PubMed Health⌕ Search

Biomedical subjects

J C Hartman

Publications and source records attributed to J C Hartman.

At least 19 recordsLinked to original sources
PubMed1998

Reduced nitric oxide reactivity of a new recombinant human hemoglobin attenuates gastric dysmotility.

The objective of this investigation was to compare the gastric motility effects of two recombinant hemoglobin variants, rHb1.1, and rHb3011, the latter having decreased nitric oxide reactivity via mutagenic alteration. Variants were administered to rats at 750 and 1500 mg/kg, i.v., prior to feeding a meal. The percentage of meal emptied was determined 45 min after feeding. rHb1.1 reduced gastric emptying significantly (48% and 71%), whereas rHb3011 was significant (42%) only at the higher dose (p < 0.05). The results suggest that rHb1.1 inhibits gastric emptying by scavenging NO, and this effect is significantly reduced by rHb3011, which has decreased NO reactivity.

Animals↗
PubMed1996

Ramiprilat attenuates hypoxia/reoxygenation injury to cardiac myocytes via a bradykinin-dependent mechanism.

Isolated rat neonatal cardiac myocytes were subjected to immersion in hypoxic (PO2 < 2 mm Hg), glucose-free Tyrode's solution for 5 h followed by concomitant reoxygenation and staining with the membrane-impermeant fluorophore, propidium iodide, in normoxic (PO2 > 150 mm Hg), serum-free culture media for 15 min in order to assess sarcolemmal damage indicative of myocyte viability due to hypoxia/reoxygenation injury. Prior to hypoxic exposure, cells were pretreated for 90 min with the angiotensin-converting enzyme inhibitor cyclopenta[b]pyrrole-2-carboxylic acid, 1-[2-[(1-carboxy-3-phenylpropyl)amino]-l-oxopropyl]octahydro-[2S-[1[R* (R*)]2 alpha, 3a beta, 6a beta]] (ramiprilat), concomitantly with ramiprilat and H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH (bradykinin B2 receptor antagonist HOE 140), the bioactive peptide Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg (bradykinin) or concomitantly with bradykinin and HOE 140. Hypoxia/reoxygenation injury to untreated control cardiac myocytes was characterized by a significant loss of sarcolemmal integrity measured at 75 +/- 4% of total cell fluorescence (mean +/- S.E., n = 42 cultures). Compared to propidium iodide staining of the above untreated control myocytes, those pretreated with 30 or 100 microM ramiprilat showed a significant reduction of propidium iodide staining to 45 +/- 9% and 40 +/- 8% (n = 9, P < 0.05) of untreated controls, respectively. Pretreatment with the protective concentrations of ramiprilat concomitant with 10 microM HOE 140 abolished the significant reduction in propidium iodide staining observed with ramiprilat alone. Similarly, pretreatment with 10 or 100 nM bradykinin significantly reduced propidium iodide staining to 35 +/- 5% and 60 +/- 10% (n = 6, P < 0.05) of the untreated hypoxic controls, respectively. In addition, concomitant pretreatment with protective concentrations of bradykinin and 10 microM HOE 140 also abolished the significant reduction in propidium iodide staining observed with bradykinin alone. The results indicate that the angiotensin-converting enzyme inhibitor ramiprilat has a protective effect on isolated cardiac myocytes exposed to hypoxia/reoxygenation and that this effect is most likely related to a local action of bradykinin on the cardiac myocyte via the activation of the kinin B2 receptor.

Analysis of Variance↗
PubMed1995

The role of bradykinin and nitric oxide in the cardioprotective action of ACE inhibitors.

