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Biomedical subjects

D N Harris

Publications and source records attributed to D N Harris.

At least 55 records · Page 3Linked to original sources
PubMed1988

Antithrombotic effects of the thromboxane A2 antagonist, SQ 28,668, in vitro and in the coronary circulation in vivo.

SQ 28,668 is a thromboxane receptor antagonist. In whole blood and platelet-rich plasma, micromolar concentrations of SQ 28,668 inhibited aggregation of human and porcine platelets induced by arachidonate and U-46,619, and the secondary phase of epinephrine-induced aggregation of human platelets. SQ 28,668 did not inhibit ADP-induced platelet aggregation and did not influence cAMP concentrations. High concentrations of SQ 28,668 inhibited platelet thromboxane synthase (IC50 = 660 microM), but SQ 28,668 did not inhibit cyclooxygenase or prostacyclin synthetase. In anesthetized pigs with pacing-induced tachycardia, placement of a critical stenosis at a focus of coronary vascular injury initiated a reproducible pattern of coronary blood flow reduction, reflecting thrombus formation at the site of injury. Treatment with SQ 28,668 (1.0 mg/kg, i.v.) abolished reductions in coronary blood flow in five of six pigs for 58 +/- 7 min and slowed the rate of blood flow reduction in the sixth. Before SQ 28,668 treatment, the rate of blood-flow reduction averaged 5.3 +/- 0.7 ml/min per min. Thirty and sixty minutes after treatment, the rates of blood-flow reduction averaged 0.6 +/- 0.6 and 2.1 +/- 1.0 ml/min per min, respectively (P less than 0.05). In control pigs, the rate of blood flow reduction before and 30 min after vehicle treatment averaged 5.7 +/- 2.0 and 5.5 +/- 1.6 ml/min per min, respectively (not significant). These findings indicate that SQ 28,668 is an effective antiplatelet agent in vitro and in vivo.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1988

Characterization of [5,6-3H]SQ 29,548 as a high affinity radioligand, binding to thromboxane A2/prostaglandin H2-receptors in human platelets.

The binding of 5,6-3H(1S-[1 alpha, 2 beta(5Z), 3 beta, 4 alpha])-7-[3-([2-[(phenyl amino)carbonyl]hydrazino]methyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5- heptenoic acid to receptors in human washed platelets (WP) and platelet membranes (PM) was characterized with regard to kinetics, saturability and competitive inhibition by putative thromboxane A2/prostaglandin H2 (TP)-receptor ligands. Specific binding of [3H]SQ 29,548 routinely amounted to 90 to 97% of total binding. The rate of association was 1.6 x 10(7) and 2.5 x 10(7) M-1 x min-1 in WP and PM, respectively. The corresponding rate of dissociation was 0.07 and 0.12 min-1, resulting in dissociation constants of 4.1 and 5.8 nM in WP and PM, respectively. Saturable binding to a single class of receptors indicated a receptor density of 2633 fmol/mg of protein in WP (1394 receptors/platelet; kd, 4.5 nM) and 1466 fmol/mg of protein in PM (kd, 11.3 nM). Specific binding of [3H]SQ 29,548 was inhibited by five antagonists (high/low affinity kd values in nanomolar), SQ 29,548 (WP, 5.2; PM, 7.3), SQ 28,668 (WP, 32; PM, 73), SQ 30,741 (WP, 28; PM, 50), BM 13,177 (WP, 140; PM, 4834) and BM 13,505 (WP, 5/379; PM, 11). Two agonists, U 44069 and U 46619, inhibited the binding in a biphasic manner, indicating binding to two receptor sites (approximately 20/80%) with kd values of 4/72 and 4/170 nM, respectively, in WP and 7/136 and 19/502 nM, respectively in PM. The demonstrated high affinity binding of [3H]SQ 29,548 to human platelet TP-receptors should make this radioligand a suitable and potentially useful tool in future studies of function, structure and regulation of TP-receptors.

Binding Sites↗
PubMed1987

Effects of captopril on sympathetic control of the heart and vasculature in dogs.

