PubMed Health⌕ Search

Biomedical subjects

R W Millard

Publications and source records attributed to R W Millard.

At least 55 records · Page 3Linked to original sources
PubMed1985

Morphological changes in the coronary circulation following experimental myocardial ischemia in swine.

The diagonal branches of the left anterior descending coronary artery in ten pigs were ligated for 5, 15, 30, 60 and 120 minutes. Pieces of occluded vessels were fixed with 2.5% buffered glutaraldehyde and processed for scanning and transmission electron microscopy. After 5 to 30 minutes of occlusion, endoplasmic reticulum and mitochondria begin to swell, vacuoles appear, and the number of pinocytic vesicles in endothelial cells decrease. After 60 minutes, endothelial cells contained numerous vacuoles, endoplasmic reticulum and mitochondria were markedly swollen, leukocytes and fragments detached from smooth muscle cells had infiltrated the subendothelial space, and endothelial cells were partially disrupted. Following 120 minutes of occlusion, internal elastic lamina had split, leukocytes had migrated into tunica media and smooth muscle cells had obviously penetrated into the subendothelial space, but no endothelial denudation or associated platelet accumulation was seen. These observations indicate that leukocyte infiltration and intrusion of partially disrupted endothelial cells precede, and may promote proliferation of medial smooth muscle cells into the tunica intima during myocardial ischemia. The events are reported for large conduit arterial branches of a main coronary artery.

Animals↗
PubMed1984

Perfluorinated organic liquids and emulsions as biocompatible NMR imaging agents for 19F and dissolved oxygen.

Emulsions of fluorocarbons are finding considerable use in physiology for intravascular oxygen transport. Their wide clinical application as blood substitutes, anti-shock, and anti-ischemic agents seems imminent. Whole body NMR imaging is rapidly gaining clinical application and may one day almost completely supplant X-ray imaging. All of the 19F compounds used in biocompatible fluorocarbon emulsions give 19F signals identical to those in the corresponding neat liquid. In concentrations of 10% w/v they are readily imaged. The paramagnetic oxygen molecule reduces T1 in such a way as to make possible whole body imaging of oxygen. T1 typically decreases from 1-4 to 0.3-0.5 seconds and is an inverse linear function of oxygen tension. Spin-lattice relaxation times versus oxygen tensions from 0 to 600 torr have been obtained for F-decalin, F-tributylamine, and F-44E. The usefulness of these 19F effects in clinical NMR imaging depends upon the sensitivity of the method and the tolerable dose. The 19F signal may find use in monitoring 19F compounds as vapors or gases dissolved in plasma or in perfluorocarbons in neat liquid or particle form.

Animals↗
PubMed1984

Effects of diltiazem, a calcium channel inhibitor, in retarding cellular damage produced during early myocardial ischemia in pigs: a morphometric and ultrastructural analysis.

A protective effect of intravenous diltiazem pretreatment on transmural histologic damage in ischemic hearts of 30 pigs was determined morphometrically. The pig hearts were rendered ischemic by ligation of the distal left anterior descending coronary artery for 20, 40 and 120 minutes in separate experiments. Heart rate, left ventricular systolic pressure and systemic diastolic pressure decreased slightly during 40 minutes of occlusion, and then recovered to control levels. However, there were no significant differences between control and diltiazem-treated groups. Blood flow, measured by the microsphere technique, was uniformly absent in the ischemic areas in both control and diltiazem-treated hearts. In the few cell layers immediately beneath the endocardium and epicardium, little cellular damage was observed in either group regardless of the duration of ischemia. In the subendocardial, mid-myocardial and subepicardial layers, less cellular damage was detected after all periods of ischemia in hearts exposed to diltiazem in comparison with that observed in control hearts. However, even in the drug-treated hearts, after 2 hours of occlusion, the cells remained severely injured. The protective effect of diltiazem on the cellular integrity in the ischemic myocardial regions appears to be independent of blood flow and may be a reflection of a direct effect of diltiazem on myocytes. The precise mechanism is unresolved. Nevertheless, in the ischemic heart without a significant collateral circulation, pretreatment with the calcium channel blocking drug, diltiazem, results in a delayed onset of cellular damage after acute coronary artery ligation and less cellular damage at ischemic periods up to 40 minutes' duration.

Animals↗
PubMed1984

A mechanical model of mitral insufficiency using canine papillary muscle preparation.

