Biomedical subjects

G J Grover

Publications and source records attributed to G J Grover.

At least 109 records · Page 6Linked to original sources

PubMed1989

Comparisons in vitro, ex vivo, and in vivo of the actions of seven structurally diverse inhibitors of angiotensin converting enzyme (ACE).

1. Seven drugs (captopril, zofenopril, enalapril, ramipril, lisinopril, fosinopril, and SQ 29,852) were compared in vitro in homogenates of aorta, brain, heart, lung, and kidney and in sera of spontaneously hypertensive rats (SHR) both with respect to potencies of their active moieties as inhibitors of angiotensin-converting enzyme (ACE), and, where applicable, rates of hydrolysis of their prodrug ester functions. 2. In ex vivo dose-response and time-course studies, the inhibitory effects of the seven drugs on tissue ACEs and their relative distributions to SHR tissues were compared following oral administration. 3. The relative potencies of the inhibitory moieties of the drugs (in parentheses) and the normalized 'equiactive' oral doses employed for time-course studies were: SQ 29,852 (1.0), 100 mg kg-1; captopril (3.5), 30 mg kg-1; enalapril (12), 20 mg kg-1; fosinopril (13), 25 mg kg-1; zofenopril (20), 10 mg kg-1; lisinopril (24), 10 mg kg-1; and ramipril (51), 5 mg kg-1. 4. Following oral administration of the drugs to SHR, the degree and duration of ACE inhibition in aorta and lung correlated with the antihypertensive actions, with ramipril, lisinopril, and zofenopril producing effects of the greatest magnitude and duration. 5. Ramipril and enalapril did not inhibit brain ACE ex vivo; captopril and zofenopril had modest but short-lasting effects; and fosinopril, lisinopril, and SQ 29,852 had long-lasting inhibitory actions, which, with the latter two, were delayed in onset. 6. All of the drugs produced significant inhibition of kidney ACE, with ramipril and fosinopril having somewhat weaker effects, perhaps due to biliary routes of excretion. 7. Captopril, fosinopril, and particularly zofenopril inhibited cardiac ACE ex vivo with degrees and durations that were marked compared with those of the other drugs; preliminary studies with isolated hearts suggest a possible relationship between inhibition of cardiac ACE and preservation of cardiac function subsequent to ischaemia.

Administration, Oral↗

PubMed1989

Role of thromboxane A2 in the control of myocardial O2 supply/consumption balance and severity of ischemia during pacing-induced ischemia.

The role of thromboxane A2 (TXA2) in the control of O2 supply/consumption variables during pacing-induced ischemia was examined using the TXA2 receptor antagonist SQ 29,548. Anesthetized, open-chest dogs were subjected to left anterior descending coronary artery (LAD) stenosis that produced significant epicardial S-T segment elevation (12 mV) only when superimposed on atrial pacing. Regional myocardial blood flow was determined using radioactive microspheres, and O2 consumption was determined by measuring O2 saturation of venous blood draining the ischemic region. The dogs were treated with saline or 0.2 mg/kg + 0.2 mg/kg/hr SQ 29,548, and the effect on ischemia was determined during 5-minute pacing-induced ischemic episodes at 10, 40, and 70 minutes postdrug or saline treatment. SQ 29,548 significantly reduced S-T elevation at 40 and 70 minutes postdrug compared with saline values and at all times measured compared with its paired predrug pace+stenosis values. SQ 29,548 reduced S-T elevation approximately 45% compared with its paired predrug values at 70 minutes. SQ 29,548 resulted in a significantly higher subendocardial-to-subepicardial flow ratio (0.70 +/- 0.10, p less than 0.05) compared with saline-treated animals (0.42 +/- 0.06), with an overall increase of flow to the ischemic region of approximately 40%. This increased flow was matched by a proportional increase in O2 consumption without a change in O2 extraction. The O2 supply/consumption balance was also unchanged by SQ 29,548 implying that despite the increase in blood flow, the ischemic region was still flow-limited.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Thromboxane receptor blockade with SQ 30,741 improves post-ischemic myocardial function in anesthetized dogs.