Experiments were conducted in pentobarbital anesthetized dogs to investigate the effects of captopril on sympathetic neuronal control of the heart and hindlimb vasculature. Captopril, 3.1 mg/kg, i.v. produced marked reductions in blood pressure and hindlimb perfusion pressure, an observation consistent with the high plasma renin activity in the test animals. Increments in hindlimb perfusion pressure elicited by electrical stimulation of the lumbar sympathetic chain were also significantly reduced following captopril administration (p less than .002). The subsequent administration of a ten fold higher dose of captopril, 31.0 mg/kg, produced no further attenuation of the neurally mediated responses. In contrast to the decreased vascular responses to nerve stimulation after captopril, the tachycardia produced by stimulation of pre- or post-ganglionic neurons to the stellate ganglion were not altered. The results of the present study suggest that captopril acts by inhibiting vascular sympathetic neuronal function when the activity of the renin-angiotensin system is elevated. The attenuation of neurally mediated vasoconstriction may be due to the interruption of angiotensin II formation, thereby, preventing the facilitatory effects of angiotensin on sympathetic neurons.

Animals↗
PubMed1987

7-Oxabicycloheptane analogs: modulators of the arachidonate cascade.

Small structural changes in a series of 7-oxabicyclo[2.2.1]heptyl acids have produced four types of agents that modify the actions of TXA2 and PG. We showed that SQ 26,655 is a TXA2 receptor agonist, SQ 28,668 and SQ 29,548 are TXA2 receptor antagonists, SQ 28,852 is a CO inhibitor, and SQ 27,986 is a PGI2/PGD2 agonist. SQ 30,077 bound reversibly with high affinity to one site in human platelet membranes. The specific binding of SQ 30,077 is competitively inhibited by the identified TXA2 receptor agonists and antagonists with an order of affinity that correlates well with their functional potencies. SQ 27,986, PDG2 and SQ 28,852 show marginal affinity, indicating that their biological actions are not mediated via the TXA2 receptor.

Arachidonic Acid↗
PubMed1987

Effect of thromboxane receptor antagonists on renal artery thrombosis in the cynomolgus monkey.

The effect of the thromboxane (Tx) A2-receptor antagonists SQ 28,668 and SQ 30,741 on platelet function and renal artery thrombosis was studied in the dialurethane-anesthetized cynomolgus monkey. Both antagonists competitively inhibited the aggregation of platelet rich plasma in vitro to arachidonic acid and U-46,619, a Tx-mimetic. SQ 30,741 was 4 to 7 times more potent than SQ 28,668 against either of these agonists. Thrombotic cyclical blood flow reductions (CFRs) were elicited by placing a critical stenosis at a crush injury site on the left renal artery. After allowing 10 consecutive CFRs, of which 95% required shaking of the vessel to restore flow, a single i.v. injection of either SQ 28,668 (1 mg/kg, n = 6), SQ 30,741 (1 mg/kg, n = 8) or vehicle (2 ml of 0.2% Na2CO3 + 10% ethanol, n = 4) was administered. Antithrombotic activity was defined as the spontaneous restoration of flow and was accompanied by a reduction in the rate of flow decline during the CFRs. Spontaneous flow restoration was observed in animals treated with SQ 28,668 (five of six) and SQ 30,741 (six of eight) but not vehicle (zero of four). The rate of flow decline was reduced only with SQ 28,668 (56 +/- 8%) and SQ 30,741 (53 +/- 10%) treatments. The antithrombotic activities of SQ 28,668 and SQ 30,741 lasted 68 +/- 6 and 224 +/- 21 min, respectively. The threshold antithrombotic dose was found to be lower for SQ 30,741 (0.20 +/- 0.03 mg/kg) than SQ 28,668 (0.61 +/- 0.09 mg/kg) in additional experiments.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Inhibition of prostaglandin biosynthesis by SQ 28,852, a 7-oxabicyclo[2.2.1]heptane analog.

