Biomedical subjects

C A Sargent

Publications and source records attributed to C A Sargent.

At least 37 records · Page 2Linked to original sources

PubMed1996

Glyburide-reversible cardioprotective effects of calcium-independent phospholipase A2 inhibition in ischemic rat hearts.

OBJECTIVES: A myocardial calcium-independent PLA2 has been described that is activated during myocardial ischemia and this enzyme may modulate ATP-sensitive potassium channels (KATP). The aim of this study was to determine the effect of an inhibitor of this enzyme, a bromoenol lactone, in isolated globally ischemic rat hearts. METHODS: Isolated rat hearts were treated for 10 min with 0.3-6 microM bromoenol lactone and then subjected to 25 min ischemia and 30 min reperfusion. RESULTS: The bromoenol lactone significantly increased coronary flow in nonischemic myocardium, and slightly reduced cardiac function at 6 microM. During global ischemia, time to contracture was significantly increased from vehicle group values in the presence of the bromoenol lactone (EC50 = 1.2 microM). During reperfusion, a concentration-dependent increase in function and a reduction in LDH release were observed for the PLA2 inhibitor. The concentrations of the PLA2 inhibitor which were significantly cardioprotective, inhibited this enzyme in membrane fractions of rat myocardium (IC50 = 0.87 microM). The KATP blocker sodium 5-hydroxydecanoate (5-HD) inhibited the increase in time to contracture observed for the bromoenol lactone. During reperfusion, 5-HD abolished the protective effects of the bromoenol lactone on cardiac function and LDH release. Glyburide had similar effects on the cardioprotective activity of the bromoenol lactone, although it only partially abolished the LDH reducing effect of this agent. CONCLUSIONS: The bromoenol lactone protects ischemic myocardium at concentrations which also inhibit calcium-independent PLA2. This cardioprotection can be attenuated by blockers of KATP, suggesting a potential mechanism for modulation of myocardial KATP.

Animals↗

PubMed1996

Myocardial calcium-independent phospholipase A2 activity during global ischemia in isolated rabbit hearts.

OBJECTIVES: To study calcium-independent phospholipase A2 activity during global ischemia in isolated rabbit hearts by measuring the hydrolysis of the endogenous choline phospholipids. METHODS: Langendorff perfused rabbit hearts were exposed to global ischemia for 15 or 60 min, or control perfusion for the same length of time. The hearts were then rapidly frozen in liquid nitrogen and lyophilized. Calcium-independent phospholipase A2 activity in the lyophilized tissue was studied by measuring accumulation of lysophospholipids resulting from hydrolysis of both the choline diacylphospholipid and the choline plasmalogen pool. RESULTS: The calcium-independent phospholipase A2 activity showed the same pH, temperature and calcium sensitivity in control and ischemic (15 min of ischemia) lyophilized myocardial tissue. Incubation of control and ischemic tissue showed no difference in the rate of accumulation of lysophospholipids when the ischemic tissue was obtained from hearts exposed to 15 min of ischemia (107 +/- 4 vs 111 +/- 7 nmol/g dry wt x min, ischemia versus control, mean +/- s.e.m., n = 8), but a significant decrease was noticed in tissue from hearts that had been exposed to 60 min of ischemia (31 +/- 9 vs 86 +/- 18 nmol/g dry wt x min, P < 0.05, n = 4). The decreased phospholipase A2 activity in tissue exposed to 60 min of ischemia was not due to enhanced metabolism of the lysophospholipids (84 +/- 15 vs 79 +/- 8 nmol/g dry wt x min, n = 4). The calcium-independent phospholipase A2 activity was considerably lower in fresh myocardial tissue compared with lyophilized tissue, but comparison of control and ischemic fresh tissue gave results comparable to those found using lyophilized tissue. The myocardial calcium-independent phospholipase A2 activity showed no plasmalogen selectivity in either control or ischemic myocardium. CONCLUSIONS: In isolated perfused rabbit hearts we found no evidence for activation of calcium-independent phospholipase A2 activity during global ischemia. With prolonged time of ischemia there was a significant decrease in calcium-independent phospholipase A2 activity.