This study was conducted to determine whether the thromboxane A2 receptor antagonist SQ 30,741 can improve post-ischemic recovery of cardiac function in anesthetized dogs. Saline or SQ 30,741 was infused throughout a 15-min coronary occlusion and 5 hr of reperfusion. Ischemic regional cardiac function was determined using subendocardial ultrasonic crystals. Despite no differences in collateral blood flow or reperfusion flow, SQ 30,741 significantly improved ventricular segmental shortening at all times measured during reperfusion. At 5 hr after the initiation of reperfusion, segmental shortening was 3 +/- 16 and 44 +/- 10% of baseline values for saline and SQ 30,741 groups, respectively. These results implicate thromboxane receptor activation in the pathogenesis of myocardial stunning, and thromboxane antagonists may be useful in mitigating this functional deficit.

Animals↗

PubMed1989

Dissociation of cardiodepression from cardioprotection with calcium antagonists: diltiazem protects ischemic rat myocardium with a lower functional cost as compared with verapamil or nifedipine.

This study was performed to determine if cardiodepression can be dissociated from cardioprotection with calcium antagonists and which one (diltiazem, nifedipine, or verapamil) can maximally protect ischemic myocardium at a given level of cardiodepression. Isolated rat hearts were subjected to 0.1, 0.5, or 1.0 microM diltiazem, verapamil, or nifedipine 10 min before global ischemia. Ischemia was maintained for 25 min, at which time reperfusion was instituted for 30 min. Pre- and postischemia function, flow, and lactate dehydrogenase (LDH) release were measured. All three drugs reduced preischemic function and improved postischemic function and reflow in a dose-dependent fashion. LDH release and contracture were also mitigated with all drugs. When the efficacy of these drugs was expressed as the ratio of LDH release versus preischemic, postdrug function (ability of drug to reduce LDH release at a given level of cardiodepression), diltiazem had a significantly lower ratio as compared with verapamil or nifedipine. When similar experiments were performed with various concentrations of calcium in the perfusion buffer (2.50, 1.25, 0.75, 0.50, 0.41 mM CaCl2) administered 10 min before ischemia and reperfusion with normal (1.25 mM) buffer, preischemic function was reduced in a concentration-dependent fashion. Despite severe reductions in function at the concentration of 0.50 mM CaCl2, LDH release was not reduced. The concentration of 0.41 mM CaCl2, which depressed function to the same degree as 0.50 mM CaCl2, reduced LDH release. This reduction in LDH release, however, was not as great as that which occurred with the high dose of the calcium antagonists. Reperfusion with 0.41 mM calcium buffer, however, nearly abolished LDH release. Thus, although all three calcium antagonists reduced the severity of ischemia, diltiazem reduces it with the lowest cost in cardiac function. Reduction in extracellular calcium reduces cardiac function, but reductions in severity of ischemia, as measured by LDH release, do not parallel these changes.

Animals↗

PubMed1989

Anti-ischemic and vasorelaxant effects of the new benzazepine calcium channel blocker SQ 31,765.

The anti-ischemic effects of SQ 31,765 or its relatively inactive enantiomer SQ 32,189 (to test for effects not related to calcium channel blockade) were determined in a model of stable angina. Anesthetized dogs were given saline (n = 6), SQ 31,765 (n = 6; 0.2 mg/kg) or SQ 32,189 (n = 6; 0.2 mg/kg) i.v. 10 min before ischemia. The effect on pacing-induced ST-segment elevation (pacing + left anterior descending coronary artery stenosis) and myocardial blood flow were determined. SQ 31,765 reduced ST-elevation (P less than .05) compared to saline at 10, 40 and 70 min after infusion (5.9 +/- 1.4 and 12.0 +/- 1.4 mV, respectively, at 70 min). SQ 32,189, which is a 10-fold less potent calcium channel blocker in coronary arteries, did not affect ST-elevation (11.8 +/- 2.1 mV). Left anterior descending coronary artery stenosis during atrial pacing resulted in a significant reduction in subendocardial flow in all groups before drug infusion (41 +/- 7, 44 +/- 7 and 35 +/- 9 ml/min/100 g for saline, SQ 31,765 and SQ 32,189, respectively) and treatment with SQ 31,765 did not affect this flow. SQ 32,189 further reduced subendocardial blood flow such that it was significantly lower compared to saline. To test for any partial agonist activity, Bay k 8644 and SQ 32,189 were tested as constrictors of porcine coronary strips in vitro. Bay k 8644 induced appreciable force whereas SQ 32,189 did not. However, the vasorelaxant potency of SQ 32,189 was decreased under hypoxic conditions. Thus, SQ 31,765 can reduce the severity of ischemia in a manner which is independent of changes in myocardial blood flow or hemodynamic alterations.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1989

Anti-ischemic effects of the potassium channel activators pinacidil and cromakalim and the reversal of these effects with the potassium channel blocker glyburide.