BACKGROUND: The angiotensin-converting enzyme inhibitor ramiprilat has been previously demonstrated to protect myocardium from ischemia/reperfusion injury. The objective of these investigations was to examine the roles of bradykinin, angiotensin II, and nitric oxide in the cardioprotective effects of ramiprilat. METHODS: Anesthetized, open-chest rabbits were instrumented for production of myocardial ischemia (30 minutes) and subsequent reperfusion (120 minutes), after which myocardial infarct size was measured. Animals were treated intravenously with either saline solution, ramiprilat (50 micrograms/kg), the bradykinin2 receptor antagonist HOE 140 (1 microgram/kg), ramiprilat + HOE 140, angiotensin II (2.5 ng.kg-1.min-1), the angiotensin II receptor antagonist losartan (20 mg/kg), ramiprilat + angiotensin II, the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (100 micrograms.kg-1.min-1), or ramiprilat + NG-nitro-L-arginine methyl ester. RESULTS: Among all treatment groups myocardial infarct size was reduced significantly below saline control only by ramiprilat (-54%) and ramiprilat + angiotensin II (-37%). Pretreatment with HOE 140 or NG-nitro-L-arginine methyl ester abolished the cardioprotective effect of ramiprilat. Neither stimulation nor antagonism of angiotensin II receptors altered infarct size from the saline control level. Also, when isolated neonatal rat cardiomyocytes were exposed to hypoxia/reoxygenation, ramiprilat (100 mumol/L) and bradykinin (10 nmol/L) improved cell viability (approximately 60%), and the protective effect of both agents was reversed by administration of HOE 140 (10 mumol/L). CONCLUSIONS: These results indicate that the in vivo cardioprotective effect of ramiprilat can be abolished by antagonizing bradykinin receptors or inhibiting nitric oxide synthase, and that the effect is not related to angiotensin II receptor activity. The potential bradykinin-sparing property of ramiprilat may promote increased bradykinin-stimulated nitric oxide production leading to cardioprotection. Part of the cardioprotective effects of ramiprilat/bradykinin/nitric oxide may occur locally as demonstrated by the in vitro results using isolated cardiomyocytes.

Adrenergic beta-Antagonists↗
PubMed1995

Protection of ischemic/reperfused canine myocardium by CL18/6, a monoclonal antibody to adhesion molecule ICAM-1.

OBJECTIVE: A blocking monoclonal antibody to intercellular adhesion molecule-1 (ICAM-1), CL18/6, previously has been demonstrated to inhibit neutrophil attachment to isolated vascular endothelium and cardiomyocytes. Due to the well known participation of ICAM-1 in the inflammatory responses associated with myocardial ischemia/reperfusion injury, we investigated if CL18/6 could attenuate myocardial ischemia/reperfusion injury in vivo. METHODS: Saline (3-5 ml, i.v., n = 6), non-blocking control MAb CL18/1D8 or CL18/6 (both 0.5 mg kg-1, i.v., n = 4) were administered prior to coronary occlusion (1 h) and subsequent reperfusion (5 h) produced by inflation of a coronary balloon angioplasty catheter in isoflurane-anesthetized, closed-chest dogs. Heart rate and arterial pressure were measured, and regional myocardial blood flow (rMBF), and myeloperoxidase activity (MPO) to index local neutrophil sequestration, were determined. Myocardial infarct size (IS) was evaluated using the tetrazolium staining technique and expressed as a percent of area at risk (AR). RESULTS: Changes in heart rate and arterial pressure were insignificant throughout the experiment. rMBF (mean +/- s.e.m.) in the ischemic subendocardium for each treatment group was: Saline (0.07 +/- 0.02 ml min-1 g-1); CL18/1D8 (0.04 +/- 0.02); CL18/6 (0.06 +/- 0.02). IS/AR% was: saline (37 +/- 3%); CL18/1D8 (39 +/- 9%); CL18/6 (15 +/- 4%*); * = significantly different from CL18/1D8 and saline, P < 0.05. MPO assayed from AR immediately adjacent to the infarct was significantly reduced below infarct MPO only in the CL18/6 treated group-36%). CONCLUSIONS: The results indicate that CL18/6 antagonism of ICAM-1 provided cardioprotection associated with reduced neutrophil activity in vulnerable myocardium, and suggest that ICAM-1 mediated neutrophil sequestration in endangered cardiac tissue is an important mechanism of myocardial ischemia/reperfusion injury.

Animals↗
PubMed1994

The trolox analog, U-78517F, attenuates hypoxic injury in isolated cardiac myocytes.

