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Biomedical subjects

M A Pfeffer

Publications and source records attributed to M A Pfeffer.

At least 145 records · Page 8Linked to original sources
PubMed1988

Atrial natriuretic factor gene expression in ventricles of rats with spontaneous biventricular hypertrophy.

A subset of Wistar-Kyoto (WKY) rats that spontaneously develops biventricular hypertrophy (BVH) in response to increased cardiac output was evaluated for ventricular expression of the atrial natriuretic factor (ANF) gene. Normal WKY rats had low levels of left ventricular ANF mRNA and minimally detectable ANF transcripts in the right ventricle. In contrast, BVH rats showed a sixfold greater ANF mRNA concentration in the left ventricle than age-matched WKY controls. BVH right ventricular ANF mRNA levels equaled those found in BVH left ventricles and were dramatically greater than WKY right ventricular controls. Unlike experimental models of hypertrophy, both left and right ventricles significantly increase ANF gene transcripts in the natural development of BVH. The left and right ventricles can concordantly respond to hypertrophy and increase ANF gene transcription.

Animals↗
PubMed1987

Ventricular enlargement and reduced survival after myocardial infarction.

Increased ventricular volume is one of the most powerful predictors of reduced survival in patients with heart disease. Despite its well-documented prognostic significance, the magnitude of the progression of ventricular dilatation from the acute to the chronic phase of myocardial infarction has only recently been appreciated. In an experimental preparation of myocardial infarction in rats, left ventricular cavitary volume increased progressively even after histologic resolution of the infarct region. We hypothesized that this remodeling of the infarcted left ventricle was a response to an increase in both systolic and diastolic wall stresses and that captopril, by reducing wall stress, would attenuate the process. For comparably sized infarcts, the captopril-treated rats had smaller ventricular volumes at common distending pressures, yet they had maintained or improved cardiac output. Most importantly, long-term captopril therapy also prolonged the survival of these rats with experimental myocardial infarction. The implication of these animal studies is that the potential exists for the attenuation of progressive ventricular enlargement and improvement of survival of patients recovering from a myocardial infarction. At the present time, no information is available in patients as to the therapeutic potential of interrupting this insidious process of ventricular dilatation in order to improve survival. Clinical trials are required to determine whether salutary benefits similar to those observed in animals can be provided to patients recovering from a myocardial infarction.

Animals↗
PubMed1987

Hemodynamic benefits and prolonged survival with long-term captopril therapy in rats with myocardial infarction and heart failure.

To determine whether the hemodynamic profile of chronic heart failure secondary to myocardial infarction could be altered, captopril was administered to female Wistar rats 3 weeks after coronary artery ligation and continued for 3 months. Captopril reduced left ventricular mass, prevented the increase in right ventricular mass observed with increasing infarct size, lessened the increase in left ventricular end-diastolic pressure, and reduced mean arterial pressure and total peripheral resistance, whereas cardiac output and heart rate were maintained. The end-diastolic volume of treated rats with moderate infarcts was significantly less than that of untreated rats, and therefore the ejection fraction index was significantly increased. In rats given captopril until death or for a period of up to 1 year, survival was significantly prolonged, particularly in those rats with moderate-sized infarcts.

Animals↗
PubMed1986

Increased left ventricular volume following myocardial infarction in man.

To determine the relationship between left ventricular volumes and the magnitude of wall motion abnormality in the chronic post myocardial infarction period, the right anterior oblique left ventriculogram was analyzed in 55 patients with left anterior descending coronary artery disease. The size of the infarct segment was determined by measuring the percentage of the circumference of the left ventricular silhouette that was akinetic and/or dyskinetic. Four groups of patients were defined with increasing degrees of wall motion abnormality based on the percent of the diastolic perimeter that was akinetic and/or dyskinetic. Marked increases in end-diastolic and end-systolic volumes were observed across groups of increasing wall motion abnormality. These large increases in volume could not be accounted for by an increase in filling pressures. Ejection fraction fell in proportion to the increase in wall motion abnormality across groups. This study demonstrated that in the chronic phase of infarction, left ventricular remodeling results in alterations in left ventricular volumes that are proportional to the degree of wall motion abnormality.

Blood Volume↗
PubMed1986

Altered sensitivity to increases in vascular resistance in rats with hypertension and myocardial infarction.