7-Oxabicyclo[2.2.1]heptane analogs of prostaglandin (PG) H2 can act as thromboxane (Tx) A2 receptor antagonists or agonists, PGI2 and/or PGD2 receptor agonists, or exhibit a mixture of the above activities. SQ 28,852, a new analog with a hexyloxymethyl omega side chain, is a potent inhibitor of PG synthesis. SQ 28,852 inhibited collagen and arachidonic acid (AA)-induced platelet aggregation and TxB2 and PGE2 formation, but did not block platelet aggregation induced by ADP or the TxA2 mimics, 9,11-azo PGH2, SQ 26,655, and U-46,619. It also blocked conversion of AA to TxB2, PGE2, and 6-keto PGF1 alpha by microsomal preparations of human platelets, bovine seminal vesicles, and bovine aortas, respectively, but did not inhibit the conversion of PGH2 to TxA2 by the platelet microsomal preparation. SQ 28,852 (p.o.) protected mice against the lethal effects of AA (75 mg/kg, i.v.). The I50 values for SQ 28,852, indomethacin and aspirin were 0.025, 0.05 and 15 mg/kg, respectively. Neither SQ 28,852 nor indomethacin protected mice from death caused by 9,11-azo PGH2. SQ 28,852 (0.01 to 1 mg/kg, i.v.) inhibited AA-induced bronchoconstriction in anesthetized guinea pigs for at least 60 min. As an inhibitor of AA-induced bronchoconstriction, SQ 28,852 was 16- and 45-times more potent than indomethacin at 3 and 60 min after i.v. administration, respectively. SQ 28,852 did not inhibit bronchoconstriction induced by histamine or 9,11-azo PGH2, indicating its specificity of action in vivo. SQ 28,852 is the first example of a new class of cyclooxygenase inhibitors whose structure is similar to that of the naturally occurring endoperoxide, PGH2.

Animals↗
PubMed1986

9,11-Epoxy-9-homo-14-oxaprosta-5-enoic acid derivatives. Novel inhibitors of fatty acid cyclooxygenase.

A novel bicyclic prostaglandin analogue, [1R-[l alpha,2 beta (5Z),3 beta,4 alpha]]-7-[3-[(hexyloxy)methyl]- 7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (1), and cogeners were found to be potent inhibitors of fatty acid cyclooxygenase. Compound 1 was the only stereoisomer out of eight possible structures that was active. Ether 1 was 20 times more potent than indomethacin (IND) in inhibiting arachidonic acid (AA) induced aggregation of human platelet-rich plasma. Compound 1 was also more potent than IND in several in vivo assays, AA-induced sudden death in the conscious mouse (2 times) and AA-induced bronchoconstriction in the anesthetized guinea pig (16-45 times).

Arachidonic Acid↗
PubMed1985

Synthesis and in vitro pharmacology of 7-oxabicyclo[2.2.1]heptane analogues of thromboxane A2/PGH2.

A series of chemically stable TXA2/PGH2 analogues modeled after the structure of the natural products was prepared in search of useful inhibitors of TXA2/PGH2-mediated pathophysiology. Each of the 16 isomers implied in structure 1 was prepared in chiral form and evaluated for activity in vitro in platelets and smooth muscle. Depending on relative side chain and carbinol stereochemistry, TXA2/PGH2 agonist and antagonist and, surprisingly, PGD2/PGI2 agonist activities were observed. The enantiomers possessing the alpha heterocycle shown in 1 were generally more potent than their mirror-image isomers.

Animals↗
PubMed1985

Pharmacological actions of SQ 29,548, a novel selective thromboxane antagonist.