Neonatal rat cardiac myocytes were subjected to 5 h of hypoxia (PO2 < 5 mmHg) in glucose-free, modified Tyrodes solution. Prior to hypoxic exposure, cells were pretreated for 90 min with media alone or containing the trolox analog, U-78517F, at 0.3, 1, or 3 microM. Hypoxic injury was characterized by a significant loss of sarcolemmal integrity [76 +/- 12% of the total cell fluorescence (mean +/- S.E., n = 14 cultures)] quantified by nuclear staining with the membrane-impermeant fluorophore propidium iodide. In addition, hypoxia also induced significant decreases in the intracellular content of creatine kinase (43 +/- 7%, n = 12), lactate dehydrogenase (25 +/- 5%, n = 8), adenosine 5'-triphosphate (49 +/- 12%, n = 6), and sulfhydryls (34 +/- 4%, n = 6). Sarcolemmal integrity was significantly preserved by pretreatment with 1 microM and 3 microM U-78517F which reduced propidium iodide staining below the hypoxic control value by 51 +/- 9% (n = 12) and 75 +/- 4% (n = 14, P < 0.01 v hypoxic control), respectively. Similar results were obtained in cells pretreated with alpha-tocopherol suggesting that these two compounds are equipotent at preserving the sarcolemmal integrity of cardiac myocytes exposed to hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

In vivo validation of a transit-time ultrasonic volume flow meter.

The objective of this investigation was to validate a transit-time ultrasound blood flow metering system in vivo. Implanted chronically and acutely on the ascending aorta of the dog, the transit-time flow probe determined varying flow rates simultaneously with measurements made by the electromagnetic flow metering method. The transit-time technique was also compared to two methods in which blood was collected volumetrically by either graduated cylinder (ascending aorta/dog) or pump withdrawal (abdominal aorta/cat). Statistical analysis of the results provided evidence that the transit-time ultrasound method measured in vivo blood flow rate no differently than the electromagnetic or pump withdrawal techniques, however, transit-time determinations of blood volume were 10% below that indicated by graduated cylinder collection. With transit time represented on the y-axis, three linear regressions of all paired blood flow measurements were calculated yielding the following slopes (delta y/delta x) and regression coefficients (r), respectively: electromagnetic (1.00, 0.98), graduated cylinder (0.85, 0.93), and pump withdrawal (0.93, 1.00). The results validate the transit-time ultrasound system used in the present investigation as an accurate method capable of measuring blood flow in both acutely and chronically instrumented animal preparations.

Animals↗
PubMed1994

Inhibition of nitric oxide synthase prevents myocardial protection by ramiprilat.

The objective of this investigation was to determine the role of nitric oxide synthase in the action of the angiotensin-converting enzyme inhibitor, ramiprilat, to reduce myocardial ischemia/reperfusion injury. Ramiprilat, the nitric oxide synthase inhibitor NG-nitro-L-NAME (L-NAME), ramiprilat plus L-NAME, or saline (n = 8 each group), were administered i.v. in intact animal preparations of experimentally induced acute myocardial ischemia. Anesthetized, open-chest rabbits were instrumented for measurement of systemic hemodynamics and left ventricular pressure from which left ventricular +dP/dtmax was derived. Animals were subjected to 30 min of left main coronary artery occlusion (marginal branch) followed by 2 hr of reperfusion. Ramiprilat (50 micrograms/kg) or saline was administered 5 min before reperfusion, and those rabbits receiving L-NAME (100 micrograms/kg/min) were pretreated starting 30 min before occlusion throughout the remainder of the experiment. After reperfusion, myocardial infarct size (IS) was determined via tetrazolium staining and expressed as a percentage of area at risk (AR). IS/AR% was significantly reduced in rabbits administered ramiprilat (19 +/- 3%) compared to those receiving saline (39 +/- 2%), ramiprilat plus L-NAME (43 +/- 4%) or L-NAME alone (43 +/- 2%; mean +/- S.E.M.; P < .05). AR as a percent of total left ventricular mass was not different between any of the four treatment groups. Systemic hemodynamic effects were not significantly different between groups. The results indicate that the effect of ramiprilat to reduce infarct size is abolished by pretreatment with L-NAME.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗
PubMed1994

Role of bradykinin in myocardial preconditioning.