Left ventricular dysfunction reduces the ability of the heart to maintain forward output when subjected to the additional stress of an increased vascular resistance. To determine the extent to which hearts from rats with both hypertension and myocardial infarction are sensitive to increases in vascular resistance, spontaneously hypertensive rats (SHR) and normotensive Wistar rats (NWR) with and without myocardial infarction (coronary artery ligation) were infused with methoxamine (0.08 to 1.6 mg/kg/min). Mean arterial pressure during methoxamine infusion was significantly lower in infarcted rats than in noninfarcted rats in each strain, due largely to a lower cardiac output in infarcted rats. When compared at equal pressures, the infarcted groups of each strain generated a lower cardiac output than did the respective noninfarcted groups, as a result of both a lower stroke volume and heart rate. During the methoxamine infusion, absolute pressure levels in SHR with large infarcts were similar to those in NWR. Thus, infarcted hearts from both hypertensive and normotensive rats, when subjected to the stress of an increase in vascular resistance, demonstrated an impairment of pumping ability that was related to the extent of left ventricular damage. Impaired pressure-generating capacity was most pronounced in SHR with large infarcts, which were unable to generate hypertensive levels of blood pressure.

Animals↗
PubMed1986

Left ventricular remodeling after myocardial infarction: a corollary to infarct expansion.

Dilatation of infarcted segments (infarct expansion) may occur during recovery from myocardial infarction, but the fate of noninfarcted segments is uncertain. Accordingly, left ventricular geometric changes were assessed by left ventricular angiography and M mode echocardiography on admission and 2 weeks later in 30 patients with their first acute transmural myocardial infarction. All patients demonstrated chest pain, ST segment elevation with subsequent development of Q waves (15 anterior, 15 inferior), and elevation of cardiac enzymes. Sequential left ventricular angiographic and hemodynamic findings were available in these patients by virtue of their participation in a study of thrombolysis in acute myocardial infarction. By that study design, all patients treated successfully with thrombolytic therapy and demonstrating improvement of flow in an occluded coronary artery underwent repeat cardiac catheterization. At 2 weeks there was a significant decrease in left ventricular and pulmonary capillary wedge pressures (p less than .01), whereas both left ventricular end-diastolic (LVEDV) and end-systolic (LVESV) volume indexes increased (p less than .01). The increase in LVEDV correlated directly with the percentage of the ventriculographic silhouette that was akinetic or dyskinetic at the initial catheterization (r = .71, p less than .001). To assess regional changes in both infarcted and noninfarcted segments, serial endocardial perimeter lengths of both the akinetic-dyskinetic segments (infarction zone) and of the remainder of the cardiac silhouette (noninfarction zone) were measured in all patients who demonstrated at least a 20% increase in their LVEDV at 2 weeks after myocardial infarction. Notably, there was a mean increase of 13% in the endocardial perimeter length of infarcted segments and a 19% increase in the endocardial perimeter length of noninfarcted segments. Serial M mode echocardiographic studies showed no significant change in the wall thickness of noninfarcted myocardial segments. Hemodynamic changes that occurred in this subgroup of patients included significant decreases in left ventricular end-diastolic and pulmonary capillary wedge pressures (p less than .05) and significant increases in angiographic cardiac index (p less than .01) and LVESV index (p less than .01). We conclude that in patients who manifest cardiac dilatation in the early convalescent period after myocardial infarction, there is remodeling of the entire left ventricle including infarct expansion of akinetic-dyskinetic segments and volume-overload hypertrophy of noninfarcted segments.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1986

Effects of hypertrophy and allylamine-induced fibrosis on mechanical properties of isolated rat heart muscles with references to the pumping function of the intact heart in the same models.

To examine the effects of hypertrophy and fibrosis on myocardial mechanics, we studied isolated left ventricular papillary muscles from 6-month-old male SHR and allylamine-fed rats. In SHR, the peak developed tension (DT) and the maximum rate of tension development (dT/dt) were higher compared to control male Wistar-Kyoto rats (WKY). With 15 min of hypoxia, the DT and the dT/dt declined similarly in both groups and the ratios of DT and dT/dt to their prehypoxic values after 15 min of hypoxia were not different in the two groups. From allylamine-fed rats, only 4 papillary muscles had more than 25% interstitial fibrosis by point-counting (AL-B group), but 9 muscles had no fibrotic involvement and their left ventricular hydroxyproline concentration was normal (AL-A group). The myocardial diameters, the passive stiffness constant and the duration of isometric contractions at Lmax were increased in AL-B group, but the resting tension, the DT at Lmax and the force-velocity relations did not differ from controls. The mechanical properties of the AL-A group muscles were not different from controls. However, when pumping function was examined in the intact heart from the AL-A group, the LVEDP was increased and the peak cardiac output normalized by body weight was decreased. Thus, hypertrophied muscle from SHR shows hyperfunction without an increase in susceptibility to hypoxic stress. Even if fibrosis progresses, hypertrophy can compensate for the reduction in contractile component up to a certain degree.(ABSTRACT TRUNCATED AT 250 WORDS)

Allylamine↗
PubMed1985

Mechanism of the negative inotropic action of leukotrienes C4 and D4 on isolated rat heart.

