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Biomedical subjects

L G Meggs

Publications and source records attributed to L G Meggs.

At least 37 records · Page 2Linked to original sources
PubMed1993

Regulation of angiotensin II receptors on ventricular myocytes after myocardial infarction in rats.

To determine the effects of acute myocardial infarction on the regulation of angiotensin II (Ang II) receptors and contractile performance of left and right ventricular myocytes, coronary artery ligation was surgically induced in rats, and Ang II receptor density and affinity and the mechanical properties of surviving muscle cells were examined 1 week later. Physiological determinations of cardiac pump function revealed the presence of ventricular failure, which was associated at the cellular level with a depression in the velocity of myocyte shortening and relengthening, a prolongation of time to peak shortening, and a reduction in the extent of cell shortening. These abnormalities in single-cell function were more prominent in left than in right ventricular myocytes. Cellular hypertrophy was documented by increases in cell length and width, which were also greater in the spared myocytes of the infarcted left ventricle. Reactive hypertrophy was accompanied by a 1.84- and 1.85-fold increase in the density of Ang II receptors on left and right myocytes, respectively. On the other hand, the affinity of Ang II receptors for the radiolabeled antagonist was not altered. However, Ang II-stimulated phosphoinositol turnover was enhanced by 3.7- and 2.5-fold in left and right myocytes, respectively, after infarction. Ventricular myocytes were found to possess the AT1 receptor subtype exclusively. In conclusion, myocardial infarction leads to impairment in the contractile behavior of the remaining cells and to the activation of Ang II receptors and effector pathway associated with these receptors, which may be involved in the reactive growth adaptation of the viable myocytes.

Angiotensin Receptor Antagonists↗
PubMed1992

Re-expression of alpha skeletal actin and regulation of alpha 1 adrenoceptor signalling in DOCA-salt hypertension in rats.

OBJECTIVE: To determine the effects of increased sympathetic nervous system activity in humoral hypertension on the regulation of surface alpha 1 adrenoceptors and signal transduction, deoxycorticosterone acetate (DOCA) salt hypertension was induced in rats and the animals killed three weeks following the initiation of hypertension. METHODS: Experiments were performed on male Sprague-Dawley rats, weighing 250-300 g, divided into two groups: DOCA-salt (n = 75), and control (n = 60). Radioligand binding studies of the alpha 1 adrenoceptors, noradrenaline stimulated phosphoinositol turnover, ADP ribosylation of 41 kD substrate by pertussis toxin, and myocardial noradrenaline content were measured in the ventricular myocardium. The expression of sarcomeric actin isoforms was examined by northern blot and hybridisation with specific oligonucleotide probes. RESULTS: The density of alpha 1 adrenoceptors was decreased by 51% in DOCA-salt treated rats. However, noradrenaline stimulated phosphoinositol turnover in myocytes from DOCA-salt hearts was not diminished. The relative quantities of pertussis toxin labelled substrates did not differ in experimental and control hearts. Myocardial noradrenaline content was reduced by 60% in DOCA-salt hearts. Northern blots on RNA extracted from hypertrophic hearts of DOCA-salt treated rats showed an upregulation of alpha skeletal actin. CONCLUSIONS: The adrenergic state present in short term DOCA-salt hypertensive hypertrophy is characterised by enhanced signal transduction via the alpha 1 adrenoceptors and the re-expression of alpha skeletal actin in enlarging myocytes.

Actins↗
PubMed1992

Chronic coronary arterial stenosis impairs alpha 1-adrenoreceptor signaling and cardiac performance in rats.