The role of bradykinin in the cardioprotective action of ischemic preconditioning was investigated in an anesthetized, open-chest rabbit model of acute coronary occlusion. A branch of the left main coronary artery was reversibly ligated to produce ischemia followed by reperfusion, after which the degree of myocardial necrosis (infarct size as a percent of area at risk) was assessed by tetrazolium staining. Before 30 min of coronary occlusion, rabbits received either ischemic preconditioning (5 min occlusion followed by 10 min reperfusion), no preconditioning, H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH (HOE 140) i.v. (bradykinin receptor antagonist, 1 micrograms/kg) plus preconditioning, HOE 140 alone, a 5-min intra-atrial bradykinin infusion (250 micrograms/kg/min) followed by a 10-min recovery period or HOE 140 plus bradykinin infusion with 10 min recovery. Systemic hemodynamic responses were similar between treatment groups except that both bradykinin infusion groups had a significantly depressed rate of left ventricular pressure development (LV+dP/dtmax) after the 10-min recovery period. Preconditioning reduced infarct size significantly (12 +/- 2%, compared to non-preconditioned controls at 41 +/- 6%), whereas pretreatment with HOE 140 abolished the cardioprotective effect (41 +/- 4%). In addition, bradykinin infusion reduced infarct size significantly (16 +/- 1%), an effect which was also prevented by HOE 140 (41 +/- 5%). HOE 140 alone did not exacerbate the degree of myocardial necrosis (43 +/- 4%). Myocardial area at risk as a percentage of total left ventricular mass was not different between the six treatment groups. The results indicate that endogenously generated bradykinin may mediate the cardioprotective events associated with ischemic preconditioning.

Amino Acid Sequence↗
PubMed1993

Reduction of myocardial infarct size by ramiprilat is independent of angiotensin II synthesis inhibition.

The angiotensin-converting enzyme inhibitor ramiprilat, the angiotensin II receptor antagonist losartan, angiotensin II, ramiprilat plus angiotensin II, or saline (N = 6 each group), were administered i.v. in anesthetized, open-chest rabbit preparations of acute myocardial ischemia. Animals were instrumented for measurement of systemic hemodynamics and left ventricular +dP/dtmax, then subjected to 30 min of left anterior descending coronary artery occlusion (marginal branch) followed by 2 h of reperfusion. Ramiprilat (50 micrograms/kg), losartan (10 mg/kg), or saline were administered prior to reperfusion, and angiotensin II (2.5 ng/kg per min) was infused 15 min prior to occlusion and throughout the remainder of the experiment. Losartan was supplemented (10 mg/kg) after 1 h of reperfusion. These non-hypotensive doses of ramiprilat and losartan were demonstrated to significantly antagonize the systemic pressor effects of i.v. challenge with angiotensin I (15% of control, maximum) and II (5% of control, maximum), respectively, for the duration of the experiment. Systemic hemodynamic and +dP/dtmax changes due to occlusion/reperfusion or drug administration were similar between treatment groups. Infarct size was measured post-experimentally using tetrazolium staining and is reported as a percent of area at risk. Infarct size/area at risk (%) was significantly lower in rabbits administered ramiprilat only (20 +/- 6%*) or ramiprilat plus angiotensin II (26 +/- 5%*), compared to those receiving saline (41 +/- 6%), angiotensin II (51 +/- 4%), or losartan (52 +/- 4%, mean +/- S.E.M., * P < 0.05). These data indicate that direct angiotensin II receptor stimulation or receptor antagonism does not alter the degree of myocardial necrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1993

Reduction of myocardial infarct size in rabbits by ramiprilat: reversal by the bradykinin antagonist HOE 140.