A canine papillary muscle is loaded to mimic the load of the myocardium in the wall of the left ventricle with atrio-ventricular valvular insufficiency. This mechanical model which simulates the atrio-ventricular valvular regurgitation is based on two simple assumptions. The assumptions arranged for the papillary muscle experiment are as follows: 1) the force that the myocardium encounters during muscle shortening is proportional to the muscle shortening velocity due to regurgitation through a narrow regurgitant orifice; and 2) the myocardium exerts a constant force while the aortic valve is open. The muscle shortening except the isotonic phase is ascribed solely to regurgitation since the aortic valve is closed during these phases. In the combined antegrade/retrograde ejection phase, which is characterized by a constant muscle force, the shortening velocity due to regurgitation is constant because of the assumed functional relation between the muscle force and shortening velocity. The amount of shortening assigned to regurgitation in this phase is given by the product of the velocity at the beginning point of the isotonic phase and the duration of this phase. The present in-vitro studies offer an alternative explanation for decrease in the regurgitant fraction as total load was reduced at a constant preload. The regurgitant fraction decreased as preload was increased at a constant total load in the present study. The regurgitant fraction also decreased by either isoproterenol or CaCl2 administration via the coronary artery.

Animals↗
PubMed1983

Mitochondrial function in canine experimental cardiac hypertrophy.

Concentric left ventricular hypertrophy was produced in puppies by coarctation banding of the aorta at age 7 weeks. Hemodynamic, morphologic and biochemical studies were carried out 18 months after the operation. Systolic blood pressure proximal to the aortic constriction was 216 +/- 16 mmHg in experimental dogs compared with 115 +/- 5 mmHg in littermate control dogs. Ejection fraction of control and experimental dogs were 59 +/- 4 and 64 +/- 7, respectively. The left ventricular end-diastolic pressure was 6.0 +/- 0.4 in control and 8.4 +/- 1.1 in experimental dogs. There was no sign of overt heart failure in the experimental dogs. Anatomical analysis of different regions of the heart indicated that LV mass in the experimental dogs was increased by about 60%. Ultrastructure of mitochondria in situ, as observed under electron microscope, was normal both in control and hypertrophic hearts. Mitochondria isolated from epicardial and endocardial regions of the stable hypertrophic hearts showed normal rates of respiration, phosphorylation, citrate synthase, and cytochrome c oxidase activities compared to those isolated from hearts of littermate control dogs. It was, therefore, concluded that mitochondrial function is adequately preserved to meet the increased demand for energy in this model of stable cardiac hypertrophy of long duration.

Animals↗
PubMed1983

Connective tissue changes in early ischemia of porcine myocardium: an ultrastructural study.

Scanning electron microscopy and transmission electron microscopy were used together with tannic acid and ruthenium-red staining to examine connective tissue damage caused by acute myocardial ischemia for 20, 40 and 120 min in pig hearts. The microsphere blood flow technique revealed that blood flow was approximately 0.02 ml/min/g in inner, middle and outer thirds of the ischemic zone. After 20 min of occlusion of the left anterior descending coronary artery, the collagen network and microfilaments became irregularly arranged. After 40 min of occlusion, ruthenium-red positive glycoprotein material around the collagen fibrils and elastin began to disappear. After 2 h occlusion, the collagen fibrils and microfilaments had separated from the basement membrane. Collagen fibrils, elastic fibers, and microfilaments were broken down and were found in decreased quantities. These results have revealed that the connective tissue remains intact during the first 20 min of coronary occlusion despite zero blood flow and mild cellular changes but does undergo prominent alterations after 40 min of occlusion.

Animals↗
PubMed1983

Hemodynamic and regional blood flow distribution responses to dextran, hydralazine, isoproterenol and amrinone during experimental cardiac tamponade.

Four different interventions were examined in dogs with cardiac tamponade. Infusion of 216 to 288 ml saline solution into the pericardium reduced cardiac output from 3.5 +/- 0.3 to 1.7 +/- 0.2 liters/min as systemic vascular resistance increased from 4,110 +/- 281 to 6,370 +/- 424 dynes . s . cm-5. Left ventricular epicardial and endocardial blood flows were 178 +/- 13 and 220 +/- 12 ml/min per 100 g, respectively, and decreased to 72 +/- 14 and 78 +/- 11 ml/min per 100 g with tamponade. Reductions of 25 to 65% occurred in visceral and brain blood flows and in a composite brain sample. Cardiac output during tamponade was significantly increased by isoproterenol, 0.5 microgram/kg per min intravenously; hydralazine, 40 mg intravenously; dextran infusion or combined hydralazine and dextran, but not by amrinone. Total systemic vascular resistance was reduced by all interventions. Left ventricular epicardial flow was increased by isoproterenol, hydralazine and the hydralazine-dextran combination. Endocardial flow was increased by amrinone and the combination of hydralazine and dextran. Right ventricular myocardial blood flow increased with all interventions except dextran. Kidney cortical and composite brain blood flows were increased by both dextran alone and by the hydralazine-dextran combinations. Blood flow to small intestine was increased by all interventions as was that to large intestine by all except amrinone and hydralazine. Liver blood flow response was variable. The most pronounced hemodynamic and tissue perfusion improvements during cardiac tamponade were effected by combined vasodilation-blood volume expansion with a hydralazine-dextran combination. Isoproterenol had as dramatic an effect but it was short-lived. Amrinone was the least effective intervention.

