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Biomedical subjects

M D Lindheimer

Publications and source records attributed to M D Lindheimer.

At least 37 records · Page 2Linked to original sources
PubMed1994

Effect of autonomic blockade on pressor responses to vasopressin in pregnant rats.

OBJECTIVE: We tested the hypothesis that gestational changes in reflex neural control of the heart and vasculature contribute to altered cardiovascular responses to vasopressin during pregnancy. STUDY DESIGN: Changes in mean arterial pressure, cardiac output, total peripheral resistance, and heart rate were measured in response to constant infusion of arginine vasopressin (0.15 to 2.5 mU/kg/min) in conscious pregnant and virgin rats (n = 9) with total autonomic blockade plus restoration of baseline hemodynamics by norepinephrine infusion. RESULTS: Resting cardiac output was 40% higher and total peripheral resistance 30% lower in pregnant animals (p < 0.01). Constant infusion of arginine vasopressin evoked equivalent changes in mean arterial pressure in both groups, but the respective contributions of cardiac output and total peripheral resistance to mean arterial pressure differed between groups. Cardiac output was unchanged and the increase in total peripheral resistance was significantly blunted in pregnant vs virgin rats during arginine vasopressin infusion. Control data in nonblocked revealed similar pressor responses to arginine vasopressin in gravid compared with virgin rats but no differences in the contributions of cardiac output and total peripheral resistance to the change in mean arterial pressure. CONCLUSION: These findings suggest that neural modulation of arginine vasopressin-induced hypertension is altered during pregnancy and are consistent with a reduction in intrinsic vascular sensitivity to arginine vasopressin during gestation.

Animals↗
PubMed1994

Gestation in women with kidney disease: prognosis and management.

Physicians may be called upon to guide patients with renal disease on the advisability of conceiving or maintaining a gestation, or to manage pregnancies permitted to continue. The prevailing view is that the degree of functional impairment and the presence or absence of hypertension prior to conception determine both pregnancy outcome and the effect of gestation on the natural history of the kidney disorder (Table 3). Normotensive women with minimal dysfunction have a greater than 90% chance of success and there is little evidence that gestation will adversely affect the disease. Presence of hypertension increases the complications rate substantially if not aggressively controlled, and prognosis is also poorer in women with moderate renal dysfunction. Most gestations in the latter group succeed, but at considerable maternal risk: over 20% of these women experience renal functional deterioration, and 30-40% of them have major problems with hypertension. Thus we tend not to recommend pregnancy in patients with moderate renal insufficiency, and definitely discourage gestation when GFR is severely impaired. We advise termination, as most of these gestations fail, and maternal risk is substantial. There are a number of diseases in which pregnancy should not be undertaken, including scleroderma and periarteritis. Some authors believe that women with membranoproliferative glomerulonephritis also do poorly, and opinions differ on the effects of gestation on IgA nephropathy, focal glomerulosclerosis, and reflux nephropathy. Table 4 summarizes our view concerning pregnancy in a number of specific renal disorders. Finally, in addition to the controversies noted above, there are other unresolved problems requiring further study. For instance, protein restriction should be avoided until the effect of this therapeutic manoeuvre on fetal development is evaluated. Also needed are conclusive studies on whether or not the physiological hyperfiltration of human pregnancy affects adversely pre-existing renal disease.

Adult↗
PubMed1994

Renal pathology in pre-eclampsia.