SQ 29,548, [1S-[1 alpha,2 beta (5Z),3 beta,4 alpha]-7-[3-[[2-[(phenylamino) carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1] hept-2-yl]-5-heptenoic acid, and the racemic modification, +/- SQ 29,548, were identified as active inhibitors of human platelet aggregation induced by arachidonic acid, collagen, epinephrine (2 degrees phase) and the thromboxane A2 mimics, 9,11-azo prostaglandin (PG) H2 and 11,9-epoxymethano PGH2. SQ 29,548 did not inhibit aggregation induced by ADP, and it did not prevent PGD2 from inhibiting ADP-induced platelet aggregation. Inhibition of platelet function by +/- SQ 29,548 was not associated with inhibition of cyclooxygenase or thromboxane synthetase or with changes in platelet cyclic AMP. In guinea-pig trachea and rat aorta, +/- SQ 29,548 competitively antagonized the activity of 9,11-azo PGH2 with pA2 values of 7.8 and 8.4, respectively. The chiral compound, SQ 29,548 competitively antagonized contractions of guinea-pig tracheal spirals caused by 11,9-epoxymethano PGH2 with a pA2 value of 9.1. The +/- SQ 29,548 competitively antagonized tracheal responses to 11,9-epoxymethano PGH2 and PGD2 with pA2 values of 8.2 and 8.3, respectively, indicating that PGD2 and the thromboxane A2 mimic probably act at the same receptor in guinea-pig tracheal smooth muscle. Contractions of guinea-pig tracheal spirals induced by PGE2 were not antagonized, and those caused by PGF2 alpha were only partially antagonized by +/- SQ 29,548. The +/- SQ 29,548 also significantly inhibited the aorta contracting activity of 11,9-epoxymethano PGH2 (pA2 = 9.1) and thromboxane A2 released from perfused guinea-pig lungs upon arachidonic acid challenge.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1984

Effects of SQ 27,427, a thromboxane A2 receptor antagonist, in the human platelet and isolated smooth muscle.

The TxA2 receptor antagonist properties of SQ 27,427 [a cyclohexylcarbinol-7-oxabicyclo(2.2.1)heptenoic acid analog] were studied in vitro both in the human platelet and various isolated smooth muscle preparations. SQ 27,427 was found to be a potent inhibitor of human platelet aggregation induced by arachidonic acid, ADP, epinephrine, collagen and the stable TxA2 agonists 9,11-azoPGH2 and SQ 26,655. Inhibition of platelet aggregation was achieved at concentrations of SQ 27,427 which did not alter TxB2 levels. SQ 27,427 was found to weakly inhibit the formation of TxB2 from arachidonic acid and had no effect on the synthesis of PGE2 or PGI2 from arachidonic acid. SQ 27,427 was also found to be a weak stimulator of platelet adenylate cyclase, being 1000 times less potent than PGI2. In isolated smooth muscle experiments, SQ 27,427 was shown to be a potent and specific TxA2 receptor antagonist. It caused competitive antagonism of 9,11-azoPGH2-induced contractions of vascular, respiratory and gastrointestinal smooth muscles. This antagonism was specific, as responses to norepinephrine, serotonin, PGE2, PGI2, PGF2 alpha, histamine, carbachol and KCl were not altered by SQ 27,427.

Adenylyl Cyclases↗
PubMed1984

Thromboxane receptor antagonist properties of SQ 27,427 in the anesthetized guinea pig.

The TXA2 receptor antagonist properties of SQ 27,427 (a novel oxabicyclo[2.2.1]heptane derivative) were studied in vivo in the anesthetized guinea pig where changes in pulmonary resistance, dynamic compliance, and mean arterial blood pressure were measured. Both the bronchoconstrictor and pressor responses to arachidonic acid (AA) and to the stable TXA2 mimic 9,11-azoPGH2 (AZO) were taken as indices of in vivo TXA2 receptor activation. The administration of SQ 27,427 (0.1-1.0 mg/kg i.v., and 10.0 mg/kg p.o.) caused dose-related inhibitions of both AA- and AZO-induced bronchoconstriction. Relative specificity of this antagonism was evidenced by the failure of SQ 27,427 (1.0 mg/kg i.v.) to inhibit histamine-induced bronchoconstriction. In the same experiments the pressor response to AA was reversed to a depressor response by SQ 27,427. This reversal was abolished by indomethacin. The pressor response to AZO was antagonized by SQ 27,427, but not by indomethacin. The reversal of the pressor response to AA by SQ 27,427 may be due to the unmasking of the depressor effect of a cyclooxygenase product, i.e., prostacyclin. It is concluded that SQ 27,427 is a relatively specific TXA2 receptor antagonist in vivo in the guinea pig.

