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Biomedical subjects

A M Lefer

Publications and source records attributed to A M Lefer.

At least 307 records · Page 17Linked to original sources
PubMed1983

Vascular responsiveness and eicosanoid production in diabetic rats.

Vascular responsiveness to vasoactive eicosanoids as well as vascular prostacyclin and thromboxane production was investigated in 7-10 weeks alloxan-diabetic rats. Aortic rings from diabetic rats exhibited increased responsiveness to carbocyclic thromboxane A2, a thromboxane analogue, when compared to control rat aortae. Isolated perfused hearts of diabetic rats showed increased vascular responsiveness to 9,11-methanoepoxy PGH2 (U-46619), an endoperoxide analogue. Diabetes resulted in a reduction in prostacyclin generation by isolated incubated aortae which was overcome by the addition of arachidonic acid but not by homogenization of incubated aortic tissue. In contrast, prostacyclin, but not thromboxane, generation was elevated in isolated perfused hearts of diabetic animals in response to moderate doses of arachidonic acid, but at high doses of arachidonate, more thromboxane was formed by perfused hearts of diabetic rats. These results suggest that different vessels can either increase or decrease their prostaglandin production in response to diabetes. The alterations in prostanoid production may be due to differential changes in prostacyclin and thromboxane synthesis in vessels which, in turn, may be related to the changes in vascular responsiveness.

Animals↗
PubMed1983

The protective effects of nifedipine in the isolated cat heart.

The calcium channel blocking agent, nifedipine, was studied during global ischemia and reperfusion in isolated cat hearts perfused with Krebs-Henseleit solution. Nifedipine was added to the reservoir and 0.1 micrograms/ml perfusate/hr of nifedipine was infused for 150 min. After 120 min of ischemia (flow at 1% of control), the heart was reperfused with nifedipine-containing perfusate for 20 min and with nifedipine-free perfusate for an additional 25 min. In control hearts, nifedipine significantly reduced the percent free activity of the lysosomal protease cathepsin D (P less than 0.01). In ischemic hearts, nifedipine protected against the increased myocardial tissue edema (P less than 0.01), the increased percent free cathepsin D activity (P less than 0.02) and the postreperfusion increased creatine kinase activity (P less than 0.01). Thus, nifedipine showed membrane stabilizing and cytoprotective activities in myocardial cells, after postischemic reperfusion. These data suggest that calcium ions contribute to the lysosome labilization and cytoplasmic enzyme leakage observed in ischemia and reperfusion, and that calcium channel blockade may protect myocardial cellular integrity during both ischemia and reperfusion.

Animals↗
PubMed1983

Studies on the mechanism of leukotriene induced coronary artery constriction.

Leukotriene (LT) C4, D4, and E4 at concentrations of 10 to 100 ng/ml were found to be potent coronary artery constrictors in the perfused cat coronary artery and perfused rat heart. In contrast, LTB4, was essentially inactive. The coronary constrictor effect of leukotrienes was not related to thromboxane release, but rather appeared to be due to a calcium mediated activation of specific leukotriene receptors.

Animals↗
PubMed1983

Modulation of circulatory responses to enkephalins by cyclooxygenase inhibitors.

1. Experiments were undertaken to examine the hemodynamic effects of intravenously administered leucine and methionine enkephalin and to determine if prostaglandin synthesis is involved in these responses. 2. Intravenous administration of leucine and methionine enkephalin (10, 30 and 100 micrograms/kg) resulted in a dose dependent and transient decline in mean arterial blood pressure in pentobarbital anesthetized cats. 3. A significant difference was observed, however, between the hemodynamic responses to leucine and methionine enkephalins before sodium meclofenamate (1 mg/kg) administration compared to post-meclofenamate induced hemodynamic changes. 4. This was confirmed with ibuprofen. 5. These findings indicate that cyclooxygenase inhibition modulates the circulatory responses to enkephalins. 6. Since cyclooxygenase is the first enzyme in the biosynthetic pathway of arachidonic acid, it is possible that prostaglandins, endoperoxides, thromboxanes or other prostanoids may be involved in mediating the circulatory responses to enkephalins.

Animals↗
PubMed1983

Prevention of extension of ischaemic damage following acute myocardial ischaemia by dazoxiben, a new thromboxane synthetase inhibitor.