Coronary stenosis was induced in rats to determine whether chronic coronary artery constriction resulted in impairment of cardiac pump performance, alterations in alpha 1-adrenoreceptor signal transduction, and inadequate myocardial hypertrophy, and these parameters were examined 6 mo later. A 50% reduction in coronary diameter was associated with an elevation in left ventricular end-diastolic pressure, whereas left ventricular peak systolic pressure, rate of pressure rise and decay were reduced. The hypertrophic response was modest, since statistically significant increases of 11% and 23% in left and right ventricular weights were measured. Radioligand binding documented an 18% and a 38% statistically significant reduction in alpha 1-adrenoreceptor density of the left and right myocardium, respectively. ADP ribosylation of the 41-kDa substrate by pertussis toxin showed a 16% significant decrease of this parameter in the left myocardium. Moreover, a 29% decrease in norepinephrine stimulated phosphoinositol turnover was seen in myocytes, and this change was statistically significant. The depressed generation of intracellular second messengers linked to the alpha 1-adrenoreceptors was found in conjunction with a 19% significant reduction in myocardial norepinephrine content. In conclusion, the long-term effects of coronary stenosis involve impaired transduction of adrenergic signals, which, in combination with constraints on myocardial growth, may participate in the onset of ventricular dysfunction in this model.

Actins↗
PubMed1991

Cellular basis of chronic ventricular remodeling after myocardial infarction in rats.

To determine whether the hypertrophic response of the surviving myocardium after infarction leads to normalization of ventricular hemodynamics and wall stress, the left coronary artery was ligated in rats. One month later, the rats were killed. In infarcts affecting an average 38% of the free wall of the left ventricle (small infarcts), reactive hypertrophy in the spared myocardium bordering and remote from the scar was documented by increases in myocyte cell volume per nucleus of 43% and 25%, respectively. These cellular enlargements resulted in a complete reconstitution of functioning tissue. However, left ventricular end-diastolic pressure was increased, left ventricular dP/dt was decreased, and diastolic wall stress was increased 2.4-fold. After infarctions resulting in a 60% loss of mass (large infarcts), myocyte hypertrophy was 81% and 32% in the regions adjacent to and distant from the scar, respectively. A 10% deficit was present in the recovery of viable myocardium. Functionally, ventricular performance was markedly depressed, and diastolic wall stress was increased ninefold. The alterations in loading of the spared myocardium were due to an increase in chamber volume and a decrease in the myocardial mass/chamber volume ratio that affected both infarct groups. Chamber dilation was the consequence of the combination of gross anatomic and cellular changes consisting, in the presence of small infarcts, of a 6% and a 19% increase in transverse midchamber diameter and in average myocyte length per nucleus, respectively. In the presence of large infarcts, transverse and longitudinal chamber diameters expanded by 27% and 11%, respectively, myocyte length per nucleus expanded by 26%, and the mural number of myocytes decreased by 10%. In conclusion, decompensated eccentric ventricular hypertrophy develops chronically after infarction, and growth processes in myocytes are inadequate for normalization of wall stress when myocyte loss involves nearly 40% or more of the cells of the left ventricular free wall. The persistance of elevated myocardial and cellular loads may sustain the progression of the disease state toward end-stage congestive heart failure.

Adaptation, Physiological↗
PubMed1991

Chronic nonocclusive coronary artery constriction in rats. Beta-adrenoceptor signal transduction and ventricular failure.

To determine the effects of chronic coronary artery constriction on the relationship between cardiac function and regulation of beta-adrenoceptor signal transduction, the left main coronary artery was narrowed in rats and the animals were killed 5 mo later. An average reduction in coronary luminal diameter of 44% was obtained and this change resulted in an increase in left ventricular end-diastolic pressure and a decrease in positive and negative dP/dt. Significant increases in left and right ventricular weights indicative of global cardiac hypertrophy were observed. Radioligand binding studies of beta-adrenoreceptors, agonist-stimulated adenylate cyclase activity, and ADP ribosylation of 45-kD substrate by cholera toxin were all depressed in the failing left ventricle. In contrast, in the hypertrophic non-failing right ventricle, beta-adrenoreceptor density was preserved and receptor antagonist affinity was increased. In spite of these findings at the receptor level, agonist stimulated cyclic AMP generation was reduced in the right ventricular myocardium. The quantity of the 45-kD substrate was also decreased. In conclusion, longterm nonocclusive coronary artery stenosis of moderate degree has profound detrimental effects on the contractile performance of the heart in association with marked attenuation of adrenergic support mechanisms.