Animals↗

PubMed1996

Amelioration of ischemia/reperfusion injury in isolated rats hearts by the ATP-sensitive potassium channel opener BMS-180448.

OBJECTIVE: Aims of this study were: (1) Evaluate by morphology and specific physiological and biochemical parameters, the protective effects of the cardioselective ATP-sensitive potassium channel opener BMS-180448 on ischemic/reperfused isolated rat heart, and (2) Determine the earliest time point ischemia-induced myocardial injury is observed by light microscopy. METHODS: Hearts from Sprague-Dawley rats were perfused on a Langendorff apparatus. After equilibration, hearts were treated with BMS-180448 (10 micro M) or vehicle (0.04% DMSO) for 10 min before the onset of ischemia. Four hearts/group were collected following 10, 18, or 25 min of ischemia. A nonischemic control group was also evaluated. Following 25 min of ischemia, another set of hearts was reperfused with oxygenated Krebs-Hensleit solution and allowed to recover for 30 min. Light and electron microscopic changes of the myocardium were semi-quantitatively evaluated together with physiological (i.e., heart rate, left ventricular diastolic pressure, time to contracture formation) and biochemical (i.e., lactate dehydrogenase, LDH, release) endpoints. RESULTS: Cardioprotective effects of BMS-180448 following ischemia/reperfusion consisted of a reduced rate of contracture formation, reduced LDH release, and enhanced recovery of contractile function during reperfusion (P < 0.05). Light microscopic evidence of myocardial damage was detected following 18 min of ischemia. Morphological changes in ischemic/reperfused hearts included interstitial edema, myofiber degeneration, and hypercontraction band formation. Ultrastructurally, swollen myofibrils, swollen mitochondria with disrupted cristae and electron-dense deposits, myofibrillar lysis, and contraction bands, were observed. Light and electron microscopic severity scores were significantly less (P < 0.05) in BMS-180448-treated hearts at the 25 min ischemic time point and in reperfused hearts, as compared to similarly-treated vehicle hearts. CONCLUSIONS: BMS-180448 ameliorates morphological evidence of ischemia/reperfusion myocardial damage in the isolated rat heart model, in agreement with physiological and biochemical parameters.

Animals↗

PubMed1995

Cardioprotective profile of the cardiac-selective ATP-sensitive potassium channel opener BMS-180448.

ATP-sensitive potassium channel (KATP) openers have direct protective effects on ischemic myocardium that are independent of vasorelaxation. Because reference KATP openers (e.g., cromakalim, pinacidil) are potent relaxants of smooth muscle, their utility for treating myocardial ischemia may be limited by hypotension. Efforts aimed at development of a cardioprotective KATP opener with less vasorelaxant activity led to identification of the arylcyanoguanidine analogue BMS-180448. In globally ischemic rat hearts, BMS-180448 was cardioprotective (EC25 for increasing time to contracture = 2.5 microM), with potency equal to that of cromakalim (EC25 = 4.9 microM) despite being significantly less potent as a peripheral smooth muscle relaxant (methoxamine-constricted rat aorta). The cardioprotective effects of BMS-180448 in isolated perfused rat heart were abolished by the KATP blockers glyburide and sodium 5-hydroxydecanoate, indicating KATP involvement in its mechanism of action. Further confirmation was obtained by demonstration of single KATP opening by BMS-180448 in guinea pig cardiac myocytes. In anesthetized dogs, cromakalim was > 100-fold more potent than BMS-180448 in decreasing blood pressure (BP). In anesthetized dogs subjected to 90-min coronary occlusion/reperfusion, BMS-180448 reduced infarct size (IS) by 50% without hemodynamic effects. BMS-180448 provides the opportunity to explore the cardioprotective actions of this class of agents without the possible complications (hypotension, coronary steal) that may be caused by the currently available KATP openers.