Aminopyridines↗
PubMed1983

Flow-independent improvement by diltiazem of ischemia-induced conduction delay in porcine hearts.

The calcium channel blocking agent, diltiazem, improves ischemia-induced conduction delays in the canine heart. It is not known, however, if the improvement of myocardial blood flow caused by diltiazem participates in this response. Accordingly, ischemia-induced conduction delay was measured during brief coronary artery occlusion before and after administration of diltiazem in nine anesthetized pigs with fixed heart rate. Acute coronary occlusion prolonged subendocardial (mean +/- standard error of the mean, 39.9 +/- 3.9 ms) and subepicardial (41.6 +/- 4.1 ms) conduction times (time to peak of the bipolar electrogram in each region) by 51 +/- 4 and 58 +/- 5%, respectively. Regional myocardial blood flow at the ischemic electrode sites was 0.006 +/- 0.002 ml/min per g and was unaffected by diltiazem. Intravenous diltiazem pretreatment (0.01, 0.1, 0.3 and 1.0 mg/kg) 5 minutes before coronary occlusion significantly reduced the ischemia-induced conduction delay in both subendocardial and subepicardial regions during coronary occlusion. The pigs in which ventricular fibrillation occurred within 10 minutes showed a significantly longer conduction delay than that observed in pigs in which ventricular fibrillation occurred later (greater than 10 minutes). Thus, the data suggest that the reduction of ischemia-induced conduction delay produced by diltiazem is independent of blood flow changes and, therefore, that diltiazem may have a beneficial antiarrhythmic action.

Animals↗
PubMed1983

Ischaemia-induced changes in canine cardiac sarcoplasmic reticulum.

Effects of myocardial ischaemia on sarcoplasmic reticulum (SR) of dog hearts were investigated. Regional ischaemia was produced by occlusion of the left circumflex artery, and a microsomal fraction enriched in vesicles of SR was isolated from subendocardium (Endo) and subepicardium (Epi) of control and ischaemic areas of the heart. No significant changes occurred in ischaemic Epi. A loss of in vitro activities (ie calcium transport and ATPase) was found for SR from ischaemic Endo which paralleled the changes in the histology of the tissue. At 5 min of coronary occlusion, Ca2+ binding and Ca2+-ATPase activities of SR from ischaemic Endo were normal. A decrease in the activities of SR was first evident at 15 min after the occlusion, decreased further at about 30 min and remained at that level at 60 min of ischaemia. The maximal rate of Ca2+ uptake did not parallel the Ca2+-binding and Ca2+-ATPase activities. The degree of cAMP-dependent phosphorylation by endogenous and exogenous protein kinase was not different between SR from control and ischaemic areas. A participatory role of SR in the ischaemic impairment of left ventricular systolic and diastolic performance is discussed.

Animals↗
PubMed1983

Reflex chronotropic and inotropic effects of calcium channel-blocking agents in conscious dogs. Diltiazem, verapamil, and nifedipine compared.

In chronically instrumented, conscious dogs, rapid injection of equihypotensive doses of three calcium channel-blocking agents, verapamil (250 micrograms/kg), diltiazem (200 micrograms/kg) and nifedipine (50 micrograms/kg), produced disparate chronotropic and inotropic responses. Although they all decreased mean arterial pressure by about 10%, heart rate (93 +/- 4 beats/min) was markedly increased to 175 +/- 12 with nifedipine, to 163 +/- 15 with verapamil, and only slightly increased to 118 +/- 7 with diltiazem. Contractile responses measured before (left ventricular dP/dtmax, 2749 +/- 131 mm Hg/sec) and during left ventricular ejection (endocardial dimension dD/dtmax, 57 +/- 4 mm/sec) were increased by 24% and 14% with nifedipine, decreased by 26% and 22% with verapamil, and were unchanged with diltiazem. These chronotropic and inotropic responses to rapid intravenous administration of the three drugs were increased in a dose-dependent manner. Similar results also were observed after slow infusion of these drugs. To determine the extent to which autonomic reflexes participated in these cardiac responses, propranolol (0.5 mg/kg) or propranolol plus atropine (0.1-0.2 mg/kg) was administered prior to injection of each calcium channel-blocking agent. Propranolol abolished the positive inotropic response to nifedipine and potentiated the negative inotropic response to verapamil. Positive chronotropic responses to verapamil, nifedipine, and diltiazem were attenuated by propranolol plus atropine. These results suggest that equihypotensive doses of the three prominent calcium channel-blocking agents exert different degrees of autonomic reflex activation in awake, unsedated dogs. These reflexes, which modulate the direct effects of calcium channel-blocking agents on chronotropic and inotropic variables of the heart, may have important clinical implications.