Adenylyl Cyclases↗
PubMed1990

Adaptive myocardial hypertrophy in the renal ablation model.

We have previously reported downregulation of the vascular alpha 1-receptor in the 5/6 renal ablation model. In this investigation we have examined the adaptive response of the heart following 5/6 renal ablation. Renal ablated and sham rats were maintained under identical conditions for 6 weeks. Despite the presence of systemic hypertension in renal ablated rats (185 +/- 10 mm Hg, P less than .01), heart weight did not differ from sham. [125I] +/- CYP binding was performed and myocardial norepinephrine (NE) content determined to evaluate myocardial sympathetic neuroeffector mechanisms. Scatchard analysis and 1-isoproterenol competition curves did not reveal a difference in the binding properties of the myocardial beta-receptor. No difference in myocardial NE was found in renal ablated and sham rats. Unexpectedly, 1-isoproterenol stimulation of adenylate cyclase was impaired in renal ablated rats (32.6 +/- 6 v 58.6 +/- 5 pmol/mg/min, P less than .01) and the dose response curve shifted to the right. We conclude that despite systemic hypertension an adaptive hypertrophic response was not present in hearts of renal ablated rats; myocardial sympathetic neuroeffector mechanisms are not altered in this model; and impaired stimulation of adenylate cyclase appears to be the result of a post-receptor defect.

Adaptation, Physiological↗
PubMed1990

Myocyte cell loss and myocyte cellular hyperplasia in the hypertrophied aging rat heart.

To determine the effects of age on the myocardium, the functional and structural characteristics of the heart were studied in rats at 4, 12, 20, and 29 months of age. Mean arterial pressure, left ventricular pressure and its first derivative (dP/dt), and heart rate were comparable in rat groups up to 20 months. During the interval from 20 to 29 months, elevated left ventricular end-diastolic pressure and decreased dP/dt indicated that a significant impairment of ventricular function occurred with senescence. In the period between 4 and 12 months, a reduction of nearly 19% in the total number of myocytes was measured in both ventricles. In the subsequent ages, similar decreases in myocyte cell number were found in the left ventricle, whereas in the right ventricle, the initial loss was fully reversed by 20 months. Moreover, from 20 to 29 months, a 59% increase in the aggregate number of myocytes occurred in the right ventricular myocardium. In the left ventricle, a 3% increment was also seen, but this small change was not statistically significant. These estimations of myocyte cellular hyperplasia, however, were complicated by the fact that cell loss continued to take place with age. The volume fraction of collagen in the tissue, in fact, progressively increased from 8% and 7% at 4 months to 16% and 22% at 29 months in the left and right ventricles, respectively. In conclusion, myocyte cellular hyperplasia tends to regenerate the ventricular mass being lost with age in the adult mammalian rat heart.

Aging↗
PubMed1990

Noncoordinate regulation of alpha-1 adrenoreceptor coupling and reexpression of alpha skeletal actin in myocardial infarction-induced left ventricular failure in rats.

To determine the effects of myocardial infarction-induced left ventricular failure on the regulation of surface alpha-1 adrenoreceptors and signal transduction, large infarcts were produced in rats and the animals killed seven days later. After the documentation of impaired left ventricular pump performance, radioligand binding studies of the alpha-1 adrenoreceptor, norepinephrine-stimulated phosphoinositol turnover, and ADP ribosylation of 41 kD substrate by pertussis toxin were examined in the hypertrophying unaffected myocardium. Moreover, the expression of sarcomeric actin isoforms was analyzed by Northern blots and hybridization with specific oligonucleotide probes. Alpha-1 adrenoreceptor density was found not to be altered in membranes obtained from the spared left ventricular tissue, whereas phosphoinositol turnover was increased 3.1-fold in the viable myocytes of infarcted hearts. Furthermore, pertussis toxin substrate was augmented 2.5-fold in membranes prepared from the surviving left ventricular myocardium. Finally, an upregulation of the skeletal actin isoform was detected in the tissue of the failing left ventricle. In conclusion, the possibility is raised that in the presence of severe myocardial dysfunction and ongoing reactive hypertrophy, effector pathways linked to the alpha-1 adrenoreceptor may stimulate the myocyte hypertrophic response which would tend to normalize cardiac hemodynamics. The reexpression of alpha skeletal actin may be a molecular indicator of the persistance of an overload on the myocardium.