Pre-eclampsia affects the kidney both functionally and morphologically. Renal haemodynamics decrease and urinary protein excretion increases, in part due to lesions affecting the glomerulus, where a combination of changes produces a characteristic appearance and permits differentiation of pre-eclamptic nephropathy from other glomerular alterations associated with hypertension in pregnancy. In pre-eclampsia the glomerulus is diffusely enlarged and bloodless, due not to proliferation, but to hypertrophy of the intracapillary cells. These alterations, best described ultrastructurally, include hypertrophy of the cytoplasmic organelles in endothelial and occasionally mesangial cells, particularly the lysosomes, which undergo marked enlargement and vacuolization (due to accumulation of free neutral lipids). These reactive changes have been termed 'glomerular capillary endotheliosis'. Other lesions, observed occasionally, include subendothelial and mesangial electron-dense deposits, as well as interposition of mesangial cell cytoplasm or mesangial matrix along an otherwise normal basement membrane. Some investigators have described immunohistological findings (presence of IgM, IgG and fibrin) which they believe specific for pre-eclampsia, and others have claimed the disease may cause focal segmental glomerulosclerosis (FSGS). We believe the immunohistological findings are non-specific and insudative, and that FSGS when present predates the pre-eclamptic complication. Finally, the renal lesions appear fully reversible and the disease has no remote cardiorenal effects on its patients.

Adult↗
PubMed1993

Hypertension in pregnancy.

Hypertension in pregnancy is still a leading cause of morbidity and mortality in mother and fetus. This review of the literature from 1991 to 1992 focuses on research relating to the causes of preeclampsia and the pathogenesis of the marked vasoconstriction so characteristic of this disease. Reports hypothesizing primary roles for endothelial cell dysfunction, aberrations in prostaglandin synthesis, fatty acid and antioxidant metabolism, as well as for dietary calcium deficiency and the renin-angiotensin system are analyzed; articles regarding clinical trials whose origins derive from some of these hypotheses, such as low-dose aspirin and calcium supplementation to prevent preeclampsia, are appraised. The review concludes by examining several controversies regarding management of pregnant women with chronic hypertension, including the proper way to measure blood pressure in pregnancy, the diastolic level at which treatment with antihypertensive medications should commence, and the choice of drugs that are safe and preferable for use during gestation.

Female↗
PubMed1993

Total autonomic blockade eliminates the attenuated pressor response to angiotensin II in pregnant rats.

Pressor responses to angiotensin II (ANG II) are markedly attenuated in reflex-intact pregnant animals, a phenomenon widely attributed to intrinsic changes in vascular reactivity. To test the hypothesis that gestational augmentation of neural reflex activity contributes importantly to this phenomenon, changes in mean arterial pressure (MAP), cardiac output (CO), and total peripheral resistance (TPR) were compared during constant infusion (25-400 ng.kg-1.min-1) of ANG II in conscious virgin and pregnant rats, using a model of total autonomic blockade (chlorisondamine chloride and methscopolamine bromide), with restoration of baseline hemodynamics by infusion of norepinephrine. Basal CO was higher and TPR lower in pregnant (CO 121.8 +/- 3.8 ml/min; TPR 0.78 +/- 0.04 mmHg.ml-1.min) compared with virgin (CO 95.9 +/- 3.9 ml/min; TPR 1.05 +/- 0.08 mmHg.ml-1.min) rats (P < 0.005). Pressor responses to ANG II were similar in both groups of reflex-blocked animals due to comparable changes in TPR and CO (not significant by repeated-measures analysis of variance). Other experiments demonstrated that changes in MAP after bolus administration of ANG II did not differ in areflexic virgin and gravid rats. Thus in the absence of autonomic control ANG II has similar effects on systemic resistance in pregnant and nonpregnant rats, suggesting that reflex neural mechanisms contribute significantly to gestational changes in pressor responsiveness. These data further suggest that pregnancy is not accompanied by a generalized decrease in vascular reactivity to all pressor agents.

Angiotensin II↗
PubMed1993

Metabolic clearance of vasopressin and an analogue resistant to vasopressinase in human pregnancy.

