Effect of volume-overload hypertrophy on the coronary circulation awake dogs.

Inadequate coronary reserve is present in left ventricular hypertrophy secondary to hypertension. Since this abnormality might be due in part to vascular hypertrophy of coronary resistance vessels in response to chronic hypertension, we studied a model of ventricular hypertrophy without hypertension. Volume-overload hypertrophy was produced by creating complete heart block in mongrel dogs; 6 to 7 weeks later the dogs were studied in the awake state. The thirteen dogs with chronic heart block had a 49% increase (P less than 0.05) in left ventricular mass compared with eight control dogs. The major findings in this study were: 1) at rest, coronary blood flow (microsphere technique) per unit weight of left ventricle was not increased in dogs with hypertrophy; and 2) the minimal coronary vascular resistance per unit weight of left ventricle calculated during iv adenosine infusion at a rate that produced maximal vasodilatation was not significantly higher in dogs with left ventricular hypertrophy than in controls (16.4 +/- 1.0 vs 14.7 +/- 1.5 kPa . litre-1 . min . 100 g, respectively). Minimal coronary vascular resistance of the entire left ventricle was significantly less in dogs with hypertrophy than controls (13.0 +/- 0.8 vs 17.3 +/- 1.7 kPa . litre-1 . min, respectively). This data suggests that vascular hypertrophy of coronary resistance vessels related to chronic hypertension may be the cause of the increased minimal coronary vascular resistance seen in dogs with pressure-overload left ventricular hypertrophy.

Effect of ethanol on electrogram changes and regional myocardial blood flow during acute myocardial ischaemia.

Acute occlusion of the left anterior descending coronary artery in dogs produced delayed conduction and diminished amplitude of bipolar electrograms recorded from ischaemic zones. Intravenous infusion of ethanol (1.2 g . kg-1), before coronary artery occlusion, delayed conduction and reduced the amplitude of electrograms recorded in normal myocardium, but attenuated ischaemia-induced electrogram changes produced by the subsequent occlusion. Ethanol (0.6 g . kg-1 iv) did not significantly alter activation of electrograms recorded from normal myocardium, but reduced ischaemia-induced electrogram changes and decreased the incidence of ventricular fibrillation elicited by rapid ventricular pacing from five of eight to one of eight dogs. Infusion of 10 or 30% (V/V) ethanol directly into a non-occluded coronary artery significantly increased conduction time and reduced electrogram amplitude recorded in the epicardium perfused by that coronary artery. These effects were more pronounced when ethanol was infused into an occluded coronary artery distal to the site of occlusion. Ethanol did not alter regional myocardial blood flow determined by labelled microspheres during ischaemia. Thus, despite a direct depressant effect on extracellular electrical activity recorded from normal and ischaemic myocardium, ethanol reduced the severity of ischaemia-induced electrogram alterations and decreased the incidence of ventricular fibrillation when given intravenously prior to coronary artery occlusion.

Abnormal subcellular localization of GABAA receptor subunits in schizophrenia brain.

Inhibitory neurotransmission is primarily mediated by γ-aminobutyric acid (GABA) activating synaptic GABA type A receptors (GABA(A)R). In schizophrenia, presynaptic GABAergic signaling deficits are among the most replicated findings; however, postsynaptic GABAergic deficits are less well characterized. Our lab has previously demonstrated that although there is no difference in total protein expression of the α1-6, ß1-3 or γ2 GABA(A)R subunits in the superior temporal gyrus (STG) in schizophrenia, the α1, ß1 and ß2 GABA(A)R subunits are abnormally N-glycosylated. N-glycosylation is a posttranslational modification that has important functional roles in protein folding, multimer assembly and forward trafficking. To investigate the impact that altered N-glycosylation has on the assembly and trafficking of GABA(A)Rs in schizophrenia, this study used western blot analysis to measure the expression of α1, α2, ß1, ß2 and γ2 GABA(A)R subunits in subcellular fractions enriched for endoplasmic reticulum (ER) and synapses (SYN) from STG of schizophrenia (N = 16) and comparison (N = 14) subjects and found evidence of abnormal localization of the ß1 and ß2 GABA(A)R subunits and subunit isoforms in schizophrenia. The ß2 subunit is expressed as three isoforms at 52 kDa (ß2(52 kDa)), 50 kDa (ß2(50 kDa)) and 48 kDa (ß2(48 kDa)). In the ER, we found increased total ß2 GABA(A)R subunit (ß2(ALL)) expression driven by increased ß2(50 kDa), a decreased ratio of ß(248 kDa):ß2(ALL) and an increased ratio of ß2(50 kDa):ß2(48 kDa). Decreased ratios of ß1:ß2(ALL) and ß1:ß2(50 kDa) in both the ER and SYN fractions and an increased ratio of ß2(52 kDa):ß(248 kDa) at the synapse were also identified in schizophrenia. Taken together, these findings provide evidence that alterations of N-glycosylation may contribute to GABAergic signaling deficits in schizophrenia by disrupting the assembly and trafficking of GABA(A)Rs.