Leukotrienes C4 and D4 (LTC4 and LTD4), possible mediators of cardiac dysfunction during inflammatory injury, may depress cardiac function by reducing coronary flow or by exerting a negative effect directly on the myocardium. We used an isovolumic rat heart preparation perfused at constant pressure and measured left ventricular developed pressure (mmHg), coronary flow (ml.min-1), oxygen extraction, and myocardial oxygen consumption and delivery (mumol O2.[gramme dry weight]-1.min-1) during infusion of five doses of angiotensin II, LTC4, LTD4 (approximately 10 to approximately 300 pmol.min-1), and noradrenaline (400 to 2000 pmol.min-1), or perfusion with medium which contained calcium at half-concentration. LTC4 and LTD4 were equipotent with angiotensin. At low effective doses, increased oxygen extraction offset the decrease in oxygen delivery, maintaining a stable level of oxygen consumption and left ventricular developed pressure. At the highest doses, angiotensin, LTC4 and LTD4 reduced coronary flow from 21 to 15, 21 to 13, and 21 to 13 ml.min-1, respectively. And, despite greater oxygen extraction of 59%, 58% and 65% for angiotensin, LTC4 and LTD4, left ventricular developed pressure fell from a baseline of 120 mmHg to 113, 106 and 92, respectively. In contrast, low calcium perfusion reduced left ventricular developed pressure (126 to 92) and oxygen extraction (46 to 30%) without changing coronary flow or oxygen delivery. These results suggest that LTC4 and LTD4 are potent coronary vasoconstricting agents which depress cardiac function by limiting oxygen delivery.

Angiotensin II↗
PubMed1985

Left ventricular hypertrophy and pressure generating capacity in aging genetically hypertensive rats.

Alterations in the relationship between the degree of left ventricular hypertrophy and the maximum pressure generating capacity were assessed in two models of genetic hypertension in rats. Both the spontaneously hypertensive rat (SHR) and the Dahl salt-sensitive (DS) rat developed systemic hypertension and progressive increases in left ventricular mass. In the DS rat, the magnitude of the hypertension and ventricular hypertrophy produced was in direct relation to the level of dietary sodium intake. At 6 months of age, the pressure generating capacity of all hypertensive rats was directly related to the left ventricular weight/body weight ratio. With the moderate level of hypertrophy observed in the 12-month-old SHRs and DS rats on a low salt diet, the correlation between left ventricular weight and augmented pressure generating capacity during isovolumic contractions was maintained. With the more severe degrees of left ventricular hypertrophy observed in 18- and 24-month-old SHRs and 12-month-old DS rats on a moderate salt diet, the further addition of ventricular mass was no longer associated with a proportional augmentation in maximal pressure development. These studies suggest that in genetic hypertension in rats, both the magnitude and duration of the hypertension are important determinants of the degree of hypertrophy and the functional status of the ventricle.

Age Factors↗
PubMed1985

Survival after an experimental myocardial infarction: beneficial effects of long-term therapy with captopril.

Although vasodilator therapy has been shown to improve functional capacity in patients with congestive heart failure, there is no evidence that such therapy can prolong survival. Coronary artery ligation in the rat was used to produce a wide range of myocardial infarct sizes and a resultant spectrum of left ventricular dysfunction. To determine the relationship between size of myocardial infarction and long-term survival and to test the hypothesis that long-term therapy with captopril could improve survival after myocardial infarction, 302 rats were randomly assigned to either placebo or captopril therapy 14 days after coronary artery ligation. The animals were kept in a laminar flow unit and followed daily for a 1 year period or until spontaneous death. Size of myocardial infarction was determined by planimetry of serial histologic sections of the left ventricle. One year survival in placebo-treated rats decreased markedly in direct relation to increasing size of infarction (from 71% in noninfarcted rats to only 8% in rats with large infarcts). Long-term captopril therapy prolonged the survival of rats with infarcts (p less than .02). The most marked improvement in survival was noted in the animals with infarcts of moderate size, in which 1 year survival was 21% in the placebo-treated rats and 48% in the captopril-treated rats. Thus, in this experimental preparation of myocardial infarction and left ventricular dysfunction, survival was inversely related to size of infarction. Long-term therapy with captopril, which we had previously shown to improve left ventricular function and lessen dilatation in the chronic phase of infarction, also had a pronounced effect on prolonging survival in this preparation of chronic infarction.