Adenosine Triphosphate↗

PubMed1995

Effect of endothelin antagonists with or without BQ 788 on ET-1 responses in pithed rats.

The overall effects of endothelin-1 (ET-1) on blood pressure are caused by a composite activation of constrictor ETA and ETB receptors and dilator ETB receptors. Therefore, it is difficult to accurately compare the ETA activity of selective ETA receptor antagonists (BQ 123 and BMS 182874) with mixed ETA/ETB antagonists (SB 209670 and bosentan) on the cumulative dose-response curve to ET-1. The development of a selective ETB antagonist (BQ 788), which inhibits both the dilator and constrictor ETB receptors, offered the opportunity to investigate the role of ETB receptors in the response to exogenous ET-1 in the pithed rat. BQ 788 (3 mg/kg) resulted in an eightfold leftward shift in the ET-1 dose-response curve, suggesting a significant involvement of ETB dilator receptors. In the absence or presence of BQ 788, each ET antagonist evoked a rightward shift from vehicle. With the exception of BMS 182874, BQ 788 increased the magnitude of the shifts. Furthermore, the profile of the shifts changed from nonparallel to parallel in the presence of BQ 788. The inclusion of BQ 788 also altered the rank order of the ET antagonists tested. The results presented describe an in vivo system that accurately characterizes the ETA activity of ET antagonists.

Animals↗

PubMed1995

Sarafotoxin S6c elicits a non-ETA or non-ETB-mediated pressor response in the pithed rat.

Sarafotoxin S6c (Sx6c) is reported to evoke depressor and pressor effects via activation of endothelin (ET) ETB receptors located on the endothelium and smooth muscle, respectively. We have examined the effects of the selective ETB receptor antagonist BQ 788 on the fall and rise in diastolic blood pressure induced by Sx6c (1 nmol/kg, i.v.) in pithed rats. A dose-dependent reduction in both depressor and pressor response was observed. BQ 788 completely ablated the Sx6c-mediated fall in blood pressure at 1 mg/kg. In contrast, the pressor response was not completely abolished by 10 mg/kg BQ 788 (10 mg/kg: 16.5 +/- 3.0 mm Hg vs. control 49.0 +/- 2.5 mm Hg). Co-administration of the ETA receptor antagonist BQ 123 (1.5 mg/kg) with BQ 788 produced no further antagonism of the Sx6c-mediated pressor response. BQ 788 plus BQ 123 (1.5 mg/kg) totally blocked the pressor response to ET-1 (0.1 nmol/kg, i.v.) suggesting a difference in the mechanism of action between the two agonists. In conclusion, a portion of the Sx6c-induced pressor response is resistant to blockade by known ETA and ETB receptor antagonists. Whether Sx6c acts on a novel ET receptor or produces a nonspecific effect remains to be determined.

Animals↗

PubMed1994

The effect of alpha 2-adrenoceptor antagonists in isolated globally ischemic rat hearts.

The alpha 2-adrenoceptor antagonist, yohimbine, has been reported to protect hypoxic myocardium. Yohimbine has several other activities, including 5-HT receptor antagonism, at the concentrations at which protection was found. Therefore we designed a study to determine if yohimbine was protecting ischemic myocardium via antagonism of alpha 2-adrenoceptors. In isolated globally ischemic rat hearts, the effects of two structurally distinct classes of alpha 2-adrenoceptor antagonists, the indole alkaloids (yohimbine and rauwolscine) and the imidazolines (idozoxan and tolazoline) were investigated. Pretreatment with yohimbine (1-10 microM) caused a concentration-dependent increase in reperfusion left ventricular developed pressure and a reduction in end diastolic pressure and lactate dehydrogenase release. The structurally similar compound rauwolscine (10 microM) also protected the ischemic myocardium. In contrast, idozoxan (0.3-10 microM) or tolazoline (10 microM) had no protective effects. The cardioprotective effects of yohimbine were partially reversed by 30 microM 5-HT. These results indicate that the mechanism for the cardioprotective activity of yohimbine may involve 5-HT receptor antagonistic activity.