The metabolic clearance rate (MCR) of arginine vasopressin (AVP) increases fourfold during human pregnancy. To explore whether circulating vasopressinase may play a role in this change, six women underwent a three-tier infusion clearance study, twice, in random order, to determine the MCRs of either AVP or 1-deamino-8-D-AVP (dDAVP, an analogue resistant to degradation by vasopressinase). Volunteers were tested in late pregnancy (LP), 24-48 h postdelivery (PD), and 5-6 (PP1) and 10-12 (PP2) wk postpartum, thus examining MCRs when vasopressinase levels were high, before and after removal of the placenta (LP and PD), and when plasma enzyme activity was becoming (PP1) and became (PP2) undetectable. Manipulation of infusate permitted comparison of MCRs at three plasma levels whose range was similar at each test period. PAVP and PdDAVP (2.2 and 10 pg/ml, respectively, during the initial infusion) increased to 8 and 31 pg/ml, stepwise increments that had no influence on respective MCRs (AVP: 3.4, 2.2, 0.77, and 0.67 l/min during LP, PD, PP1, and PP2 compared with 0.18, 0.21, 0.17, and 0.15 l/min for dDAVP). Comparison of similar and submaximal urinary osmolality revealed PdDAVP values three- to fourfold greater than PAVP. Von Willebrand factor (VWF) and factor VIIIc levels increased almost fourfold in response to dDAVP during pregnancy, but only doubled in the nonpregnant state; these differences did not reach significance. We conclude that although AVP disposal rates increase fourfold in pregnancy, those of dDAVP change little, suggesting a role of vasopressinase in the increased MCR of AVP in gestation (as well as in the genesis of certain polyuric disorders of pregnancy).(ABSTRACT TRUNCATED AT 250 WORDS)

Arginine Vasopressin↗
PubMed1993

Hypertension in pregnancy.

High blood pressure, which complicates approximately 10% of all pregnancies, remains a major cause of morbidity and mortality for both mother and fetus. A relative paucity of investigative data, as well as the frequent difficulty in making an etiological diagnosis by clinical criteria alone, may be among the reasons why there are many conflicts about the management of hypertension during pregnancy. This clinical conference summarizes current concepts regarding the hypertensive disorders of gestation, focusing on the most dangerous cause, preeclampsia-eclampsia. It further highlights a recent report of the Working Group on High Blood Pressure in Pregnancy convened by the National High Blood Pressure Education Program at the National Heart, Lung, and Blood Institute (the Consensus Report). Among the Working Group's most interesting recommendations in controversial areas were a return to the classification schema suggested by the American College of Obstetricians and Gynecologists in 1972, use of the fifth Korotkoff sound to determine diastolic blood pressure levels, and institution of treatment with antihypertensive drugs for sudden elevations of blood pressure near term to diastolic levels greater than or equal to 105 mm Hg or for levels of 100 mm Hg or higher in pregnant women with chronic hypertension. The Consensus Report further recommended parenteral hydralazine and methyldopa as the drugs of choice for the acute hypertensive crisis and management of chronic hypertension, respectively, based on the long histories of safe use of these agents in gravidas. Parenteral magnesium sulfate remained the preferred therapeutic approach for avoiding or treating the convulsive complication, eclampsia, but the Working Group underscored the need for controlled trials of magnesium's efficacy. Finally, they noted that diuretics should be avoided in preeclampsia, but that these drugs can be continued during gestation if taken before conception, and may be prescribed to pregnant women with chronic hypertension who appear overly salt sensitive.

Adolescent↗
PubMed1991

Osmotic and volume control of vasopressin release in pregnancy.

This article, a review of factors controlling vasopressin (AVP) release in pregnancy, extends our contribution to a symposium in this journal published in 1987 (vol X, pp 270-275). Body tonicity decreases (approximately 10 mOsm/kg) very early in pregnancy due to decrements in the osmotic thresholds for AVP release and thirst. In addition, the metabolic clearance rate (MCR) of AVP markedly increases between gestational week 10 and midpregnancy, and is paralleled by the appearance and increase of circulating cystine aminopeptidase (vasopressinase), while the MCR of 1-deamino-8-D-AVP (DDAVP), an analogue resistant to inactivation by the enzyme, changes little in pregnancy. These increases (MCR of AVP and plasma vasopressinase) may explain certain syndromes of transient diabetes insipidus (DI) that complicate gestation. Finally, mechanisms responsible for the altered osmoregulation in pregnancy are obscure, but chorionic gonadotropin may be involved in the changes during human gestation.

Animals↗
PubMed1991

Hypertension in pregnancy: advances and controversies.