Animals↗
PubMed1983

Chronotropic, inotropic, and vasodilator actions of diltiazem, nifedipine, and verapamil. A comparative study of physiological responses and membrane receptor activity.

The three major, chemically distinct calcium channel-blocking drugs, diltiazem, nifedipine, and verapamil, produce coronary vasodilation in the conscious dog. Coronary vascular resistance was reduced by 50% with an intravenous dose of 3 micrograms/kg nifedipine, 30 micrograms/kg verapamil, and 100 micrograms/kg diltiazem. In conscious dogs, nifedipine and verapamil increased heart rate, whereas diltiazem produced a smaller increase in heart rate. The rate of left ventricular pressure development in conscious dogs was unaffected by diltiazem, increased by nifedipine, and decreased by verapamil. Tachycardia was reversed to bradycardia and consistent negative inotropic effects were demonstrated by all three drugs only after combined autonomic blockade with atropine and propranolol in conscious dogs. In isolated dog coronary artery strips contracted ex vivo with 50 mM potassium chloride, the ID50 for relaxation was 0.01 microM for nifedipine, 0.02 microM for verapamil, and 0.30 microM for diltiazem. In isolated ex vivo hearts, all agents produced dose-dependent negative chronotropy with a 25% reduction in spontaneous heart rate achieved by 0.09 microM nifedipine, 0.20 microM verapamil, and 0.40 microM diltiazem. Similarly, the rate of force development in isolated myocardial strips was 50% depressed by nifedipine, 0.03 microM; verapamil, 0.10 microM; and diltiazem, 0.40 microM. On a membrane level, nifedipine, verapamil, and diltiazem interacted with a putative receptor or site associated with a calcium channel specifically labelled with [3H]nimodipine. The specific binding to cardiac sarcolemma was competitively inhibited by nifedipine, only partly inhibited by verapamil, and was stimulated by diltiazem. The effects of verapamil and diltiazem, but not the effect of nifedipine, occurred at pharmacologically active concentrations. Considerable nonspecific binding of dihydropyridines to sarcolemma may account, at least in part, for discrepancies between their dissociation constants on purified sarcolemma and their ED50 in pharmacological effects. Diltiazem and verapamil (1 microM) did not alter [3H]nimodipine nonspecific binding. These results strongly suggest that calcium channel-blocking drugs may have different sites of action.

Animals↗
PubMed1983

Studies on mechanisms of diltiazem-induced protection of the ischemic myocardium: selective myocardial depressant action of diltiazem on an ischemic isolated blood-perfused canine papillary muscle preparation.

The effect of diltiazem on the contractile and vascular responses to 2 min of total occlusion and reperfusion was investigated in isolated blood-perfused canine papillary muscle preparations. Diltiazem, in doses (3 and 10 micrograms/min) that increased coronary blood flow but did not change developed tension and maximum rate of tension development (dT/dt) in papillary muscle before occlusion, attenuated tension development between 40 and 120 sec of ischemia. At-60 sec postocclusion, developed tension was at 36 +/- 4, 37 +/- 5 and 44 +/- 4% below preocclusion levels for 3, 10 and 100 micrograms/min of diltiazem, respectively (nondiltiazem treated = 24 +/- 3%). The dT/dt increased to 22 +/- 6% above preocclusion value during ischemia in nondiltiazem-treated preparations. This was blocked by diltiazem in a dose-dependent fashion. Propranolol and nitroprusside did not modify the developed tension and the increase in dT/dt of the papillary muscle during occlusion. On reperfusion, an overshoot in developed tension to 22 +/- 4% above preocclusion level was observed. This was significantly reduced by diltiazem and propranolol but not by nitroprusside. Diltiazem inhibited the maximal peak reactive hyperemia response after 2 min of occlusion by 30 to 38%. Both propranolol and nitroprusside did not change this response. The results show that diltiazem selectively depresses the inotropic state of the ischemic myocardium and suggest that a diltiazem-induced reduction in myocardial oxygen consumption during ischemia may contribute to the protection of ischemic myocardium and the reduction in reactive hypermia response in the ischemic heart.