We wished to determine, using a novel specific antagonist of BK2, HOE 140, (a) if the angiotensin-converting enzyme (ACE) inhibitor, ramiprilat, reduces myocardial infarct size in a well-established animal model of ischemia/reperfusion with minimal coronary collateralization, and (b) if the reduction in myocardial infarct size occurred through a bradykinin-dependent mechanism Saline vehicle, ramiprilat, HOE 140, or ramiprilat plus HOE 140 (n = 6 each group), was administered intravenously (i.v.) in intact animal preparations of experimentally induced acute myocardial ischemia. Anesthetized, open-chest rabbits were instrumented for measurement of systemic hemodynamics and left ventricular pressure (LVP), from which LV + dP/dtmax was derived. Animals were subjected to 30-min left main coronary artery occlusion (marginal branch) followed by 2-h reperfusion. Ramiprilat (50 micrograms/kg) or saline was administered before reperfusion, and rabbits receiving HOE 140 were pretreated before occlusion (1 microgram/kg). In separate duration of action experiments (n = 6 each group), the above doses of ramiprilat or HOE 140 had significant vascular antagonism of sufficient duration against serial challenge with angiotensin I (AI) or bradykinin, respectively. After reperfusion, myocardial infarct size (IS) was determined by tetrazolium staining and expressed as a percentage of area at risk (AR). IS/AR% was significantly reduced in rabbits that received ramiprilat (20 +/- 6%, p < 0.05) as compared with those that received saline (41 +/- 6%), ramiprilat plus HOE 140 (47 +/- 2%), or HOE 140 alone (43 +/- 4%, mean +/- SEM). AR as a percentage of total LV mass was not different between any of the four treatment groups. Tachycardia was observed during early reperfusion in each group treated with ramiprilat.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin I↗
PubMed1992

Influence of desflurane, isoflurane and halothane on regional tissue perfusion in dogs.

The actions of desflurane, isoflurane and halothane on regional tissue perfusion were studied using radioactive microspheres in dogs chronically instrumented for measurement of arterial and left ventricular pressure, global (left ventricular dP/dtmax) and regional (percent segment shortening) contractile function, and diastolic coronary blood flow velocity. Systemic and coronary haemodynamics and regional tissue perfusion were measured in the conscious state and during anaesthesia with equihypotensive concentrations of desflurane, isoflurane, and halothane. All three volatile anaesthetics (P < 0.05) increased heart rate and decreased mean arterial pressure, left ventricular systolic pressure, and left ventricular dP/dtmax Myocardial perfusion was unchanged in subendocardial midmyocardial, and subepicardial regions by the administration of either dose of desflurane. No redistribution of intramyocardial blood flow (endo/epi ratio) was observed during desflurane anaesthesia. Although regional myocardial perfusion was reduced (P < 0.05) in a dose-related fashion by halothane and by isoflurane at high concentrations, redistribution of intramyocardial blood flow was not observed during halothane or isoflurane anaesthesia. All three volatile anaesthetics reduced blood flow to the renal cortex, but only desflurane produced a decrease in renal cortical vascular resistance. Hepatic blood flow decreased in response to halothane but not desflurane or isoflurane. Concomitant decreases in hepatic resistance were observed during administration of desflurane and isoflurane. Dose-related decreases in intestinal and skeletal muscle blood flow were observed during halothane and isoflurane but not desflurane anaesthesia. The results suggest that desflurane maintains myocardial, hepatic, intestinal, and skeletal muscle blood flow while halothane and isoflurane decrease regional tissue perfusion in these vascular beds to varying degrees during systemic hypotension in the chronically instrumented dog.

Anesthetics↗
PubMed1991

Alterations in collateral blood flow produced by isoflurane in a chronically instrumented canine model of multivessel coronary artery disease.

The actions of isoflurane and adenosine on left ventricular myocardial perfusion during a total occlusion of the left anterior descending coronary artery and concomitant stenosis of the left circumflex coronary artery were investigated in dogs chronically instrumented for measurement of systemic and coronary hemodynamics, regional myocardial contractile function (via ultrasonic sonomicrometers), and myocardial blood flow (via the radioactive microsphere technique). An Ameroid constrictor was implanted on the left circumflex coronary artery to produce a slowly progressive stenosis that gradually depleted the coronary reserve of the distal vascular bed. The reductions in reserve were evaluated by daily measurement of baseline left circumflex coronary blood flow velocity and the hyperemic response to injection of adenosine. At a stage of moderate or severe left circumflex stenosis development, the left anterior descending coronary artery was totally occluded via a hydraulic occluder to simulate multivessel coronary artery disease, and control measurements of hemodynamics, regional contractile function, and myocardial blood flow were completed. In separate groups of experiments, either adenosine (0.64 and 1.28 mg/min) or isoflurane (1.6-1.8 and 2.3-2.5%, end-tidal) was administered and measurements remade during steady state hemodynamic conditions. Finally, diastolic aortic pressure and heart rate were adjusted to levels present in the control state during administration of adenosine or isoflurane, and additional measurements were recorded. Isoflurane reduced mean arterial pressure, left ventricular systolic pressure, and the rate of increase of left ventricular pressure at 50 mmHg (positive dP/dt50) without change in heart rate. Administration of isoflurane decreased blood flow in normal, stenotic, and occluded regions; however, when arterial pressure and heart rate were restored to levels present in the conscious state, myocardial perfusion in all regions was maintained at control levels. Ratios of flow between occluded and normal or stenotic zones remained unchanged from the conscious state during a constant aortic pressure and heart rate. Similar results were obtained in dogs with either a moderate or severe left circumflex coronary artery stenosis. In contrast, adenosine produced a dose-related decrease in collateral flow and occluded-to-normal or occluded-to-stenotic zone flow ratio. The results of this investigation indicate that adenosine but not isoflurane redistributes blood flow away from collateral-dependent myocardium to other regions in a chronically instrumented canine model of multivessel coronary artery disease.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine↗
PubMed1991