Advances in prenatal care have resulted in a substantial decline in the number of serious complications associated with high blood pressure during pregnancy. Nevertheless, the hypertensive disorders remain a significant cause of maternal and fetal morbidity, and even mortality [Rochat et al. 1988]. In addition, hypertension in pregnancy is a topic that generates considerable controversy, ranging from the correct manner to measure blood pressure in gravidas, to major disputes concerning management considerations. The pervasiveness of such controversies [Cunningham and Pritchard 1984, Ferris 1984, Disdale 1988, Kaplan et al. 1988] led the United States' National Institutes of Health, through its National High Blood Pressure Education Program, to convince a working group whose "consensus" report has just been published (1990), and is recommended reading for physicians who manage gravidas. This review focuses on preeclampsia, and includes observations concerning the pathogenesis of this disorder as well as strategies to prevent its occurrence. Conflicting opinions regarding the management of preeclamptic women will also be discussed, highlighting the recommendations made by the NIH consensus group (NHBPEP 1990). Space considerations limit the references cited, and the reader is referred to a chapter [Barron 1991] and several texts [Chesley 1978, Rubin 1988] for a more complete survey of the literature.

Antihypertensive Agents↗
PubMed1990

Regulation of blood pressure in pregnancy: pressor system blockade and stimulation.

Contributions of the autonomic nervous system (ANS), renin-angiotensin system (RAS), and arginine vasopressin (AVP) to basal mean arterial pressure (MAP) were evaluated in near-term pregnant and virgin rats as follows. MAP and heart rate (HR) were measured before and after ganglionic, alpha-adrenoreceptor, RAS, and/or AVP blockade. In addition, pressor responses to angiotensin II (ANG II), norepinephrine, phenylephrine, or AVP were determined in ganglionic-blocked animals. In both groups decrements in MAP were greatest after ganglionic or alpha-blockade, intermediate after RAS blockade, and negligible after AVP-V1 antagonism ([d(CH2)5Tyr(Me)]AVP). Recovery of MAP was also similar in the two groups except after phentolamine when MAP and HR remained lower in gravid rats. Superimposition of RAS or AVP blockade during phentolamine infusion suggested that ANG II and AVP were less effective in supporting MAP during alpha-blockade in pregnancy. Pressor responses to ANG II and norepinephrine during ganglionic blockade were markedly blunted during pregnancy; however, those to phenylephrine and AVP were unchanged. We conclude that contributions of ANS, RAS, and AVP to basal MAP are similar in pregnant and virgin rats; neural mechanisms dominating in both groups. However, recovery during alpha-blockade is impaired during gestation, apparently due to blunted HR responses and decreased pressor contributions of ANG II and AVP. This may be explained, in part, by decreased vascular reactivity to ANG II, although a similar mechanism cannot be invoked for AVP.

Adrenergic alpha-Antagonists↗
PubMed1990

Influence of humoral and volume factors on altered osmoregulation of normal human pregnancy.

These studies were designed to characterize mechanisms leading to decreased plasma osmolality (Posmol) and osmotic thresholds (T) for arginine vasopressin (AVP) release (TAVP) and thirst (Tthirst) in pregnancy. First, the influence of the pregnancy hormone, human chorionic gonadotrophin (hCG), was tested in six nonpregnant women who received hypertonic saline during the luteal phase of the menstrual cycle on two occasions (randomly allocated), once after 15,000 IU of hCG when Posmol, TAVP, and Tthirst decreased 6, 5, and 5 mosmol/kgH2O, respectively (P less than 0.01). In contrast, hCG pretreatment of males (n = 6) had no significant effect. Next, the role of decreased effective vascular volume (underfilling) was evaluated in seven women undergoing hypertonic saline infusion in the presence and absence of head-out water immersion (randomly allocated) during early and late pregnancy and postpartum. Posmol, TAVP, and Tthirst were not influenced by immersion and remained 10 mosmol/kgH2O lower in pregnancy (P less than 0.01). Central redistribution of intravascular volume consistently lowered hematocrit and rate of rise of PAVP per unit increment in Posmol (P less than 0.01). Although these data failed to support the hypothesis that the osmoregulatory change in human pregnancy is attributable to decrements in effective central volume (underfill), they do suggest that hCG may play a role.