Animals↗
PubMed1985

Influence of chronic captopril therapy on the infarcted left ventricle of the rat.

To determine whether the relationship between infarct size and ventricular performance, volume, and compliance could be altered favorably, captopril was administered to rats for 3 months following coronary artery ligation. Baseline left and right ventricular and systemic arterial pressures and aortic blood flow, and maximal stroke volume and cardiac indices attained during a volume loading, were measured. Passive pressure-volume relations of the left ventricle were determined, and the slopes of segments of this relation were analyzed to characterize ventricular chamber stiffness. In untreated rats, left ventricular end-diastolic pressure progressively rose (from 5-28 mm Hg) as a function of infarct size, whereas, in captopril-treated rats, filling pressure remained within normal limits (5 +/- 1 mm Hg) in all but those with extensive infarcts. Chronic captopril therapy reduced baseline mean arterial pressure and total peripheral resistance, yet maintained cardiac and stroke outputs in rats both with and without infarcts. In untreated rats, maximal pumping ability progressively declined with increasing infarct size, whereas, in captopril-treated rats, peak stroke volume index remained within normal limits in all but those with extensive infarcts. The in vitro left ventricular volumes of captopril-treated rats were significantly less than those of untreated rats. The maintenance of forward output from a lesser dilated left ventricle yielded an index of ejection fraction for treated rats with moderate and large infarcts that was significantly elevated compared with that of untreated rats with infarcts of comparable size. Left ventricular chamber stiffness, which fell as infarct size increased in untreated rats, was normalized by chronic captopril therapy. Thus, captopril attenuated the left ventricular remodeling (dilation) and deterioration in performance that were observed in rats with chronic myocardial infarction.

Animals↗
PubMed1984

Ventricular performance in rats with myocardial infarction and failure.

Ventricular performance was assessed in rats three weeks following coronary artery ligation and the subsequent production of a wide range of infarct sizes. The entire spectrum of ventricular dysfunction was observed, from minimal impairment to overt congestive heart failure. Rats with small infarcts ejected normal baseline and volume-stressed forward outputs from a modestly dilated ventricular chamber. Rats with moderate infarcts exhibited normal baseline hemodynamics but had a reduced reserve flow capacity when challenged with a volume load despite considerable ventricular dilatation. Rats with large infarcts demonstrated frank congestive heart failure with elevations in both left and right ventricular filling pressures and consequent right ventricular hypertrophy; marked reductions in both baseline and volume-stressed forward outputs; and ventricular volumes that were twice those of rats without infarcts. Thus, a progressive impairment in ventricular performance and an increase in chamber volume occurred in relation to infarct size in rats with healed myocardial infarction.

Animals↗
PubMed1984

Renal and systemic hemodynamic responses to intravenous infusion of leukotriene C4 in the rat.

We studied the systemic and renal hemodynamic effects of leukotriene C4 (2 micrograms/kg per min for 5 minutes, iv) in the rat. During the period of its infusion, leukotriene C4 produced a significant elevation of mean arterial pressure and reductions in cardiac output and renal blood flow, as measured by electromagnetic flow probes. These effects were abolished by FPL55712 , a putative antagonist of sulfidopeptide leukotrienes, but not by saralasin or indomethacin. Leukotriene C4 also resulted in an average loss of 20% in plasma volume which, during the postinfusion period, perpetuated the low cardiac output state and thus provoked the release of angiotensin II. This vasoactive peptide sustained the elevation in systemic vascular resistance and the reduction in renal blood flow over a 70-minute postinfusion observation period. Consequently, glomerular filtration rate fell by approximately 50%. These angiotensin II-mediated effects were abolished by saralasin. Indomethacin prevented the leukotriene C4-induced loss of plasma volume and, thus, allowed for the significant recovery of cardiac output and renal blood flow during the post-infusion period, thereby preserving glomerular filtration rate. We conclude that leukotriene C4 exerts direct systemic and renal vasoconstrictor, as well as cardiodepressant effects, during the period of its infusion. By virtue of its vasopermeability enhancing effect, leukotriene C4 also results in an immediate loss of plasma volume, an effect which requires the presence of secondarily generated cyclooxygenase products and which perpetuates the hemodynamic abnormalities observed beyond the period of leukotriene C4 infusion.