1 Dazoxiben, a new thromboxane synthetase inhibitor, at an infusion rate of 5 mg/kg/h inhibited the ischaemia-induced increase in circulating thromboxane B2 in cats. 2 Dazoxiben also restored the S-T segment of the electrocardiogram toward normal values after the onset of ischaemia, and prevented the rise in plasma creatine kinase activity usually observed during myocardial ischaemia. 3 Associated with the above changes were reduced loss of myocardial creatine kinase activity and amino-nitrogen concentration in the ischaemic region of those cats treated with dazoxiben. 4 No significant effects of dazoxiben were observed on heart rate, mean arterial blood pressure or the product of the two, the pressure-rate index. Therefore, dazoxiben does not protect by reducing myocardial oxygen demand. 5 The mechanism of the protective action of dazoxiben in acute myocardial ischaemia seems to be either due to prevention of the constrictor and cytolytic actions of thromboxane A2 or to metabolic and cellular actions of dazoxiben unrelated to thromboxane synthetase inhibition.

Animals↗
PubMed1983

Responsiveness of platelets and coronary arteries from different species to synthetic thromboxane and prostaglandin endoperoxide analogues.

1--Platelet-rich plasma (PRP) from humans, cats, dogs (after addition of 10 microM adrenaline), rabbits and guinea-pigs aggregated in response to sodium arachidonate or 9,11-azo-prostaglandin H2, while PRP obtained from sheep was unresponsive to either agent. 2--The stable thromboxane (Tx) analogues, carbocyclic TxA2 (CTA2) and pinane TxA2 (PTA2) significantly inhibited these aggregatory responses in platelets from humans, dogs and guinea-pigs, while PTA2 but not CTA2 produced significant inhibition in cat platelets. The aggregatory response of PRP from rabbits was not significantly blocked by either analogue. 3--CTA2 and the endoperoxide analogue 9,11-methanoepoxy PGH2 (U-46619) constricted coronary arteries from cats, dogs, rabbits and guinea-pigs, while sheep vessels were unresponsive to either analogue. 4--Vasoconstrictor responses to U-46619 were significantly attenuated by PTA2 in vessels from all species. However, constriction produced by CTA2 was blocked significantly only in vessels from cats, dogs and guinea-pigs. 5--These results demonstrate the species differences which exist in the responsiveness of platelets and coronary arteries to thromboxane and endoperoxide analogues. Furthermore, the results illustrate the importance of species selection in the study of thromboxane antagonists for potential therapeutic use.

Animals↗
PubMed1983

Hyperreactivity of coronary vasculature in platelet-perfused hearts from diabetic rats.

Coronary vascular responsiveness to platelet-produced eicosanoids was examined in isolated perfused hearts of alloxan-diabetic rats. Coronary perfusion pressure was increased in isolated hearts of control and diabetic rats on perfusion with platelets and arachidonic acid (AA). However, the increase in perfusion pressure was approximately twofold higher in hearts of diabetic rats when compared with those isolated from control rats. This was associated with increased thromboxane B2 (TxB2) and prostaglandin F2 alpha (PGF2 alpha) production that was comparable in platelet-perfused hearts of control and diabetic animals. Ibuprofen, a cyclooxygenase inhibitor, blocked the increase in perfusion pressure and TxB2 and PGF2 alpha production by greater than 90% in both control and diabetic hearts perfused with platelets and AA. Dazoxiben, a thromboxane synthetase inhibitor, blocked the increase in perfusion pressure by 50%, totally inhibited TxB2 production, but increased PGF2 alpha production by 60% in both groups of platelet-perfused hearts. Increased levels of PGF2 alpha and possibly other constrictor eicosanoids (e.g., leukotriene D4) may account for the partial constriction observed in platelet-perfused hearts with dazoxiben. Results of the present study suggest that vascular reactivity to vasoconstrictor eicosanoids is increased in hearts of diabetic animals.

Animals↗
PubMed1983

Protective actions of ibuprofen in arachidonate-induced sudden death.