The direct cardioprotective efficacy of the potassium channel activators pinacidil and cromakalim was determined in isolated globally ischemic rat hearts. Isolated buffer-perfused rat hearts were subjected to 25 min of ischemia followed by 30 min of reperfusion. These hearts were pretreated with 1 to 100 microM pinacidil, 1 to 7 microM cromakalim or vehicle. Pinacidil resulted in significant improvements in reperfusion function and cardiac compliance, though it did not significantly reduce lactate dehydrogenase release at any concentration. The protective effects of pinacidil were greatest at a 10 microns concentration and were slightly diminished at higher concentrations (30 and 100 microns). Although not affecting the severity of ischemia alone, 10 microM glyburide (potassium channel blocker) completely reversed the protective effects of pinacidil on reperfusion function and compliance. Cromakalim (7 microM) resulted in a greater than 50% improvement in reperfusion function and compliance and unlike pinacidil significantly reduced lactate dehydrogenase release by approximately 50%. At 1 microM, glyburide alone did not significantly affect the severity of ischemia but reversed the protective effects of cromakalim. Not only did glyburide reverse the protective effects of cromakalim, it resulted in a worsening of ischemia compared to vehicle, an effect not seen with glyburide alone. Thus, both pinacidil and cromakalim appear to have direct cardioprotective efficacy, though some differences between them may be possible. The mechanism of their protective effects appears to be via potassium channel opening as the potassium channel blocker glyburide reverses the protective effect of these compounds. Intracellular electrophysiological studies showed that ischemia-induced depolarization was reversed with cromakalim, which increased the resting potential nearly back to preischemic levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Effect of the thromboxane A2 receptor antagonist SQ 30,741 on ultimate myocardial infarct size, reperfusion injury and coronary flow reserve.

We determined if the thromboxane A2 antagonist SQ 30,741 can reduce ultimate myocardial infarct size and reperfusion injury. Anesthetized dogs were subjected to left circumflex coronary artery occlusion for 90 min at which time reperfusion was instituted. In one study, SQ 30,741 (1 mg/kg + 1 mg/kg/hr) was given either 10 min postocclusion (n = 7) or 2 min (n = 9) before reperfusion along with their appropriate vehicle controls in a model of 90 min of occlusion and 5 hr of reperfusion. Infarct size was reduced 50% (P less than .05) when SQ 30,741 was given 10 min postocclusion and 30% (P less than .05) when given only during reperfusion. Flow reserve using maximally dilating doses of adenosine was determined 3 hr postreperfusion in vehicle (10 min postocclusion, n = 10), SQ 30,741 (10 min postocclusion, n = 6) and nonischemic (n = 5) animals. Maximal subendocardial flow was reduced during reperfusion in ischemic animals, but SQ 30,741 improved this compared to vehicle animals (400 +/- 95, 88 +/- 25 and 208 +/- 48 ml/min/100 g; nonischemic, vehicle, SQ 30,741 groups, respectively). To determine if myocardial salvage can be observed 24 hr postocclusion with SQ 30,741 or the cyclooxygenase inhibitor aspirin, dogs were given vehicle (n = 9), SQ 30,741 (10 min postocclusion up to 4 hr postreperfusion) or aspirin (n = 9, 40 mg/kg 30 min preocclusion) and infarct size was determined 24 hr postocclusion (90 min left circumflex coronary artery occlusion + reperfusion).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗

PubMed1988

Effect of the thromboxane receptor antagonist SQ 29,548 on myocardial infarct size in dogs.