Actins↗
PubMed1989

Left ventricular response to exercise and autonomic control mechanisms in end-stage renal disease.

Left ventricular (LV) function during rest and during exercise was evaluated in patients with end-stage renal disease (ESRD) in whom other causes of LV dysfunction were eliminated through rigid selection criteria. Autonomic function was also assessed in these patients with Valsalva's maneuver and plasma catecholamine determinations. Echocardiography and radionuclide ventriculography in the group with ESRD revealed no abnormalities of LV wall motion or ejection fraction. During graded exercise, patients with ESRD achieved 85% of age-predicted heart rate, and no differences in exercise tolerance or LV function were observed. Valsalva's response was abnormal in patients with ESRD, and post exercise the norepinephrine level was markedly increased (12.5 +/- 1.43 vs 8.28 +/- 0.82 nmol/L). Our results fail to indicate an independent adverse effect of ESRD on LV function.

Adult↗
PubMed1988

Myocardial hypertrophy: the effect of sodium and the role of sympathetic nervous system activity.

Dietary sodium and the myocardial alpha 1-receptor have been implicated in the hypertrophic response of myocardial tissue. Alterations in sodium homeostasis have been demonstrated to influence sympathetic nervous function, centrally and peripherally. In this investigation, we have examined the effect of dietary sodium on the development of myocardial hypertrophy; and the role of sympathetic neuroeffector mechanisms in the hypertrophic response. Studies were performed in three groups of uninephrectomized rats: A-regular diet; B-1% saline/regular diet; C-1% Saline/doca/regular diet. Groups A and B did not develop systemic hypertension (SHT). Saline treatment increased heart weight and the density of surface alpha 1-receptors; myocardial norepinephrine (NE) was reduced. Group C developed SHT. Heart weight was greatest in Group C; and myocardial NE was severely depleted. Downregulation of myocardial alpha 1-receptors, a finding consistent with the hyperadrenergic state, was observed in Group C. Our results suggest dietary sodium may modulate hypertrophic response in myocardial tissue, by altering sympathetic neuroeffector mechanisms.

Animals↗
PubMed1988

Amelioration of systemic hypertension by converting enzyme inhibition in the renal ablation model.

Hypertension associated with a reduction in renal mass has been traditionally thought of as a volume-dependent state. Recent investigations suggest important roles for systemic and glomerular resistance vessels in the pathogenesis of systemic hypertension (SHT) and progression of end-stage renal disease. To examine this relationship, investigations were performed in two groups of rats maintained for 6 weeks following 5/6 renal ablation. Group A received converting enzyme inhibition (CEI) for 6 weeks. Group B received no treatment. Systolic blood pressure and weight of remnant kidney tissue were both increased in group B (P less than 0.01). BUN did not differ in groups A and B; however, renal PGI2 excretion was increased in group A (P less than 0.01). Renal morphology was preserved in group A, with little or no evidence of glomerular sclerosis. CEI prevents SHT and enhances renal PGI2 excretion in this model. The selective increase in PGI2 may mediate systemic and renal effects of this agent.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1988

Upregulation of the vascular alpha-1 receptor in malignant DOCA-salt hypertension.