Steal-prone coronary circulation in chronically instrumented dogs: isoflurane versus adenosine.

The influence of isoflurane and adenosine on left ventricular myocardial blood flow was investigated in dogs chronically instrumented for measurement of systemic and coronary hemodynamics, regional myocardial contractile function (with ultrasonic sonomicrometers), and myocardial perfusion (by the radioactive microsphere method). An Ameroid constrictor was implanted on the left circumflex coronary artery to produce a progressive stenosis that gradually reduced vascular reserve of the distal perfusion territory. The depletion of reserve was evaluated by daily monitoring of the hyperemic response to adenosine. A stenosis of moderate severity was considered present when left circumflex reserve was attenuated by approximately 60-70%. During left circumflex stenosis development, the left anterior descending coronary artery was totally occluded for 2 min each hour eight times daily with a hydraulic occluder to stimulate coronary collateral development over a period of 9-13 days. Contractile dysfunction during and flow debt repayment after each brief occlusion were used to monitor coronary collateral development. After stenosis and collateral development had occurred, the left anterior descending coronary artery was permanently occluded to simulate a condition of multivessel coronary artery disease with enhanced collateral development. In separate groups of experiments, hemodynamics and myocardial perfusion were measured before and after administration of adenosine (0.54 and 1.08 mg/min) or isoflurane (1.1 and 1.9%, end-tidal) and in the presence of either agent during adjustment of diastolic aortic pressure and heart rate to control levels. Total left anterior descending coronary artery occlusion in the presence of a moderate left circumflex stenosis produced an increase in mean arterial and left ventricular end diastolic pressures. Isoflurane decreased arterial pressure, left ventricular systolic pressure, and positive rate of increase of left ventricular pressure (dP/dt50) without altering heart rate. Administration of the high concentration of isoflurane reduced blood flow in normal areas and in regions distal to the partial (from 1.05 +/- 0.10 to 0.76 +/- 0.11 ml.min-1.g-1) or total coronary occlusion (from 0.64 +/- 0.10 to 0.41 +/- 0.11 ml.min-1.g-1). However, when arterial pressure and heart rate were restored to levels present in the conscious state, perfusion in all zones was maintained at control levels (1.06 +/- 0.11 for the stenotic and 0.69 +/- 0.12 ml.min-1.g-1 for the occluded region). Ratios of transmural blood flow between occluded and normal or occluded and stenotic zones were not different from the conscious state during a constant aortic pressure and heart rate.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine↗
PubMed1991

Influence of desflurane on regional distribution of coronary blood flow in a chronically instrumented canine model of multivessel coronary artery obstruction.