Adult↗
PubMed1990

Pressor effect of endothelium-derived relaxing factor inhibition in conscious virgin and gravid rats.

We used pressor responses to N-methylarginine (NMA), a specific inhibitor of endothelium-derived relaxing factor (EDRF) biosynthesis, to assess the contribution of EDRF to control of basal blood pressure in conscious, chronically instrumented virgin and gravid rats. Hypotheses were that NMA would raise blood pressure in conscious animals in spite of intact cardiovascular reflexes and that differing effects in virgin and pregnant animals would reveal contributions of EDRF to the physiological vasodilation of pregnancy. Basal mean arterial pressure (MAP) and heart rate (HR) were 106 +/- 12 mmHg and 394 +/- 27 beats/min (n = 31) in virgin and 102 +/- 8 mmHg and 378 +/- 18 beats/min (n = 14) in gravid rats. After NMA (150 mg/kg iv), increments in MAP and decreases in HR were similar in each group (virgin, delta MAP = 38 +/- 12 mmHg, delta HR = -65 +/- 27 beats/min, n = 14; gravid, delta MAP = 33 +/- 8 mmHg, delta HR = -63 +/- 20 beats/min, n = 6). Pretreatment with excess L-arginine reduced pressor responses to NMA by 80% in both pregnant and virgin animals. In contrast, L-arginine had no significant effect on the pressor response to phenylephrine (6.4 mg/kg iv). EDRF contributes importantly to regulation of basal blood pressure in conscious animals, and pregnancy does not alter the pressor effect of EDRF inhibition in the rat.

Animals↗
PubMed1989

Volume homeostasis and osmoregulation in human pregnancy.

This chapter reviews alterations in volume and sodium homeostasis and osmoregulation during human pregnancy. Pregnant women undergo extracellular and plasma volume increases of 50-70%, and these changes accompany marked cumulative sodium retention shared by both mother and fetus. Pregnancy alters several factors with opposing effects on renal salt handling; however, mechanisms by which gestational sodium accumulation and volume expansion are achieved remain obscure. Furthermore, despite substantial increases in absolute blood volume, considerable uncertainty exists as to how this volume is sensed, particularly in late pregnancy when a rapid increase in volume is associated with decreases in peripheral resistance and blood pressure. Attempts to assess 'effective' intravascular volume suggest that pregnant women sense their volume as normal. Osmoregulation is also changed. Body tonicity and the osmotic thresholds for AVP release and thirst decrease by about 10 mosm/kg. The mechanisms responsible for the osmoregulatory changes are obscure. Haemodynamic stimuli such as decrements in blood pressure and of 'effective circulating volume' do not seem to account for them. Of the many increments in hormone levels known to accompany gestation, only hCG has so far been implicated in these changes. Pregnant women experience three- to fourfold increments in AVP disposal rates between early and mid pregnancy; this may be caused by the striking rise in circulating cystine-aminopeptidase (vasopressinase) which also occurs during this period. The increments in MCR may be one reason why the hormonal response to a given osmotic stimulus appears to decrease in late pregnancy. All these alterations permit speculation on the manner in which the decrease in Posm occurs and is maintained within narrow limits. Lowering the osmotic threshold to drink stimulates a rise in water intake and dilution of body fluids. Since AVP release is not suppressed at the usual level of hypotonicity, AVP continues to circulate at levels sufficient to permit water retention. Posm continues to decline until it decreases below the new osmotic thirst threshold, when a new steady state is established. At this point water turnover, too, resembles that in the non-pregnant state. The change in MCR and the marked increment in plasma vasopressinase may explain certain observations regarding disordered water metabolism during late pregnancy. These are the transient DI syndromes due either to subclinical hypothalamic disease or to a disorder peculiar to pregnancy which is AVP-resistant but dDAVP-responsive; the latter analogue resists degradation by vasopressinase.

Arginine Vasopressin↗