The effect of thromboxane A2/prostaglandin endoperoxide receptor blockade on infarct size following myocardial ischemia plus reperfusion was determined in dogs. In anesthetized dogs SQ 29,548 (0.2 mg/kg/h) caused a 1,000-fold shift in the dose flow-response curve of renal and mesenteric beds to U-46619, indicating potent receptor blockade. The vasoconstrictor response of the left circumflex coronary artery (LCX) to U-46619 was completely inhibited by SQ 29,548. Three additional groups of anesthetized dogs were subjected to LCX occlusion and 10 min later were given (a) SQ 29,548 (0.2 mg/kg loading dose + 0.2 mg/kg/h infusion intravenously, i.v., n = 7), a thromboxane A2/prostaglandin endoperoxide receptor antagonist; (b) vehicle (n = 7); and (c) SQ 28,585 (0.2 mg/kg loading dose + 0.2 mg/kg/h infusion i.v., n = 3), an inactive compound structurally related to SQ 29,548. After 90 min of occlusion, the LCX was reperfused for 5 h. The area at risk and infarct size were then determined. The cardiac area at risk was similar in size for all groups. Infarct size as a percentage of the total area at risk was large, 79 +/- 2% in vehicle controls, but this was markedly reduced to 45 +/- 8% with SQ 29,548 treatment. SQ 28,585 did not alter infarct size as compared with vehicle controls. Area at risk and infarct size were highly correlated (r = 0.95) in vehicle-treated animals. None of the drug treatments resulted in a significantly altered hemodynamic status. Thus, blockade of thromboxane A2/prostaglandin endoperoxide receptors during ischemia plus reperfusion resulted in a significant salvage of myocardial tissue and suggests a deleterious role for thromboxane A2 in ischemia.

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

PubMed1988

Effect of nifedipine on regional O2 consumption in ischemic myocardial tissue.

The effect of intravenous (i.v.) nifedipine (5 micrograms/kg/min) on regional O2 supply/consumption variables was determined in 14 anesthetized open-chest dogs subjected to left anterior descending coronary artery (LAD) stenosis sufficient to reduce blood flow 50%. Myocardial blood flow was measured using radioactive microspheres, and regional arterial and venous O2 saturations were determined using microspectrophotometry. During LAD occlusion, blood flow and O2 consumption were decreased in the ischemic region while O2 extraction was increased. With nifedipine treatment, LAD flow (flow probe) was increased 44% as compared with the initial occluded value, with most of this increase going to the subepicardium (microspheres). Flow to the ischemic subendocardium was not changed with nifedipine treatment. Ischemic subepicardial O2 consumption increased slightly in nifedipine-treated animals as compared with saline values, whereas O2 extraction decreased slightly. In the subendocardial region, nifedipine resulted in a significant decrease in O2 extraction, with a slight decrease in O2 consumption as compared with saline controls. The O2 supply/demand ratio was significantly improved with nifedipine only in the subendocardium of the ischemic region. This suggested that nifedipine could increase O2 consumption in the ischemic subepicardium through proportional increase in O2 supply while it decreased O2 consumption in the subendocardium relative to O2 supply.

Animals↗

PubMed1988

The effect of the thromboxane A2/prostaglandin endoperoxide receptor antagonist SQ 30,741 on myocardial infarct size and blood flow during myocardial ischemia and reperfusion.

The effect of the thromboxane A2 (TXA2) receptor antagonist SQ 30,741 on infarct size and myocardial blood flow during coronary occlusion and reperfusion was determined. In anesthetized dogs, the left circumflex coronary artery (LCX) was occluded and after 10 min a continuous infusion of SQ 30,741 (1 mg/kg + 1 mg/kg/h, i.v.) or saline was begun. After 90 min of LCX occlusion, the LCX was reperfused for 5 h and infarct size was then determined. Myocardial blood flows before, during, and after occlusion were determined using radioactive microspheres. SQ 30,741 resulted in a significant decrease in infarct size (34% +/- 6% of left ventricular area at risk) compared to controls (60% +/- 9%). Cardioprotection was also found with SQ 30,741 when infarct size was normalized for both area at risk and predrug collateral flow. The protective effect of SQ 30,741 occurred without an increase in collateral flow. At 1 h postreperfusion, subendocardial flow was significantly higher in SQ 30,741-treated animals (109 +/- 15 ml/min/100 g) compared to controls (71 +/- 16 ml/min/100 g). SQ 30,741, in the dose resulting in infarct size reduction, produced a 95% inhibition of platelet TXA2 receptors throughout the experiment as measured by dose-dependent inhibition of the ex vivo platelet shape change response to U-46,619, a TXA2 mimetic. Thus, a dose of SQ 30,741 that results in TXA2 blockade also results in myocardial salvage without changes in collateral flow.