Sympathetic denervation limited to a region of acutely ischemic canine myocardium increases excitability threshold and duration of bipolar electrograms.

This study determines the direct effects of sympathetic denervation on excitability threshold and bipolar electrograms in acutely ischemic myocardium. Regional denervation was performed by application of phenol to the epicardium surrounding the ischemic zone in order to eliminate the possible hemodynamic effects that global cardiac denervation may exert on the ischemic zone. Data were obtained during serial occlusions (less than or equal to 6 minutes in duration) of left anterior coronary artery in open-chest dogs with sympathetic denervation performed before the last occlusion. Late diastolic threshold was measured every 5 seconds by a constant voltage pacemaker which automatically registered threshold in stimulus duration. During ischemia, regional denervation (n = 9) increased peak excitability threshold from 240 +/- 51 (standard error of the mean) to 552 +/- 182 mus (p less than 0.05) and prolonged electrographic duration in epicardium from 19 +/- 3 to 25 +/- 4 ms (p less than 0.025) and in endocardium from 20 +/- 3 to 25 +/- 4 ms (p less than 0.01). Phenol application did not alter aortic pressure, ischemic wall motion (sonomicrometer technique), or ischemic zone blood flow (microsphere technique). Thus, acute sympathetic denervation when limited to ischemic myocardium increases the peak excitability threshold and concomitantly prolongs duration of bipolar electrograms.

Effects of cardiac hypertrophy secondary to hypertension on the coronary circulation.

For many years clinicians have suspected that hypertrophied ventricles have an inadequate coronary circulation. Recent studies have confirmed early observations that flow per gram in hypertrophied ventricles is normal at rest. However, coronary vascular resistance is greatly increased when hypertension is the cause of left ventricular hypertrophy. Studies that have employed labeled microspheres to assess regional myocardial perfusion have shown that the transmural distribution of myocardial perfusion is often abnormal in dogs with left ventricular hypertrophy. In addition, studies of cardiac hypertrophy in many animal models have shown that maximal coronary vasodilatation is limited substantially. Furthermore, when hypertrophied hearts are subjected to a physiologic stress that induces coronary vasodilatation, endocardial underperfusion occurs frequently. Thus, studies in animals suggest that cardiac hypertrophy adversely affects the coronary circulation. The availability of new techniques for estimating phasic and transmural coronary blood flow in man should make it possible to extend these studies to patients with cardiac hypertrophy.

Comparison of interventricular septal motion studied by ventriculography and echocardiography in patients with atrial septal defect.

Abnormal systolic interventricular septal motion is an echocardiographic manifestation of right ventricular volume overload. In order to determine the anatomical basis for this echocardiographic finding, septal motion recorded by left lateral or left anterior oblique ventriculograms was compared with echocardiography ventricular septal motion. Thirteen patients with secundum atrial septal defects and 7 control patients with trivial or no heart disease were included in the study. We found that on ventriculograms the systolic motion of the interventricular septum was similar in both atrial septal defect and control patients. That is, the cephalic third of the septum moved anteriorly in systole in 9 of the 13 patients with atrial septal defect and in 3 of the 7 controls. The caudal two-thirds of the septum moved posteriorly in all patients. These results are compatible with the theory that argues that the echocardiographic abnormalities of septal motion in patients with atrial septal defect result from an end-diastolic septal flattening or bowing of the septum into the cavity of the left ventricle.

Effects of short- and long-term left ventricular hypertrophy on coronary circulation.

Although most studies suggest that coronary vasodilator responses are impaired in dogs with cardiac hypertrophy, the factors that contribute to this impairment have not been elucidated. To determine if the duration of hypertrophy was an important determinant, we studied coronary vasodilator responses in awake dogs with two-kidney renal hypertension of 6 wk (n = 11) and 6 mo (n = 8) duration. The dogs with hypertension (6 wk and 6 mo) and left ventricular hypertrophy (LVH) had about a 25% (P less than 0.05) increase in LV mass and mean arterial pressure. During maximal coronary vasodilation induced with 4.7 microM . kg-1 . min-1 iv adenosine, maximal flow was significantly decreased in both groups of hypertensive dogs, and minimal coronary vascular resistance was increased by about 50% (P less than 0.05). Minimal coronary vascular resistance was similar in dogs with 6 wk and 6 mo of hypertension and LVH. These experiments suggest that 1) mild LVH (25% increase in LV mass) can significantly decrease coronary dilator reserve and 2) within the time frame examined (6 wk to 6 mo), the duration of hypertension and LVH does not increase the coronary vascular abnormalities associated with cardiac enlargement.