Sodium arachidonate given intravenously at a dose of 2 mg/kg is uniformly lethal in rabbits. Rabbits die within 2-5 min following a dramatic decrease in mean arterial blood pressure (MABP), and in circulating platelets, and a large increase in plasma thromboxane B2 (TxB2) concentration. The nonsteroidal anti-inflammatory agent, ibuprofen, given 15 min prior to challenge with sodium arachidonate, significantly protects against the abrupt decrease in MABP and in circulating platelets and prevents the increase in circulating TxB2 concentrations. These rabbits all survive the lethal effects of arachidonic acid when given ibuprofen at doses of 0.75, 6.25 or 12.5 mg/kg intravenously 15 min prior to arachidonate challenge. At 0.375 mg/kg, only 20% of the animals survive. Concomitant with survival is a significant attenuation of the decrease in MABP (84 +/- 8 mm Hg without ibuprofen vs. 1 +/- 1 to 33 +/- 12 mm Hg with 12.5-0.75 mg/kg ibuprofen). Similarly, these rabbits show a greatly reduced loss of circulating platelets, and virtually no increases in the formation of TxB2. Ibuprofen protects against arachidonate-induced sudden death in a dose-related manner. The mechanism of the protection appears to involve prevention of adherence or aggregation of platelets and the subsequent formation of thromboxane A2. The net result is prevention of pulmonary thrombosis, the major pathological event in triggering sudden death.

Animals↗
PubMed1983

Beneficial actions of nalorphine during hemorrhagic shock in cats.

Endogenous opiates have been reported to have detrimental effects on the circulatory system during hemorrhagic shock. However, the specific opiate receptor subtype which mediates these actions has not been defined. In the present study, we have utilized the mixed agonist/antagonist, nalorphine (N-allylnormorphine), which exhibits kappa (kappa) and sigma (sigma) receptor agonism as well as mu (mu) receptor antagonism, to investigate the role of the mu receptor in hemorrhagic shock. Nalorphine (2 mg/kg) produced no significant changes in any observed experimental variable in sham-shocked animals. Shocked animals treated with nalorphine (2 mg/kg) maintained significantly higher final mean arterial blood pressures (MABP) than animals which received only vehicle (102 +/- 3.8 vs 61 +/- 6.6 mm Hg, respectively, p less than 0.001). In addition, nalorphine significantly reduced the rise in plasma MDF activity observed in untreated hemorrhaged animals (42 +/- 3.0 vs 59 +/- 4 U/ml, p less than 0.02). Our results support a significant role for the mu receptor in the deleterious actions of endogenous opioids during hemorrhagic shock.

Animals↗
PubMed1983

Actions of opiate antagonists with selective receptor interactions in hemorrhagic shock.

The broad-spectrum opiate antagonist naloxone has been shown previously to reverse hypotension and improve survival in hemorrhaged animals. Three new opiate antagonists with different receptor affinities and activities were utilized to investigate the role of the "mu"- and "kappa"-receptors in hemorrhagic shock. Cats in hemorrhagic shock (40 mm Hg for 150 min) and shamshock controls were given J-7747 (delta-antagonist), C-7000 (delta-antagonist and k-agonist) or MR-2266 (k-antagonist). Shock cats given the delta-antagonist J-7747 had a significantly higher final MABP than cats given vehicle as did the cats given C-7000, the delta-antagonist k-agonist. However, the k-antagonist MR-2266 did not result in a significantly greater MABP than untreated hemorrhaged cats. Both J-7747 and C-7000 significantly prevented the increase in plasma MDF activity observed in untreated shock cats, but MR-2266 did not. These results indicate that opiate receptors other than at k-receptor sites are involved in the pathophysiology of hemorrhagic shock. Our findings also introduce the possibility of the therapeutic use of opiate antagonist-analgesics that induce analgesia via the kappa receptor.

Animals↗
PubMed1983

Effectiveness of ethylketocyclazocine in hemorrhagic shock.

The protective effect exerted by opiate antagonists in hemorrhagic shock appears to involve blockade of endogenous opioid substances at opiate receptors. The existence of several types of opiate receptors has been proposed. Previous work has shown that mu and delta opiate receptors may be involved in the shock process, but that k receptors appear not to be critically involved in the pathogenesis of shock. Administration of the potent k receptor agonist ethylketocyclazocine to hemorrhaged cats resulted in significant improvement in final mean arterial blood pressure and significant improvement in final plasma MDF activities compared to hemorrhaged cats given only vehicle. These data indicate that k receptor activation does not exacerbate the shock state, thus supporting the hypothesis that k receptors are not involved in the development of circulatory shock. Ethylketocyclazocine may act as an antagonist at the epsilon opiate receptor, indicating possible involvement of this receptor type in the pathogenesis of circulatory shock.

Animals↗
PubMed1983

Salutary effects of anisodamine in murine traumatic shock.