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

PubMed1988

The role of thromboxane A2 in reperfusion injury.

Thromboxane A2 (TXA2) receptor antagonists can limit infarct size in models of coronary occlusion and reperfusion, but it was unknown if these compounds can mitigate reperfusion injury. Anesthetized open chest dogs were subjected to left circumflex coronary (LCX) occlusion for 90 min. Two minutes before reperfusion, the dogs were given iv saline (0.9% NaCl) or the TXA2 antagonist SQ 29,548 (0.2 mg/kg + 0.2 mg/kg/hr). Reperfusion was instituted for 5 hr at which time infarct size was determined. Regional myocardial blood flow was determined before, during, and after occlusion. SQ 29,548 treatment resulted in a significant reduction in infarct size (57 +/- 7 and 34 +/- 8% of the left ventricular area at risk infarcted in the saline and SQ 29,548 groups, respectively). No differences in collateral flow during occlusion were observed between groups, but SQ 29,548 treatment resulted in a significantly higher subendocardial reperfusion flow (54 +/- 10 and 93 +/- 14 ml/min/100g for the saline and SQ 29,548 groups, respectively). Thus, TXA2 seems to play a role in exacerbating reperfusion injury and TXA2 receptor blockade may have potential as a mode of therapy for ischemia-reperfusion damage.

Animals↗

PubMed1988

Thromboxane A2 antagonist and diltiazem-induced enhancement of contractile function: the effect of timing of treatment.

We determined the ability of the thromboxane A2 antagonist SQ 29,548 or diltiazem to enhance postischemic myocardial function and if the effects of these compounds were occurring during occlusion or reperfusion periods. Anesthetized open-chest dogs were pretreated with i.v. saline, SQ 29,548 (0.20 mg/kg + 0.20 mg/kg/hr) or diltiazem (0.18 mg/kg) 15 min before the left anterior descending coronary artery was occluded. In another group, animals were given saline, SQ 29,548 or diltiazem 1 min before reperfusion. The occlusion was maintained for 15 min and reperfusion instituted for 5 hr. Subendocardial segmental shortening was monitored throughout the experiment using sonomicrometry. Left anterior descending coronary artery occlusion resulted in marked systolic bulging to similar levels in all groups. Upon reperfusion, function returned immediately but, after several min, hypokinesia existed in saline-treated animals. At 5-hr postreperfusion, percentage of shortening returned to only 20% of base-line values in saline-treated animals. Both diltiazem and SQ 29,548 pretreatment resulted in significant (P less than .05) improvements in function such that at 5-hr postreperfusion, shortening returned to 60% of base-line values. When given immediately before reperfusion, SQ 29,548 still resulted in significant protection of function, although this occurred much later compared to pretreated animals. Diltiazem did not improve function when given immediately before reperfusion. SQ 29,548 improves reperfusion function and, thus by inference, thromboxane A2 may play a role in postischemic hypokinesia and some of its protective effects may occur during reperfusion. Diltiazem seems to protect reperfusion function only when present during ischemia per se.

Animals↗

PubMed1988

Effect of diltiazem on infarct size, reperfusion flow and flow reserve: the effect of timing of treatment.

This study was performed to determine if improved subendocardial reflow seen with diltiazem pretreatment after left circumflex coronary (LCX) occlusion is due to a direct vasodilatory effect of diltiazem on the reperfused bed or due to an increased flow maximum or reserve. In the first part of this study anesthetized dogs were subjected to saline or diltiazem (infused starting before, 10 min after LCX occlusion or 2 min before reperfusion; 0.18 mg/kg + 0.45 mg/kg/hr i.v. for all groups) treatment with a 90-min LCX occlusion and 5-hr reperfusion and myocardial blood flow and infarct size were determined at the end of the experiment. In the second part, maximal flow using intracoronary adenosine was determined at 1 and 3 hr postreperfusion in the ischemic bed when pretreated with saline or diltiazem. Myocardial infarct size was reduced significantly only in animals pretreated with diltiazem compared to saline-treated animals. At 1-hr postreperfusion, subendocardial flow (microspheres) was significantly higher only with diltiazem pretreatment compared to the saline group (100 +/- 17 vs. 54 +/- 8 ml/min/100 g, respectively) and subendocardial reperfusion flows were negatively correlated to infarct size (r = 0.97, P less than .05). Thus, diltiazem only improves reflow and infarct size when infused before occlusion and this improved reflow does not occur via a direct vasodilator action of diltiazem. When maximal vasodilating doses of adenosine were given, flow in the ischemic region was nearly identical for saline and diltiazem pretreated groups despite higher preadenosine flows in the diltiazem group (higher resting flow occurred at the expense of the existing flow reserve).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗

