose-related change in the rate of mucociliary transport [-1.1 +/- 2.7 (SE) mm/min after 1 microgram/kg, 9.8 +/- 2.9 mm/min after 5 micrograms/kg, and 14.4 +/- 4.3 mm/min after 8 micrograms/kg of soman]. Pretreatment with atropine completely prevented the response to soman, whereas pretreatment with pralidoxime did not significantly alter the response. We postulate that soman's effect on mucociliary transport relates directly to its cholinergic activity. Failure of pralidoxime to inhibit the effects of soman may relate to pralidoxime's inability to reactivate acetylcholinesterase successfully.     

Effect of thrombolysis on myocardial injury: recombinant tissue plasminogen activator vs. alfimeprase

Plasmin-dependent thrombolytic agents are potentially prothrombotic and proinflammatory. Alfimeprase, a zinc-containing metalloproteinase, degrades fibrin directly and achieves thrombolysis independent of plasmin formation. This study examines the hypothesis that thrombolysis in the absence of plasmin generation results in improved myocardial salvage on reperfusion. The thrombolytic effects of recombinant tissue plasminogen activator [rt-PA; 0.022 mg/kg, 1/10 of which was administered as a loading dose; the rest (9/10) was infused over 60 min by intracoronary (ic) administration] or alfimeprase (0.5 mg/kg over 1 min ic) were evaluated in a canine model of arterial thrombosis involving electrolytic injury of the left circumflex (LCX) coronary artery. Both agents induced thrombolysis, with onset of reperfusion being more rapid after alfimeprase compared with rt-PA (1.5 +/- 0.6 vs. 10.1 +/- 2.1 min). In the absence of adjunctive therapy, time to reocclusion after alfimeprase was 3.2 +/- 0.5 min compared with 77.5 +/- 31.9 min with rt-PA. The glycoprotein IIb/IIIa platelet receptor antagonist CRL-42796 prolonged reperfusion time after thrombolysis with alfimeprase or rt-PA. The effect of each lytic agent on myocardial infarct size was examined in a separate group of dogs subjected to 60 min of LCX coronary artery ligation and 4 h of reperfusion. Myocardial infarct size, expressed as percentage of the risk region, was larger (32.16 +/- 3.95%) after rt-PA compared with alfimeprase (19.85 +/- 3.61%) or that of the saline control group (18.46 +/- 3.34%). rt-PA in contrast to alfimeprase, a direct-acting fibrinolytic agent, is associated with an increase in myocyte reperfusion injury.     

Left ventricular catecholamines during acute myocardial infarction in the dog

To determine whether changes in left ventricular catecholamine content occur during the first 30 to 90 min of acute myocardial infarction, myocardial catecholamine (radioenzymatic assay) over the interval was studied in the dog. In nine pentobarbital-anesthetized opened-chest dogs without coronary ligation, myocardial catecholamine at 2.5 h after pentobarbital (i) consisted mainly of norepinephrine (87% total catecholamine), (ii) showed a base to apex gradient in norepinephrine (1.44 +/- 0.10 vs. 1.03 +/- 0.10 micrograms/g, p less than 0.05) and dopamine (0.20 +/- 0.03 vs. 0.12 +/- 0.02 micrograms/g, p less than 0.05) but not epinephrine (0.017 vs. 0.016 micrograms/g), and (iii) showed no difference in norepinephrine, dopamine, or epinephrine across basal, mid, and apical left ventricular transverse planes spanning the vascular territories of the two coronary arteries. In 18 pentobarbital-anesthetized dogs with coronary ligation, (i) norepinephrine, measured in 14 regions across the mid left ventricle after 90 min ischemia in four dogs, was less in the ischemic center of the occluded bed than normal myocardium (1.01 +/- 0.04 vs. 1.29 +/- 0.04 micrograms/g, p less than 0.05), and (ii) norepinephrine was unchanged in normal myocardium of 14 dogs at 30, 60, 90 min, and 48 h but decreased in ischemic myocardium by 31% at 60 min (0.89 +/- 0.10 vs. 1.29 +/- 0.08 micrograms/g, p less than 0.025) and 79% at 48 h (0.27 +/- 0.04 vs. 1.26 +/- 0.08 micrograms/g, p less than 0.001). Thus, norepinephrine depletion from ischemic but not normal myocardium is detectable by 60 min during acute myocardial infarction.     

Corticotropin-releasing factor inhibits the acute inflammatory response of rat pawskin to cold injury

The anti-inflammatory effects of human/rat corticotropin-releasing factor (CRF), a 41-residue peptide hormone, on an experimental model of cold injury were examined. Male albino rats were anesthetized with sodium pentobarbital 60 mg/kg ip and the paws immersed for 1 or 2 min in a 22% NaCl solution maintained at -20 +/- 0.5 degrees C. Swelling in response to cold was measured by changes in paw volume using the fluid displacement method, and protein leakages from blood vessels were measured using Evans blue and Monastral blue dyes. Thirty minutes after cold exposure the paw volume increased from 1.5 +/- 0.1 to 2.4 +/- 0.1 ml/paw and the Evans blue content increased from 4 +/- 1 to 178 +/- 9 micrograms/pawskin. These responses to cold were inhibited by 40 to 60% after CRF was injected 56 micrograms/kg sc 30 min before or 28 micrograms/kg iv 10 min before or 5 min after cold exposures. Microscopic studies of the skin showed that CRF reduced leakage of Monastral blue pigment from the vascular compartment into the walls of capillaries and venules. The anti-inflammatory effects of CRF were blocked by alpha-helical CRF(9-41), a CRF receptor antagonist, injected 92 micrograms/kg iv 5 min before and 15 min before cold exposure.     