Airway Resistance↗
PubMed1982

Radionuclide evaluation of valvular regurgitation.

A non-invasive nuclear medicine technique for the assessment of aortic and mitral regurgitation may be of importance in the management of patients with valvular disease. Rigo et al (1979) introduced a method based on measuring the ratio of the left ventricular stroke volume to the right ventricular stroke volume from radionuclide equilibrium gated blood-pool images of the heart. In this paper we report our results using this technique. They indicate that caution should be exercised, and in particular that methods used to define the ventricular regions of interest must be carefully examined.

Aortic Valve Insufficiency↗
PubMed1981

9 alpha-homo-9,11-epoxy-5,13-prostadienoic acid analogues: specific stable agonist (SQ 26, 538) and antagonist (SQ 26, 536) of the human platelet thromboxane receptor.

A newly synthesized 9 alpha-homo-9,11-epoxy-5,13-prostadienoic acid analogue, SQ 26, 536, (8(R)9(S)11(R)12(S)-9 alpha-homo-9,11-epoxy-5(Z), 13(E)-15S-hydroxyprostadienoic acid) inhibited arachidonic acid (AA)-induced platelet aggregation with an I50 value of 1.7 microM. SQ 26,536 did not inhibit prostaglandin (PG) synthetase activity of bovine seminal vesicle microsomes or thromboxane (Tx) synthetase activity of lysed human blood platelets. SQ 26,536 also inhibited platelet aggregation induced by epinephrine (secondary phase), 9,11-azoPGH2 and collagen but did not inhibit the primary phase of epinephrine-induced aggregation or ADP-induced platelet aggregation. SQ 26,538 (8(R)9(S)11(R)12(S)-9 alpha-homo-9,11-epoxy-5(Z),13(E)-15R-hydroxyprostadienoic acid), a 15-epimer of SQ 26,536, induced platelet aggregation with an A50 value of 2.5 microM. SQ 26,536 competitively inhibited SQ 26,538-induced platelet aggregation with a Ki value of 3 microM. Neither indomethacin, a PG synthetase inhibitor, nor SQ 80,338 (1-(3-phenyl-2-propenyl)-1H-imidazole), a Tx synthetase inhibitor, inhibited SQ 26,538- or 9,11-azoPGH2-induced platelet aggregation. These data indicate that SQ 26,536 and SQ 26,538 are stable antagonist and agonist, respectively, of the human blood platelet thromboxane receptor.

Adenosine Diphosphate↗
PubMed1981

Pulmonary perfusion imaging applied to prediction of pulmonary vascular pressures in mitral and aortic valve disease.

Radionuclide lung perfusion imaging was performed on 27 patients with valvular disease of the left heart. The ratio of upper to total counts for the lungs, determined by computer, was correlated against pulmonary vascular mean pressures. A close correlation (r = 0.91) was obtained against pulmonary wedge pressure. After corrective cardiac surgery upper/total ratios fell towards normal in four patients in whom pulmonary vascular pressures were measured and the correlation persisted. This simple non-invasive index can be used to follow changes in pulmonary venous hypertension.

Adult↗
PubMed1981

left ventricular segmental wall motion-a comparison between equilibrium radionuclide angiography and contrast angiography.

The qualitative assessement of left ventricular wall motion using a four-point scale has been compared between left ventricular contrast angiography and equilibrium radionuclide angiography in the 30 degrees right anterior oblique projection. Analysis was carried out for five segments of the left ventricle. Four modes of analysis of equilibrium radionuclide angiography were compared and the reproducibility assessed. Overall accuracy of equilibrium radionuclide angiography compared to contrast angiography was greater than 82% to within one degree of motion. One method using a cine display, averaged 97%. We suggest that equilibrium radionuclide angiography using the cine display is the non-invasive investigation of choice in the screening of patients with suspected regional wall motion abnormalities.

Adult↗