Anisodamine, an alkaloid originally extracted from the Chinese herb Anisodus tanguticus, has been reported to possess beneficial actions in septic, superior mesenteric artery occlusion, and hemorrhagic shock. We have investigated its actions in traumatic shock in rats. Anisodamine (2.5 mg/kg) increased survival time from 1.4 +/- 0.2 h to 3.1 +/- 0.3 h (P less than 0.001) in traumatized rats with 50% of the drug-treated animals surviving at least 3.5 h. Drug treatment had no significant effect on plasma cathepsin D activity (12.0 +/- 2.3 vs 10.4 +/- 1.7; vehicle- vs drug-treated, respectively). However, plasma myocardial depressant factor accumulation was significantly blunted by anisodamine, 62 +/- 5 vs 41 +/- 5 U/ml (P less than 0.02), indicating that prevention of MDF formation may be one protective mechanism of this substance.

Animals↗
PubMed1983

Cardioprotective actions of a selective thromboxane synthetase inhibitor in acute myocardial ischemia.

OKY-1581, a new thromboxane synthetase inhibitor, at an infusion rate of 1.5 mg/kg/hr inhibited the ischemia-induced increase in circulating thromboxane B2 in cats. Although OKY-1581 failed to restore the S-T segment of the electrocardiogram toward normal values after the onset of ischemia, it prevented the rise in plasma creatine kinase activity usually observed during myocardial ischemia. In addition, OKY-1581 reduced the loss of myocardial creatine kinase activity in the ischemic region of those cats treated with OKY-1581 indicating a significant cardioprotection. No significant effects of OKY-1581 were observed on heart rate, mean arterial blood pressure or the product of the two, the pressure-rate index. Therefore, this agent does not protect by reducing myocardial oxygen demand. The mechanism of the protective action of OKY-1581 in acute myocardial ischemia appears to be either due to prevention of the constrictor and cytolytic actions of thromboxane A2 or to metabolic and cellular actions of OKY-1581 unrelated to thromboxane synthetase inhibition.

Acrylates↗
PubMed1982

The pathophysiologic role of myocardial depressant factor as a mediator of circulatory shock.

Myocardial Depressant Factor (MDF) is a small peptide circulating in the blood of all mammalian species tested in a variety of shock states including endotoxic, hemorrhagic, cardiogenic, bowel ischemic, acute pancreatitis, burn, and traumatic shock. MDF is produced by the action of proteolytic enzymes released by the ischemic pancreas. MDF acts to depress myocardial contractility, constrict the splanchnic arteries and impair reticuloendothelial system phagocytosis. Several pharmacologic agents prevent the formation of MDF including membrane stabilizers (e.g., glucocorticoids), protease inhibitors (e.g., aprotinin), converting enzyme inhibitors (e.g., captopril), prostaglandins (e.g., PGE1 and PGI2), thromboxane synthetase inhibitors (e.g., imidazole, PTA2) and local anesthetics (e.g., lidocaine). Prevention of MDF formation or action improves survival. Thus, MDF is an important mediator of shock pathophysiology and should be considered in the therapy of circulatory shock states.

Animals↗
PubMed1982

Beneficial action of a new opiate antagonist (Win 44,441-3) in hemorrhagic shock.

The new opiate antagonist Win 44,441-3 (-)-isomer was infused intravenously in cats at a rate of 2 mg . kg-1 . h-1 to determine its effect in hemorrhagic shock. Hemorrhaged cats treated with Win 44,441-3 maintained post reinfusion mean arterial blood pressure (MABP) at a higher value compared to cats receiving only the vehicle. Final MABP was 70 +/- 11 mm Hg for cats receiving vehicle compared to 103 +/- 7 mm Hg for cats receiving Win 44,441-3. These values represent 60 +/- 9% and 85 +/- 6% of initial MABP for the vehicle- and Win 44,441-3-treated cats respectively. Win 44,441-2 (+)-isomer, the inactive stereoisomer of Win 44,441-3, was also infused at 2 mg . kg-1 . h-1 in cats subjected to hemorrhagic shock. The final pressure in this group was 72 +/- 8 mm Hg which is 61 +/- 8% of the initial pressure for this group. Win 44,441-3 and Win 44,441-2 were both ineffective in moderating increases in circulating lysosomal hydrolase activity in shocked cats. Neither isomer stabilized lysosomal membranes or retarded proteolysis in vitro. Plasma myocardial depressant factor was significantly reduced by the opiate antagonist, Win 44,441-3 during shock. Our results show that the systemic infusion of an opiate antagonist improves the hemodynamic state of cats subjected to hemorrhagic shock while the (+)-isomer which lacks opiate antagonist activity produces no such improvement.

Animals↗