Adenosine↗
PubMed1982

Differential cardiovascular effects of calcium channel blocking agents: potential mechanisms.

The three major calcium channel blocking agents, diltiazem, nifedipine and verapamil, inhibit calcium entry into excitable cells. Despite this apparent common action at the cell membrane, these drugs produce quantitative and frequently qualitative differences in cardiovascular variables (for example, heart rate, atrioventricular [A-V] conduction and myocardial inotropic state) when evaluated at equieffective vasodilator doses. All three drugs increase coronary blood flow in a dose-dependent fashion (nifedipine greater than diltiazem = verapamil), and produce a negative inotropic effect in vitro in isolated atria and ventricles, also in a dose-dependent manner (verapamil greater than nifedipine greater than diltiazem). However, in conscious dogs nifedipine increases, verapamil decreases and diltiazem has little effect on the inotropic state. A-V conduction is slowed by diltiazem and verapamil but not by nifedipine in anesthetized dogs and in conscious dogs as judged from the P-R interval in the electrocardiogram. Heart rate is slowed in pentobarbital-anesthetized animals but is accelerated in conscious dogs (nifedipine greater than verapamil greater than diltiazem). Nifedipine also appears to interfere significantly with the arterial baroreceptor reflex by an apparent vagolytic action that is less evident with diltiazem and verapamil. Diltiazem, and possibly verapamil and nifedipine as well, appears to retard myocardial damage that accompanies ischemia. The mechanisms and sites of action of these drugs are presumed to be at the cell membrane; however, intracellular sites may also be involved.

Animals↗
PubMed1982

Prevention of calcium paradox-related myocardial cell injury with diltiazem, a calcium channel blocking agent.

The effect of diltiazem on creatine kinase release and tissue adenosine triphosphate content was investigated during calcium paradox in the isolated perfused rat heart. Creatine kinase loss was minimal during the calcium-free phase, but there was a 100-fold increase in creatine kinase release after reperfusion with normal calcium-containing medium. Diltiazem reduced creatine kinase loss by 35 percent when added to calcium-free medium and by approximately 80 percent when added to both calcium-free and reperfusion media. Adenosine triphosphate content was significantly increased from 2.98 mumol in untreated calcium paradox hearts to 5 mumol/g dry weight in diltiazem-treated hearts. With hypothermia the calcium paradox injury was completely inhibited if the temperature of calcium-free perfusion was maintained at 15 degrees C. Diltiazem appears to exert its protective effect through its ability to prevent the cellular separation and alterations in the gap junctions during calcium deprivation of cells and to limit calcium entry into the cells after reperfusion with calcium-containing medium.

Adenosine Triphosphate↗
PubMed1982

Transmural cellular damage and blood flow distribution in early ischemia in pig hearts.

Transmural histological changes were determined morphometrically in the left ventricular free wall of 20 pigs after ligation of distal left anterior descending coronary artery for 10, 20, 40, and 120 minutes. Hemodynamics were recorded and regional blood flow distribution was measured in the ischemic zone. Coronary occlusion produced regional transmural ischemia without producing significant systemic hemodynamic change. The microsphere blood flow technique revealed that blood flow was less than 0.05 ml/min per g in all layers of the ischemic zone, i.e., inner, middle, and outer thirds. Ischemic cellular damage was classified and quantified from grade 0 to grade 5 (0 being normal and 5 being the most severe damage) with light microscopy and confirmed by electron microscopy. Layers of 200 micrometers immediately beneath the endocardium and epicardium showed minimal ischemic damage of less than grade 1.4 regardless of duration of ischemia in all hearts. In the ischemic left ventricular wall, except for the above layers, a definite transmural gradient of the cellular damage existed from the inner third (grade 2.3 +/- 0.1) to the outer third (grade 1.3 +/- 0.2) at 20 minutes of ischemia and at 40 minutes of ischemia (grades 3.6 +/- 0.1 and 1.9 +/- 0.3, respectively). The transmural ischemic damage gradient disappeared at 120 minutes of ischemia, where the inner and outer third ischemic grades were both 5.0 +/- 0.1. The data suggest that the limited ischemic damage which occurs in the few cell layers beneath endocardium and epicardium may be explained by regional collateral blood flow. An early ischemic damage wavefront phenomenon does exist in the pig myocardium and is independent of myocardial blood flow and its distribution. The transmural cell damage gradient may be the result of transmural gradients of wall stress and intramyocardial pressure in vivo. Therefore, it appears that factors other than blood flow are the major determinants of ischemic cellular damage in the left ventricular wall of hearts lacking a collateral blood supply.

Animals↗