Adrenergic alpha-2 Receptor Antagonists↗

PubMed1994

Characterization of rabbit myocardial phospholipase A2 activity using endogenous phospholipid substrates.

We have developed an assay for studying myocardial phospholipase A2 activity by measuring accumulation of lysophospholipids resulting from hydrolysis of the endogenous choline glycerophospholipid pool. This assay was used to characterize phospholipase A2 activity in rabbit myocardium. Lyophilized rabbit myocardium was incubated at 37 degrees C in Tris-HCl buffer containing either ethylene glycol bis(beta-aminoethyl ether) N,N'-tetraacetic acid (EGTA)/EDTA or calcium, and palmitoyl-lysophosphatidylcholine (P-LPC), oleoyl-LPC, stearoyl-LPC, and 16:0-lysoplasmenylcholine were measured using a recently developed HPLC method. The identity of the individual species was confirmed by ion-spray LC-MS-MS. In the presence of EGTA/EDTA, incubation for up to 30 min caused a linear increase in all lysophospholipids. The main increases were found in P-LPC and 16:0-lysoplasmenylcholine, which increased by 37 +/- 3 (mean +/- SE, N = 8) and 48 +/- 3 nmol/g dry wt x min, respectively. The apparent phospholipase A2 activity was found to be calcium, temperature, and pH sensitive. The pH optimum was between 6.5 and 8.0, and incubation at room temperature and 45 degrees C decreased the activity by 80 and 40%, respectively. Studies of the metabolism of the formed lysophospholipids showed a substantial metabolism of the lysophospholipids that accounted for about 40% of the total phospholipase A2 activity. This method offers a novel approach to study phospholipase A2 activities by measuring accumulation of products resulting from hydrolysis of endogenous phospholipid pools.

Animals↗

PubMed1994

A rearrangement on chromosome 5 of an expressed human beta-glucuronidase pseudogene.

A novel transcript containing homology to exons 5, 9, 10, and 11 of the beta-glucuronidase gene has been shown to be derived from Chromosome (Chr) 5. In situ hybridization analysis has shown that this transcript is homologous to four loci on Chr 5 (5p13.3, 5p15.1, 5q13.1, and 5q15), two loci on Chr 6 (6p11.2 and 6p21.3), and one on Chr 22 at 22q11.2. Analysis of cosmid clones from Chr 5 has defined three distinct contigs in which there are tandem genomic repeats of a unit containing sequences homologous to exons 5, 9, and 10 but not 11. Pulsed-field gel electrophoresis (PFGE) analysis has shown that the length of these repeats is highly variable between unrelated individuals, indicating that these regions of Chr 5 are prone to rearrangement. These sequences may be important with respect to stability around the Chr 5 centromere.

Base Sequence↗

PubMed1994

Role of endothelin receptor subtype B (ET-B) in myocardial ischemia.