PubMed1987

The effect of diltiazem on ST-segment elevation and myocardial blood flow distribution during pacing-induced ischemia.

The purpose of this study was to determine if diltiazem can reduce the severity of pacing-induced ischemia independently of increases in overall and microregional ischemic blood flow. Sixteen anesthetized dogs were subjected to atrial pacing and had their left anterior descending coronary arteries (LAD) occluded until significant ST-elevation occurred. Cessation of pacing resulted in abolition of ST-segment elevation. ST-elevation as well as hemodynamics were measured during 5 min periods of pacing + LAD stenosis before, and 10, 40 and 70 min after treatment with intracoronary (i.c., just distal to the stenosis) diltiazem (1.8 micrograms/kg), i.v. diltiazem (180 micrograms/kg) or saline. Myocardial blood flow was measured using radioactive microspheres under baseline conditions, pacing, pacing + stenosis, and pacing + stenosis + drug (70 min post-drug). Both i.c. and i.v. diltiazem significantly and similarly reduced pacing-induced ST-elevation at 40 and 70 min post-drug with the highest measured reductions occurring for both at 70 min (50-60% reduction). Overall ischemic regional myocardial blood flow was unaffected by i.c. and i.v. diltiazem. Diltiazem given i.v. resulted in reduced flow in the lightly ischemic region and increased flows in the subepicardial half of the severely ischemic region. Diltiazem given i.c. resulted in a reduced subepicardial flow in the lightly ischemic region with no other changes occurring in the other regions. Thus, both i.c. and i.v. diltiazem can reduce the severity of pacing-induced ischemia and, in the doses given, in an equivalent fashion. Diltiazem also seems to be able to reduce severity of ischemia in a manner independent of increases in ischemic region flow and in fact can reduce flow in marginally ischemic tissue.

Animals↗

PubMed1987

Beta-adrenoceptor stimulation and blockade during myocardial ischemia in dogs: effect on cardiac O2 supply and consumption.

The effect of beta-adrenoceptor blockade and activation on ischemic regional and microregional myocardial O2 supply/consumption parameters was assessed in 28 open chest, anesthetized dogs. Ten minutes after LAD occlusion, dogs were given i.v. saline, 2 mg/kg propranolol, 0.2 mg/kg pindolol, or 1 microgram/kg per min isoproterenol. Coronary blood flow was determined using radioactive microspheres before and 2 h after LAD occlusion while O2 supply/consumption parameters were determined using microspectrophotometry. Ischemia resulted in a 66% reduction in subendocardial flow in controls in the ischemic zone and no experimental treatment significantly altered this flow. Pindolol resulted in a significant improvement in the ischemic regional subendocardial/subepicardial flow ratio (from 0.69 in the control ischemic region to 0.88 during pindolol treatment). O2 extractions were significantly increased and O2 consumptions were significantly depressed in the ischemic regions of all groups. O2 extractions were increased to a lesser degree in the ischemic region with the use of pindolol and propranolol. Propranolol and pindolol both significantly decreased the proportion of veins with low (0-20%) O2 saturations in the ischemic region indicating an improved microregional distribution of blood flow and/or O2 consumption within the ischemic region.

Adrenergic beta-Agonists↗

PubMed1987

Effect of aortic stenosis on oxygen balance in partially ischemic myocardium.