The influence of desflurane on myocardial perfusion measured by a microsphere technique during a total occlusion of the left anterior descending coronary artery and concomitant moderate or severe stenosis of the left circumflex coronary artery was evaluated in chronically instrumented dogs. Hemodynamics, regional contractile function, and myocardial blood flow were measured during the conscious state and after anesthesia with desflurane (8.2%-9.2% and 12.5%-12.7%) with and without control of arterial pressure. Total left anterior descending occlusion produced in combination with a left circumflex coronary artery stenosis significantly (P less than 0.05) increased heart rate and left ventricular end diastolic pressure in the absence of desflurane anesthesia. Desflurane, administered only in the presence of left anterior descending occlusion and left circumflex stenosis, significantly (P less than 0.05) decreased mean arterial pressure, left ventricular systolic pressure, and left ventricular positive dP/dt50 without change in heart rate. Blood flow to the subendocardium of normal myocardium was reduced during the high concentration of desflurane (P less than 0.05), but perfusion of the subepicardium and midmyocardium was maintained at conscious levels. When the left circumflex stenosis was of moderate severity, only blood flow to the subendocardium distal to the stenosis was reduced by desflurane (P less than 0.05). In the presence of a severe stenosis, perfusion was decreased in the subepicardium, midmyocardium, and subendocardium of the stenotic zone (P less than 0.05). During the reduction in arterial pressure produced by desflurane, collateral blood flow in the left anterior descending region was reduced in dogs with either a moderate or severe left circumflex stenosis (P less than 0.05). When arterial pressure and heart rate conditions observed in the postocclusion conscious state were restored during the high concentration of desflurane, myocardial blood flow in all regions returned to those levels present in the conscious state (P less than 0.05). Ratios of flow between occluded and normal zones were decreased when hypotension produced by desflurane was uncontrolled, but when arterial pressure and heart rate were adjusted to conscious postocclusion levels using partial thoracic aorta occlusion and atrial pacing, the ratio remained at conscious control levels regardless of the degree of left circumflex stenosis severity (P less than 0.05). Results of this investigation indicate that desflurane does not redistribute blood flow away from collateral-dependent myocardium to other regions via a "coronary steal" mechanism in a chronically instrumented canine model of multivessel coronary artery disease.

Anesthetics↗
PubMed1990

A model of multivessel coronary artery disease using conscious, chronically instrumented dogs.

The present investigation was undertaken to develop a reproducible model of multivessel coronary artery disease including a total occlusion of one vessel and a stenosis of an adjacent vessel in chronically instrumented dogs. Utilizing sterile techniques, we surgically prepared dogs for measurement of heart rate, arterial pressure, left ventricular pressure, and blood flow velocity in the left anterior descending (LAD) and left circumflex (LCCA) coronary arteries. A hydraulic occluder and Ameroid constrictor were implanted around the LAD and LCCA, respectively. Pairs of piezoelectric crystals were implanted within the subendocardium of the LAD and LCCA perfusion territories to measure regional contractile function (segment shortening). A catheter was placed in the left atrial appendage for injection of radioactive microspheres to measure regional myocardial perfusion. Beginning on the second day following implantation, 25, 50, and 100 micrograms bolus injections of adenosine were administered daily via the left atrium to evaluate LAD and LCCA coronary reserve. Although LAD reserve remained intact, the hyperemic response of the LCCA was progressively attenuated as stenosis severity increased during slow closure of the Ameroid constrictor. When the LCCA vasodilator response to adenosine was reduced by 50% (moderate stenosis; no change in resting flow velocity) or 70% (severe stenosis; 20% reduction in resting flow velocity), the LAD was acutely occluded (via inflation of the hydraulic occluder) to simulate multivessel coronary artery disease. After a hemodynamic steady state was established during coronary occlusion, radioactive microspheres were administered to compare regional perfusion within normal myocardium to flow in myocardium supplied by the occluded or stenotic coronary arteries. In dogs with a stenosis of moderate severity, transmural myocardial blood flow was significantly decreased (-83%) only in the occluded zone. However, in dogs with a severe coronary artery stenosis, reductions in perfusion in both stenotic (-31%) and occluded (-87%) regions were demonstrated. Subendocardial/subepicardial flow ratios were significantly reduced in both stenotic and totally occluded regions in the presence of severe stenosis, but this occurred only in the occluded (LAD) zone of dogs with a moderate LCCA stenosis. This preparation provides a model whereby the vasodilator reserve of a progressively constricted coronary artery can be quantified and simultaneously compared to the reserve of a normal vessel. With acute occlusion of the normal artery, a multivessel disease state can be simulated and verified by measurement of regional myocardial perfusion. The model is reproducible, free of the influence of anesthesia and acutely performed surgery, and the degree of stenosis is easily varied over time.