Ciprofloxacin concentrations in serum, bone and bone marrow of rabbits

Ciprofloxacin concentrations were determined in serum, bone and bone marrow of rabbits. Four experimental groups of animals were examined: group A (n = 6) received a dosage of 60 mg/kg/day intramuscularly for 4 weeks, groups B (n = 6), C (n = 15) and D (n = 15) received dosages of 120 mg/kg/day subcutaneously for 2 days, 2 weeks, and 4 weeks, respectively. In the kinetic portion of the study, peak serum concentrations of ciprofloxacin measured at the 15 min sampling time were: 2.61 +/- 0.27 micrograms/ml in the 60 mg/kg/day group (group A) and 3.24 +/- 0.78 micrograms/ml in the 120 mg/kg/day group (group B). At necropsy, rabbits in group A had mean ciprofloxacin concentrations of 3.60 +/- 2.27 micrograms/ml in serum, 2.24 +/- 1.19 micrograms/g in marrow and 1.19 +/- 0.44 micrograms/g in bone. Rabbits in group B achieved mean levels of 4.02 +/- 1.23 micrograms/ml in serum, 2.48 +/- 0.79 micrograms/g in marrow, and 1.35 +/- 0.40 micrograms/g in bone. Rabbits in group C achieved mean levels of 5.65 +/- 2.16 micrograms/ml in serum, 3.74 +/- 1.33 micrograms/g in marrow and 1.92 +/- 0.94 micrograms/g in bone. Rabbits in group D achieved mean levels of 7.24 +/- 2.50 micrograms/ml in serum, 4.48 +/- 1.68 micrograms/g in marrow, and 1.93 +/- 0.54 micrograms/g in bone. Differences between mean values for the four experimental groups were not statistically significant.     

Mitigation of pulmonary hyperoxic injury by administration of exogenous surfactant

We studied the effects of surfactant supplementation on the progression of lung injury in rabbits exposed to 100% O2 for 64 h and returned to room air for 24 h. At this time, rabbits not treated with surfactant exhibit a severe lung injury with hypoxemia, increased alveolar premeability to solute, decreased total lung capacity (TLC) and lung edema. For surfactant treatment, 125 mg of calf lung surfactant extract (CLSE), suspended in 6-8 ml of normal saline, were instilled intratracheally at 0 and 12 h posthyperoxic exposure. At 24 h postexposure, these CLSE-treated rabbits compared with saline controls had significantly higher amounts of lung phospolipids (34 +/- 4 vs. 4.5 +/- 0.6 mumol/kg body wt) and increased TLC (42 +/- 2 vs. 27 +/- 1 ml/kg), with significantly lower amounts of alveolar protein (36 +/- 3 vs. 56 +/- 3 mg/kg) and decreased lung wet weight-to-dry weight ratios (5.6 +/- 0.1 vs. 6.3 +/- 0.3). Surfactant supplementation also decreased the degree of lung atelectasis as reflected by the increase in arterial O2 partial pressure (PaO2) after breathing 100% O2 for 20 min (PaO2 = 460 +/- 31 vs. 197 +/- 52 Torr). These findings indicate that instillation of exogenous surfactant mitigates the progression of hyperoxic lung injury in rabbits.     

Cardioprotective effect of prostacyclin and 7-oxo-PGI2 in rats against chronic isoproterenol damage

Isoproterenol (ISO) was injected in 5 mg/kg i.p. doses to rats, daily for two weeks. We evaluated the developed myocardial hypoxia and necrosis quantitatively by histological methods. To follow the time course of cardioprotection prostacyclin or 7-oxo-PGI2 were injected daily, i.p. 5, 30 min and 1, 2, 3, 4 hours before or after the ISO to groups of ten rats, respectively. Cardioprotection was defined as the reduction of necrotized areas and was expressed as percentage change compared to the control (saline treated) group. 1 microgram/kg PGI2 and 50 micrograms/kg 7-oxo-PGI2+ showed nearly equipotent cardioprotection (37.3-7.9% and 38.3-6.8%, respectively). The peak effect of both compounds appeared when injected prior to ISO in the 120. min but the action of 7-oxo-PGI2 was more prolonged. The different doses of prostacyclin analogs given after the ISO injection were ineffective with the exception of 50 micrograms/kg 7-oxo-PGI2 (29.75 +/- 5.2%).     

Enhanced vascular effects of the Ca(2+) channel agonist Bay K 8644 in pregnant rabbits

Hemodynamic studies were performed to determine if blunting of vascular pressor responsiveness to vasoconstrictors during pregnancy may be due to impaired L-type voltage-dependent calcium channels (L-VDCC). Bay K 8644 (BAY), an L-VDCC agonist, was infused in pregnant and nonpregnant anesthetized rabbits (10, 20, 40, and 60 microg/kg) and pregnant and nonpregnant conscious, chronically instrumented (conscious) rabbits (10, 25, and 50 microg/kg). BAY infusions resulted in greater elevation of mean arterial pressure in both anesthetized pregnant (n = 6) vs. nonpregnant (n = 6) (P < 0.05) and conscious pregnant (n = 10) vs. nonpregnant (n = 10) rabbits (P < 0.05). Fractional increase over baseline of total peripheral resistance index was greater in pregnant (36 +/- 5 to 78 +/- 14%) vs. nonpregnant rabbits (14 +/- 4 to 52 +/- 6%) (P < 0.02). Cardiac output index did not differ. There was a single high-affinity L-VDCC antagonist aortic binding site with similar number and affinity in pregnant (n = 7) and nonpregnant (n = 7) rabbits. In conclusion, stimulation of L-VDCC induces greater pressor responses in pregnant rabbits with heightened peripheral vasoconstriction. This does not appear to be due to a change in L-VDCC receptor parameters.