Animals↗
PubMed1984

Role of angiotensin II in the altered renal function of congestive heart failure.

Glomerular and tubule functions were assessed by micropuncture in rats with extensive myocardial infarction produced by ligation of the left coronary artery 4 weeks prior to study. When compared to sham-operated control rats, rats with myocardial infarction involving 40 +/- 4% of the left ventricular circumference had lower mean arterial pressure (96 +/- 5 vs. 122 +/- 4 mm Hg, P less than 0.005), and higher left ventricular end-diastolic pressure (24 +/- 3 vs. 5 +/- 0 mm Hg, P less than 0.001). Renal cortical microcirculatory dynamics of rats with myocardial infarction were characterized by reduced glomerular plasma flow rate (75 +/- 8 vs. 165 +/- 17 nl/min, P less than 0.005), but a proportionately lesser decline in single nephron glomerular filtration rate (28.0 +/- 2.8 vs. 41.7 +/- 3.1 nl/min, P less than 0.025), accounting for the observed rise in single nephron filtration fraction (0.38 +/- 0.02 vs. 0.25 +/- 0.02, P less than 0.005). These renal hemodynamic alterations in myocardial-infarcted rats were accompanied by a striking elevation in efferent arteriolar resistance (3.03 +/- 0.31 vs. 0.95 +/- 0.16 X 10(10) dyn X sec X cm-5, P less than 0.001). In addition, fractional proximal fluid reabsorption, assessed by end-proximal tubule fluid-to-plasma inulin concentration ratio, was elevated (2.21 +/- 0.12 vs. 1.64 +/- 0.09, P less than 0.025). The intravenous infusion of teprotide, an angiotensin I-converting enzyme inhibitor, led to the return of glomerular plasma flow rate, single nephron filtration fraction, single nephron glomerular filtration rate, efferent arteriolar resistance, and fractional proximal fluid reabsorption in myocardial-infarcted rats to, or toward, the levels found in control rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1984

Pharmacologic regression of cardiac hypertrophy in experimental hypertension.

The normal heart has the capacity to either augment or reduce its mass in relation to long-term alterations in hemodynamic and metabolic demands. However, once cardiac hypertrophy is established, as in hypertensive heart disease, it is less clear whether the augmented mass can revert to normal with control of arterial pressure. In experimental models in which systemic hypertension is induced in genetically normotensive animals, left ventricular weight generally returns toward normal with the removal of the inciting stimulus for the hypertension. However, when arterial pressure control is achieved by pharmacologic therapy, and the inciting stimulus (mechanical or genetic) is intact, the results of pressure reduction on ventricular weight are much more variable than that observed with the removal of a mechanical stimulus for hypertension. It is hypothesized that pharmacologic pressure reduction elicits secondary adjustments in cardiorenal and neurohumoral function which have important influences on ventricular hypertrophy.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1983

Prevention of the development of heart failure and the regression of cardiac hypertrophy by captopril in the spontaneously hypertensive rat.

The spontaneously hypertensive rat (SHR) exhibits both a compensated phase of cardiac hypertrophy in which forward output is maintained despite persistently elevated systemic arterial pressures and a decompensated phase in which cardiac performance has deteriorated in spite of further hypertrophic growth. To determine whether chronic antihypertensive therapy prevents the development of heart failure and the progression of cardiac hypertrophy in SHR with advanced hypertension, captopril (2 g/l of drinking water), a converting enzyme inhibitor, was administered to 14 month old female SHR and normotensive American Wistar rats (NWR) for 10 months. The severe left ventricular hypertrophy of the 24 month old untreated SHR (4.37 +/- 0.2 mg/g v. 2.50 +/- 0.06 mg/g, untreated NWR) was markedly reduced (P less than 0.02) by captopril (3.01 +/- 0.1 mg/g). Chronic therapy prevented the reduction of both baseline and maximal cardiac indices in SHR, but did not alter blood flow in NWR. Left ventricular dilatation was present in 24 month old SHR and, as peak stroke volume index was diminished, the ejection fraction index of the SHR was reduced. Captopril restored this index in SHR to normal. The relation of ejection fraction index and afterload (peak systolic wall stress) was depressed in untreated SHR, but was normal in treated SHR. Thus, chronic therapy with captopril prevented the development of severe cardiac dysfunction and produced a marked regression of cardiac hypertrophy in SHR with advanced hypertensive heart disease.

Age Factors↗