Previous work indicated that endothelin (ET) may be involved in the pathogenesis of myocardial ischemia, although the relative importance of the ET receptor subtypes is presently not clear. The purpose of this study was to determine the role of myocardial ET-B receptors in mediating ischemic/reperfusion damage in isolated rat hearts. Saturation binding analyses were conducted with [125I]ET-1 and [125I]IRL-1620 to assess changes in ET-A and ET-B receptor binding. Total ET receptor density (Bmax) was greater in atrial versus ventricular tissue. ET-A Bmax was 8 to 10-fold greater than ET-B Bmax. In ischemic and ischemic/reperfused atrial tissue neither the equilibrium dissociation constant (Kd) nor Bmax for ET-B receptors was changed. The ET-B receptor Kd in ischemic or ischemic/reperfused ventricular tissue was also unchanged. In ischemic ventricular tissue there was a trend towards an increased ET-B Bmax, which was accentuated after ischemia/reperfusion. No changes were found in ET-A Bmax or Kd in ischemic ventricular or atrial tissue. The physiological importance of this receptor subtype in ischemic myocardium was determined using the selective ET-B agonist, sarafotoxin S6c. In non-ischemic tissue no effect on coronary flow or function were observed with sarafotoxin S6c. Furthermore, no changes were seen in ischemic time to contracture or any of the reperfusion indexes of myocardial damage. The sarafotoxin S6c utilized was active as it inhibited [125I]ET-3 binding to ET-B receptors (Ki = 0.1 nM). Thus, the pro-ischemic effect of ET-1 seems to be mediated by ET-A receptors. ET-B receptors do not appear to play a role in the pathogenesis of myocardial ischemia.

Animals↗

PubMed1994

Characterisation of the novel gene G11 lying adjacent to the complement C4A gene in the human major histocompatibility complex.

Twelve transcriptional units have now been located in a 160 kb segment of DNA that includes the genes encoding members of the serum complement system C2, Factor B (Bf) and C4 within the class III region of the human major histocompatibility complex (MHC). The common arrangement of these genes is tel-C2-Bf-RD-G11-C4A-[P450c21A-YA-XA]-C4B-[P450c21B-YB ]-+ ++TNX-cen. Characterisation of cDNA and genomic clones corresponding to the novel gene G11 has revealed that the gene spans approximately 9.1 kb of DNA and is split into 7 exons. The 5' end of the gene is associated with a CpG-island while the 3' end of the gene lies 611 bp from the transcriptional start site of the C4A gene. The approximately 1.4 kb G11 mRNA, which is expressed in a number of different cell types including monocytes, hepatocytes, epithelial cells, T and B lymphocytes, encodes protein products of 254 or 258 amino acids due to differential use of two splice sites lying 12 bp apart at the end of exon 3. These polypeptides share homology with a limited number of proteins including human cytochrome P450XIB1 and the tyrosine kinase transforming protein from fujinami virus. Duplication of the C4/P450c21 transcriptional unit occurred by a nonhomologous recombination event. Sequence analysis of a 1.5 kb segment of DNA flanking the C4B gene has revealed that 914 bp of the 3' end of the G11 gene also lies 611 bp from the transcriptional start site of the C4B gene.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed1994

The glycerol kinase gene family: structure of the Xp gene, and related intronless retroposons.

The human glycerol kinase gene family consists of at least six genomic loci, four of which encode expressed sequences. The X-linked gene responsible for GKD maps to Xp21.3. Analysis of cosmid and YAC clones shows that this locus is in excess of 50 kbp, and is comprised of 19 exons. In contrast, the remaining members of the gene family, on chromosomes 1, 4 and Xq, appear to be organized as intronless genes. Northern analysis shows expression of GK transcripts of three sizes in a wide range of adult tissues. Only the smallest hybridizing species is present in testis where it occurs at an elevated level. Two different testis transcripts have been identified and both of these originate from chromosome 4.

Amino Acid Sequence↗

PubMed1994

Pyruvate increases threshold for preconditioning in globally ischemic rat hearts.