Valvar aortic stenosis can result in myocardial underperfusion with or without coronary obstruction. The purpose of this study was to determine how hearts with valvar aortic stenosis without hypertrophy can maintain their oxygen supply/consumption balance with partial left anterior descending coronary artery (LAD) occlusion. Open-chested, anesthetized dogs (n = 9) were subjected to mild valvar aortic stenosis and then to a reduction of LAD flow to 50% of baseline, while controls (n = 9) received partial LAD occlusion without aortic stenosis. Blood flows were determined before and after aortic stenosis and after LAD occlusion using radioactive microspheres. The hearts were then removed for microspectrophotometric analysis of regional venous and arterial oxygen saturation. Aortic stenosis resulted in a pressure gradient of approximately 50 mm Hg, representing mild aortic stenosis. Only a slight increase in myocardial blood flow was seen with aortic stenosis. Ischemia resulted in a significant drop in blood flow in control (40%) and aortic stenosis (55%) animals compared with their own preocclusion values. These ischemic region flows were not different from each other. Aortic stenosis itself did not alter oxygen extraction, although partial occlusion similarly increased extraction for all groups in the ischemic zone. The LAD occlusion resulted in a decreased oxygen consumption in the occluded region of all groups, with no differences noted between control and aortic stenosed animals. Thus, mild, acute aortic stenosis without hypertrophy does not appear to significantly increase the severity of an ischemic episode precipitated by partial LAD occlusion.

Acute Disease↗

PubMed1987

Effect of intracoronary diltiazem on ST-segment elevation and myocardial blood flow during pacing-induced ischemia.

This study was performed to determine if diltiazem can reduce the severity of pacing-induced ischemia independently of its peripheral hemodynamic effects and of increases in ischemic region blood flow. Twelve anesthetized dogs were subjected to atrial pacing and had their left anterior descending coronary arteries (LAD) occluded gradually until ischemia ensued (greater than 10 mV epicardial ST-segment elevation). Cessation of pacing resulted in abolition of ST-segment elevation. ST-segment elevation, as well as peripheral and coronary hemodynamics, was measured during 5-min periods of pacing + LAD stenosis before and 0, 30, and 60 min after treatment with intracoronary (just distal to the stenosis) saline or 1.8 micrograms/kg diltiazem. Myocardial blood flow was measured using radioactive microspheres during pacing, pacing + stenosis, and pacing + stenosis + drug treatment at 60 min. Diltiazem significantly reduced ST-segment elevation approximately 50% at 0, 30, and 60 min compared with elevations seen in animals treated with saline as well as predrug values. No changes in blood pressure, heart rate, or LAD flow occurred with diltiazem. Overall ischemic tissue flow and its transmural distribution were not different with diltiazem compared with saline treatment. Thus, diltiazem can decrease the severity of pacing-induced ischemia independently of its peripheral effects and of increased ischemic region blood flow.

Animals↗

PubMed1987

T4-induced cardiac hypertrophy and the perfused and total microvasculature of the heart.

The purpose of the present investigation was to determine the effects of thyroxine (T4), which induces myocardial hypertrophy, on the number per square millimetre and volume per cubic millimetre of both the total and perfused portions of the arteriolar and capillary beds of the heart. Studies were conducted in the subendocardial and subepicardial regions of the left ventricle of anesthetized open-chest rabbits. Fluorescein isothiocyanate-dextran (i.v.) or radioactive microspheres (intra-atrial) were injected to label the perfused microvessels or to determine coronary flow in three groups of rabbits: controls, and rabbits given 0.5 mg/kg T4 for 3 days and for 16 days. Fluorescent photography was used to identify the perfused microvessels. An alkaline phosphatase stain was employed to locate the total microvascular bed. There were 2369 +/- 638 (SD) capillaries/mm2 and 4 +/- 3 arterioles/mm2 in control hearts. These decreased significantly to 1380 +/- 199/mm2 and 1 +/- 1/mm2, respectively, after 16 days of T4. In controls, 60 +/- 5% of the capillaries and 59 +/- 21% of the arterioles were perfused. This increased significantly to 90 +/- 5 and 86 +/- 18%, respectively, by 16 days of T4 treatment. Similar changes, although smaller, were observed after 3 days of T4. Coronary blood flow increased to 1.7 times control after 3 days and 2.9 times after 16 days of T4. No significant subepicardial versus subendocardial differences were observed in any condition or measurement. Thus, the physiological response to the increased work and increase in anatomic minimum diffusion distance is to increase flow and the proportion of the capillary bed perfused to at least maintain physiological diffusion distances.

Animals↗