Adenosine↗
PubMed1990

Volatile anesthetics and regional myocardial perfusion in chronically instrumented dogs: halothane versus isoflurane in a single-vessel disease model with enhanced collateral development.

The influence of halothane and isoflurane on regional myocardial blood flow was investigated in chronically instrumented dogs with a well developed coronary collateral circulation. Dogs were implanted with an Ameroid constrictor on the left anterior descending (LAD) coronary artery to produce slowly progressive coronary artery occlusion and collateral development. Contractile function in the collateral-dependent region was ascertained periodically during brief balloon cuff occlusion or during atrial pacing to characterize the degree of ongoing collateral development. Following documentation of enhanced collateral perfusion by the lack of contractile dysfunction during brief balloon cuff occlusion or atrial pacing at 50 days postimplantation, dogs were anesthetized (inhalation induction) with halothane (1.5% or 2.5%; n = 7) or isoflurane (2.0% or 3.0%; n = 8) using equihypotensive inspired concentrations of either agent. Radioactive microspheres were administered to measure regional myocardial perfusion during the conscious state and at stable hemodynamic states during both low and high concentrations of each volatile anesthetic. Myocardial blood flow during anesthesia was also determined following the adjustment of arterial pressure and heart rate to conscious levels by administration of phenylephrine and atrial pacing, respectively. Over the course of collateral development, balloon cuff-induced contractile dysfunction and pacing-induced contractile dysfunction in the collateral-dependent zone were reduced, indicating extensive collateral development. Halothane and isoflurane decreased global and regional indices of contractility and arterial pressure in a dose-dependent manner, but only isoflurane reduced coronary vascular resistance. Both anesthetics decreased myocardial perfusion within normal and collateral-dependent regions; however, flow was restored to levels found in the conscious state coincidental with control of arterial pressure and heart rate. Neither anesthetic alone, nor with concomitant control of arterial pressure and heart rate, produced a maldistribution of blood flow transmurally or between normal and collateral-dependent zones. The results suggest that both halothane and isoflurane, although decreasing major determinants of myocardial oxygen demand, do not unfavorably alter the regional distribution of coronary blood flow in a single-vessel disease model with enhanced collateral development.

Anesthesia, Inhalation↗
PubMed1990

Actions of isoflurane on myocardial perfusion in chronically instrumented dogs with poor, moderate, or well-developed coronary collaterals.

The influence of isoflurane on myocardial perfusion (determined by the radioactive microsphere technique) in normal regions and areas distal to a left anterior descending (LAD) coronary artery occlusion was evaluated in dogs that were chronically instrumented for measurement of systemic and coronary hemodynamics and had varying degrees of coronary collateral development. In 17 dogs, an Ameroid constrictor was implanted on the LAD coronary artery to produce a slowly progressive occlusion that stimulated development of the collateral circulation. Collateralization was allowed to progress in three groups of dogs to a poor (3 +/- 1 days), moderate (19 +/- 4 days), or well-developed (50 days) stage postsurgery. After the indicated period of time had elapsed, the LAD coronary artery was occluded (via Ameroid constrictor and/or balloon cuff occluder). Radioactive microspheres were administered during the conscious state and at 2% and 3% inspired concentrations of isoflurane. A fourth set of microspheres was injected at 3% isoflurane with heart rate and blood pressure adjusted to conscious levels. Isoflurane produced equivalent changes in systemic hemodynamics in all groups, including an increase in heart rate and decreases in arterial pressure and left ventricular peak positive dP/dt. Regional contractile function of normal myocardium was reduced by isoflurane in all groups. Isoflurane (3%) significantly decreased subepicardial, subendocardial, and transmural blood flow in normal and collateral-dependent regions in all groups. Myocardial perfusion returned to levels present in the conscious state when arterial pressure and heart rate were adjusted to those levels present prior to induction of anesthesia. Neither the left ventricular transmural distribution nor the collateral-dependent to normal zone flow ratio was altered from conscious levels by isoflurane in any group with or without changes in blood pressure and heart rate. The results indicate that isoflurane does not redistribute coronary blood flow from collateral-dependent to normal regions in a single-vessel coronary artery disease model. The actions of isoflurane are also independent of the degree of coronary collateral development.

Anesthesia, Inhalation↗