Relationship between changes in left ventricular bipolar electrograms and regional myocardial blood flow during acute coronary artery occlusion in the dog.

The purpose of this study was to determine whether a quantitative relationship existed between a reduction in regional myocardial blood flow, measured by radiolabeled microspheres, and the degree and type of changes in myocardial activation recorded in bipolar left ventricular subepicardial and subendocardial electrograms, in open-chest dogs following acute coronary artery occlusion. We found that the degree of regional myocardial ischemia was related quantitatively to the reduction in amplitude recorded with bipolar electrograms in the subepicardium and subendocardium, and to the increase in duration of subepicardial electrograms. Other characteristics measured in electrograms did not relate to the degree of ischemia. Despite a comparable reduction in regional myocardial blood flow, subepicardial conduction delay exceeded that recorded in the subendocardium, which often exhibited accelerated conduction.

Myocardial infarction in dogs with chronic hypertension and left ventricular hypertrophy.

Chronic hypertension increases the risk of myocardial infarction and the morbidity and mortality associated with it. Although accelerated atherosclerosis is partially responsible, other abnormalities in the coronary circulation associated with hypertension, such as decreased coronary vascular capacity and capillary density, could also contribute. To evaluate the effects of these nonatherosclerotic abnormalities, we produced sudden coronary occlusion in nine chronically hypertensive dogs. The mean aortic pressure and left ventricular mass were about 50% greater in hypertensive dogs than in the nine controls. Before occlusion and 5 min and 49 h after occlusion, myocardial blood flow was measured with tracer microspheres. Also, the extent of infarction in selected myocardial segments was quantified histologically. We found that coronary occlusion reduced flows to a similar extent, and that, over a 48-h period, collateral flow increased to a similar extent in the two groups. In addition, the amount of necrosis associated with a given degree of ischemia was similar in the two groups. Although the extent of the left ventricle that became ischemic was greater in the hypertensive dogs (28 +/- 2 vs. 18 +/- 4%; P < 0.05), chronic hypertension and left ventricular hypertrophy did not limit the recruitment of collateral supply or increase the amount of necrosis associated with a given degree of ischemia.

Liposome concentration in canine ischemic myocardium and depolarized myocardial cells.

To determine whether liposomes (microscopic phospholipid vesicles) may be useful in delivering drugs to a region of myocardial ischemia, we studied the concentration of positively charged and neutral liposomes containing 131I-albumin and horseradish peroxidase in ischemic myocardium of 20 dogs during the first 4 hours of experimental myocardial infarction. We studied the interaction of liposomes containing fluorescent dyes and horseradish peroxidase with isolated contracting cardiac myocytes. We found that positively charged and neutral liposomes accumulated in poorly perfused myocardium and that positively charged liposomes accumulated in the ischemic region to a greater extent than neutral liposomes [138 +/- 21 vs. 81 +/- 9% (mean +/- SE) of the concentration of liposomes in uninvolved myocardium]. Electron microscopic examination of this myocardium showed liposome contents to be located in the vascular space, in endothelial cells, and in ischemic myocytes. We found high potassium environment and that liposomal contents were scattered throughout the interior of the cells in the electron micrographs of some of the isolated myocytes. Anoxia alone for 20-30 minutes did not modify the liposome-isolated myocyte interaction or cause depolarization of the cells. We conclude that liposomes may be useful as drug carriers to depolarized ischemic myocardium, although significant uptake by normal myocardial cells cannot be expected with lecithin, cholesterol, and octadecylamine liposomes we used.

Limitations of thallium-201 myocardial perfusion scintigrams.

The reliability of myocardial perfusion scintigrams with thallium-201 (201Tl) for detecting areas of hypoperfusion was assessed in 16 closed-chest dogs. Variable areas of ischemia were produced either by occluding or stenosing the left anterior descending coronary artery. Cardiac scintigrams taken in four projections were compared with regional myocardial perfusion maps. Segmental concentrations and segmental perfusions were quantitated by counting the emissions from 201Tl and the microspheres in each of 96 segments of the left ventricle. In addition, studies with a phantom were performed. The results indicate: 1) The emissions from 201Tl and from microspheres correlated well in ischemic segments (r = 0.93 +/- SE 0.02). 2) Seven of twelve ischemic hearts had definitely abnormal scintigrams and in each of these the hypoperfused zone was greater than 4.9 grams and perfusion was decreased by more than 45%. 3) In the phantom, abnormal scintigrams could be detected in the presence of lesser deficits than in the dogs. The limitation of the thallium perfusion scintigrams will be the inconsistent detection of small perfusion deficits.