In this investigation we describe regulation of the vascular alpha-1 receptor and functional properties of resistance vessels in malignant hypertensive DOCA-salt rats (DOCA-salt). Uninephrectomized control and DOCA-salt rats were maintained for 6 weeks; microscopic renal morphology provided an index of vascular injury. Radioligand binding studies indicated a striking increase in the density of mesenteric alpha-1 binding sites in DOCA-salt (542 +/- 44 fm/mg) vs. salt control (206 +/- 4 fm/mg) and water control (223 +31 fm/mg) P less than .01. The affinity of the receptor for the radioligand [125I] (+/-) BE 2254 was reduced in DOCA-salt rats. Electrical nerve stimulation and agonist dose response curves were performed on isolated perfused mesenteric arteries. A singular correlation between increased receptor density and vascular responses in DOCA-salt rats could not be demonstrated. The norepinephrine (NE) content of mesenteric arteries was reduced in DOCA-salt (1001 +/- 32 ng/g) vs. water control (1522 +/- 44 ng/g) and saline control (1538 +/- 30 ng/g) P less than .01. Our results indicate, upregulation of the mesenteric alpha-1 receptor occurs in DOCA-salt rats, however, additional factors participate in the vascular response to adrenergic stimulation in this model.

Animals↗
PubMed1986

Effect of chronic uremia on the cardiovascular alpha 1 receptor.

Adrenergic dysfunction in uremia has been well described. Several lines of evidence suggest disorders of blood pressure regulation and myocardial response may occur secondary to adrenergic dysfunction; attenuated pressor response to norepinephrine (NE) in uremia; attenuated chronotropic responses during dialysis induced hypotension. Since the adrenergic receptors are the effector component of the adrenergic nervous system, we have employed the partially nephrectomized uremic rat, to examine the effect of chronic uremia (4-6 weeks) on the binding properties of alpha 1 receptors in rat mesenteric artery and myocardial tissue. The results indicate that moderate levels of uremia alter the binding properties of both the alpha 1 vascular and myocardial receptor.

Animals↗
PubMed1982

Renal vascular tachyphylaxis to angiotensin II: specificity of the response for angiotensin.

Hypotheses concerning angiotensin's role in states characterized by severe and sustained renal vasoconstriction, must account for the poorly sustained renal response to this agent in healthy animals and man. To assess the specificity of renal vascular tachyphylaxis to angiotensin II (AII), renal blood flow was measured with an electromagnetic flowmeter in eight anesthetized dogs. Bolus injections of AII and norepinephrine into the renal artery were adjusted to produce at least a 50% reduction in renal blood flow, and were followed by a continuous infusion of AII sufficient to reduce renal blood flow acutely by 60 +/- 10%. The response to the continuous infusion was poorly sustained, blood flow returning to near baseline within 10 minutes: At this time the response to bolus administration of AII was lost, but the response to norepinephrine was sustained. At 30 minutes the response to norepinephrine was also reduced, and there was no response in three of the eight dogs. After stopping the AII infusion, renal vascular responsiveness to norepinephrine returned almost immediately, but 30-60 minutes were required before responsiveness to AII was restored. We conclude that there is true, specific renal vascular tachyphylaxis to AII--which may well reflect receptor modulation or occupation--and that with time an additional, non-specific vasodilator mechanism can come into play.

Angiotensin II↗
PubMed1982

Contrast medium-induced renal vasoconstriction and endogenous vasoconstrictor hormones.

Hypertonic solutions, such as contrast media (meglumine/sodium diatrizoate-76%; Renografin-76), induce vasoconstriction in the renal vascular bed via an unknown mechanism. We assessed a possible role of two vasoconstrictor hormones known to be released by the kidney, angiotensin II (AII) and the prostaglandin, thromboxane. Specific inhibition of AII at the smooth muscle receptor level by saralasin (0.33-0.75 microgram/kg/min, IA) did not attenuate the response. Inhibition of prostaglandin formation by indomethacin (4 mg/kg, IV), likewise, did not prevent the decrease in renal perfusion. We conclude that neither AII nor the prostaglandin system mediate the contrast medium-induced renal vasoconstriction.

Animals↗