Isolated rat hearts can be protected by preconditioning, although this has not been found when they are perfused with pyruvate. We addressed the question of whether pyruvate could increase the threshold for preconditioning in isolated rat hearts and whether this could be overcome with increased durations of ischemia. A protocol of four periods of 5 min of ischemic preconditioning (4 x 5 min) protected hearts (improved recovery of function, reduced lactate dehydrogenase release) not perfused with pyruvate from a subsequent 30-min period of global ischemia, but did not protect pyruvate-perfused hearts. Pilot studies indicated that hearts perfused in the presence of pyruvate must be ischemic for approximately 40% longer to produce equivalent ischemic damage in nonpyruvate-treated hearts. Thus the preconditioning period of 5 min was increased by approximately 40% to 7 min to produce equivalent degrees of preconditioning. Hearts preconditioned with the 4 x 7 min protocol with pyruvate were significantly protected against a subsequent severe global ischemia (enhanced recovery of function, reduced lactate dehydrogenase release). High-energy phosphates were measured at the end of the preconditioning protocol (before final global ischemia) to determine whether there was a correlation between cardioprotection and high-energy phosphate levels. There was no correlation between ATP, ADP, or AMP levels and the efficacy of preconditioning. However, an increase in creatine phosphate was associated with cardioprotection, although the importance of this in mediating preconditioning is doubtful. Thus the ability to precondition rat hearts is somewhat dependent on their energy source, but this appears to be due to changes in the severity of the ischemic preconditioning event.

Animals↗

PubMed1993

Effects of endogenous and exogenous lysophosphatidylcholine in isolated perfused rat hearts.

In isolated Langendorff perfused rat hearts, treatment with exogenous palmitoyl-lysophosphatidylcholine (P-LPC; 3-50 microM) under normoxic conditions, resulted in reduced heart rate (HR), coronary flow (CF) and contractile function. After 30 min Krebs perfusion, following P-LPC infusion, HR and CF remained reduced and contractile function continued to deteriorate. End diastolic pressure (EDP) and lactate dehydrogenase (LDH) release in LPC treated hearts were significantly increased from controls. Myocardial lysophosphatidylcholine (LPC) levels after 25 min global ischemia were significantly higher than controls (463 +/- 10 for control vs 550 +/- 15 nmol/g dry wt for ischemia). Following 30 min reperfusion an increase from control was still observed (475 +/- 11 for control vs. 594 +/- 17 for ischemia+reperfusion). Analysis of molecular species of LPC demonstrated that palmitoyl, oleoyl and stearoyl were increased after 25 min ischemia. After 30 min of reperfusion only palmitoyl and stearoyl were significantly increased. After 25 min treatment with 3 microM P-LPC and 30 min normoxic perfusion, myocardial LPC was three-fold higher than after 25 min ischemia. Treatment with 0.2 microM exogenous P-LPC resulted in myocardial tissue LPC levels (562 +/- 23) equivalent to those seen after 25 min ischemia (550 +/- 15). Compared to time matched controls hearts perfused with 0.2 microM P-LPC displayed no significant reductions in contractile function nor increase in LDH release. Thus, in isolated rat hearts, the increase in LPC seen after 25 min of global ischemia may not solely mediate the contractile dysfunction and LDH release observed.

Animals↗

PubMed1993

Structure and expression analysis of a member of the human glutamate dehydrogenase (GLUD) gene family mapped to chromosome 10p11.2.

Glutamate dehydrogenase (GLUD) is a key metabolic enzyme of the mitochondrion, playing an important role in mammalian neuronal transmission. GLUD deficiency has been associated with certain forms of neurodegeneration in the human cerebellum. Genomic DNA blot hybridization analysis and identification of a large number of GLUD-specific genomic clones have suggested that human GLUD is encoded by a multigene family consisting of at least six members. A functional GLUD gene, GLUD1, has been mapped to chromosome 10q22.3-23 and a full-length "processed" GLUD gene, GLUDP1, to chromosome Xq22-23. In the context of studing the structure, the role, and the chromosomal organization of the other family members, we have analysed in detail, a cosmid clone solely reactive with the 3' region of the GLUD cDNA. Structure and expression analysis of its GLUD-specific region suggests that it represents a truncated "processed" GLUD pseudogene. Fluorescence in situ hybridization using the entire cosmid as a probe, mapped this GLUD gene locus, termed GLUDP5, to chromosome 10p11.2.