Phenol topically applied to canine left ventricular epicardium interrupts sympathetic but not vagal afferents.

The intracardiac pathways carrying the cardiovascular reflex responses mediated by cardiac sympathetic and vagal afferent fibers were examined in this study. We investigated the response to epicardial applications of bradykinin (5 micrograms) and nicotine (50 micrograms) before and after regional epicardial applications of 85% phenol in chloralose anesthetized open-chest dogs. Bradykinin stimulated sympathetic afferents, while nicotine stimulated vagal afferents. Topical applications of phenol were used to interrupt these pathways. Before phenol encircling, bradykinin significantly increased--whereas nicotine significantly decreased--mean arterial blood pressure when applied at the same sites. After phenol, nicotine applied to all sites within and outside the phenol circle continued to decrease mean arterial pressure, whereas bradykinin applied to sites within the circle no longer increased mean arterial pressure. Removal of aortic and carotid baroreceptors did not significantly affect these responses. Painting horizontal stripes of phenol on the anterior and posterior left ventricular free wall basal to the site of bradykinin application eliminated the elevation in mean arterial pressure produced by bradykinin. Reapplication of bradykinin basal to the stripe restored its response. Phenol stripes eliminated the nicotine vasodepressor response only when the stripe was painted in the atrioventricular groove. When bradykinin and nicotine were injected via a nonocclusive intracoronary catheter, both drugs elicited an early depressor response (interrupted by vagotomy) and, in some animals a late pressor response (interrupted by stellectomy). Epicardial phenol encircling the flow distribution of the cannulated coronary artery interrupted most or all of the sympathetic afferents mediating pressor responses to bradykinin or nicotine, while leaving the depressor responses intact. The depressor responses were eliminated by applying phenol to the atrioventricular groove or by transecting the cervical vagi. These data suggest that sympathetic afferent fibers travel in the superficial subepicardium in an apex-to-base direction. Vagal afferent fibers travel deeper in the myocardium until they approach the atrioventricular groove, where they ascend to the superficial subepicardium.

Interruption of sympathetic and vagal-mediated afferent responses by transmural myocardial infarction.

We have demonstrated previously that sympathetic and vagal afferents travel in an apical-to-basal course in the heart, and can be stimulated selectively with epicardial applications of bradykinin and nicotine, respectively. In this study we tested the hypothesis that transmural myocardial infarction interrupts sympathetic and vagal afferent fibers traveling through the infarction and produces regions of afferent denervation in areas apical to the infarction. In open-chest, chloralose-anesthetized dogs, transmural myocardial infarction was created by embolizing a diagonal branch of the left anterior descending coronary artery with a vinyl latex solution that was injected directly into the artery and hardened rapidly. The transmural nature of the infarction was verified by the nitro blue tetrazolium staining technique for dehydrogenase enzymes. Epicardial applications of bradykinin (5 micrograms) and nicotine (50 micrograms) were used to stimulate chemically sensitive sympathetic and vagal afferent nerve endings, respectively. Twenty-nine dogs were studied before and 90 min after creation of transmural myocardial infarction. In 20 dogs, epicardial bradykinin applied before production of transmural myocardial infarction produced a maximal pressor response of 13 +/- 3 mm Hg 40 sec after application (p less than .01 vs preapplication values), while topical nicotine produced a maximal depressor response of 14 +/- 2 mm Hg (p less than .01 vs preapplication values) 20 sec after application at all sites tested. Ninety minutes after production of transmural myocardial infarction, epicardial sites basal to the infarction continued to respond normally to both drugs, while sites within the area of infarction and apical to the area (noninfarcted myocardium) no longer showed a pressor response to topical bradykinin or a depressor response to topical nicotine.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of ventricular hypertrophy on the coronary circulation.

Recent animal studies suggest that cardiac hypertrophy compromises the coronary circulation. Although flow per gram of ventricle in most animal models of hypertrophy is normal, coronary vasodilator responses to pharmacological or physiological stimuli are mildly impaired. Studies of regional perfusion indicate that the limitation of coronary vasodilator capacity in hypertrophied ventricles primarily affects the endocardium. In contrast to studies in animals, measurements of coronary reactive hyperemia in man suggest that coronary dilator responses are profoundly depressed in patients with severe left ventricular hypertrophy secondary to aortic stenosis. These studies in man demonstrate that alterations in the coronary circulation secondary to cardiac hypertrophy are of sufficient magnitude to contribute to the development of angina and heart failure (secondary to endocardial fibrosis) in patients with aortic stenosis.