Amino Acid Sequence↗

PubMed1993

Cloning of the X-linked glycerol kinase deficiency gene and its identification by sequence comparison to the Bacillus subtilis homologue.

cDNA clones from a human adult testis cDNA library were isolated and sequenced as part of a programme to produce expressed sequence tags (ESTs). ESTs were used routinely to search DNA and protein sequence databases. One clone (142) showed 60% identity to the Bacillus subtilis glycerol kinase gene at both the DNA and amino acid sequence levels. Analysis of DNA from somatic cell hybrids carrying deleted X chromosomes, has shown that clone 142 detects homologous sequences between Xp21.2-p22.1 (the interval containing the locus responsible for glycerol kinase deficiency--GKD). These sequences are deleted in two patients with GKD. Clone 142 also detects homologous sequences on Xq and at several autosomal loci. The sequences of clone 142 and two further cDNA clones isolated from a human foetal brain cDNA library are presented.

Amino Acid Sequence↗

PubMed1993

Cardioprotective effects of the cyanoguanidine potassium channel opener P-1075.

P-1075 is a cyanoguanidine ATP-sensitive potassium channel opener (KATP) that relaxes smooth muscle and shortens myocardial action potential duration (APD) at concentrations in the nanomolar range. Most KATP openers have antiischemic potencies in the micromolar range. We wished to determine if the relatively high cardiac potency of P-1075 could be translated into high antiischemic potency. Isolated rat hearts were pretreated with 10-300 nM P-1075 followed by 25-min global ischemia and 30-min reperfusion. Before ischemia, P-1075 had little effect on cardiac function, although it did increase coronary flow. During ischemia, P-1075 significantly increased time to contracture in a concentration-dependent manner (EC25 = 57 nM). P-1075 also improved recovery of contractile function significantly and reduced lactate dehydrogenase (LDH) release during reperfusion (at concentrations > or = 60 nM). Treatment with 75 nM P-1075 both before and after ischemia did not add to the protective effects observed after preischemic treatment. Treatment with P-1075 only during reperfusion was not cardioprotective. The protective effects of P-1075 were completely abolished by the KATP blocker glyburide (100 nM). In addition, P-1075 relaxed methoxamine-constricted aorta with a higher potency relative to antiischemic potency. Thus, P-1075 has cardioprotective effects similar to that of other reference KATP openers, except that P-1075 is approximately 100-fold more potent relative to most other tested KATP openers. These results demonstrate that P-1075 is the first KATP opener that protects ischemic myocardium at nanomolar concentrations.

Animals↗

PubMed1993

Protective effect of serotonin (5-HT2) receptor antagonists in ischemic rat hearts.

Serotonin (5-HT) may play a role in exacerbating thrombosis and coronary spasm during myocardial ischemia, but its role in mediating myocardial damage directly is not clear. We determined the effect of the 5-HT2 receptor antagonists cinanserin (0.1-10 microM), ketanserin (0.3-10 microM), and LY 53857 (1-10 microM) on time to contracture, recovery of contractile function, and lactate dehydrogenase (LDH) release after 25-min global ischemia and 30-min reperfusion in isolated rat heart. All 5-HT2 antagonists significantly increased time to contracture in a concentration-dependent manner (EC25 = 1.6, 5.5, and 6.1 microM for cinanserin, ketanserin, and LY 53857, respectively). These compounds also significantly reduced LDH release and improved recovery of contractile function during reperfusion. 5-HT > or = 30 microM significantly reduced time to contracture, indicating a proischemic effect. The proischemic effect of 5-HT was abolished by ketanserin and cinanserin. Inhibition of 5-HT synthesis by parachlorophenylalanine resulted in significant cardioprotection, further indicating the involvement of 5-HT in the pathogenesis of ischemia in this model. Although cinanserin and ketanserin had alpha 1-adrenoceptor blocking effects, LY 53857 was devoid of this activity at concentrations exhibiting cardioprotection. Therefore, 5-HT may exacerbate ischemic injury in rat heart, and this exacerbation appears to be mediated specifically by 5-HT2 receptors.

Animals↗