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Biomedical subjects

C M Heesch

Publications and source records attributed to C M Heesch.

At least 19 recordsLinked to original sources
PubMed2001

CNS effects of ovarian hormones and metabolites on neural control of circulation.

Pregnant women often experience orthostatic hypotension, and pregnancy is associated with increased susceptibility to hemorrhagic hypotension. Experiments evaluating arterial baroreflex control of efferent sympathetic nerve activity in virgin and term-pregnant rats revealed that arterial baroreflex sympathoexcitation is attenuated, while sympathoinhibitory responses are well-maintained or potentiated. Following a hypotensive challenge, pregnant animals exhibit attenuated Fos expression in the rostral ventrolateral medulla (RVLM), suggesting that unloading of arterial baroreceptors results in less excitation of presympathetic neurons in the brain stem. Other experiments, in which afferent baroreceptor discharge was recorded, suggest that this was not due to differences in afferent baoreceptor function. GABAergic mechanisms are responsible for tonic inhibition of sympathoexcitatory neurons in the RVLM and the major metabolite of progesterone, 3 alpha-OH-dihydro-progesterone (3 alpha-OH-DHP), which is elevated in pregnancy, is the most potent endogenous positive modulator of CNS GABAA receptor function. Additional experiments revealed that acutely administered 3 alpha-OH-DHP, either intravenously or directly into the RVLM, mimicked the effects of pregnancy on baroreflex control of efferent sympathetic nerve activity and potentiated pressure sensitivity of spinally projecting RVLM neurons. Preliminary experiments using semiquantitative RT-PCR, evaluated the relative expression of three subunits (alpha 1-3) of the GABAA receptor, and suggest that chronic exposure to elevated levels of ovarian hormones can result to changes in GABAA receptor subunit composition. It is likely that changes in control of sympathetic outflow in pregnancy are related to complex interactions between genomic and nongenomic actions of ovarian hormones and metabolites.

Animals↗
PubMed2001

Afferent baroreceptor discharge in pregnant rats.

The baroreflex function curve is shifted to lower operating pressures, efferent sympathoexcitatory responses are attenuated, and sympathoinhibitory responses are potentiated in pregnant compared with virgin rats. It has been proposed that during pregnancy, elevated levels of 3 alpha-hydroxy-dihydroprogesterone (3 alpha-OH-DHP), a major metabolite of progesterone, may contribute to this difference, because acute intravenous administration of 3 alpha-OH-DHP to virgin female rats mimics the effects of pregnancy on the baroreflex. To determine whether changes in the afferent limb might contribute to these baroreflex responses, the effects of pregnancy and 3 alpha-OH-DHP on aortic depressor nerve activity were assessed in the current study. Baroreceptor discharge curves were obtained in Inactin-anesthetized rats by recording aortic nerve activity during ramp increases and decreases in mean arterial pressure (MAP) [intravenous phenylephrine and nitroprusside infusion] before [(control, C) 15 min (E1), and 30 min (E2) after 3 alpha-OH-DHP (220 microg/kg bolus + 22 microg x kg(-1) x min(-1) infusion iv)]. Baseline blood pressure was significantly lower in pregnant (109 +/- 4.4 mmHg) compared with virgin (122 +/- 2.8 mmHg) rats. The only significant difference in the baroreceptor discharge curves was a decrease in curve midpoint in pregnant rats (virgin = 140 +/- 2.7 vs. pregnant = 124 +/- 3.6 mmHg). 3 alpha-OH-DHP had no effect on afferent baroreceptor discharge curves in either virgin or pregnant groups. These results suggest that pressure-dependent baroreceptor resetting may contribute to a shift in the baroreflex curve to lower operating pressures, but cannot completely explain differences in baroreflex function between virgin and pregnant animals.

20-alpha-Dihydroprogesterone↗
PubMed2000

Cocaine activates platelets and increases the formation of circulating platelet containing microaggregates in humans.

OBJECTIVE: To determine whether there is evidence of platelet activation following in vivo cocaine administration in humans, as cocaine abuse is associated with myocardial infarction and stroke, and platelet activation leading to thrombosis is a possible mechanism. SETTING: University hospital. DESIGN AND SUBJECTS: Following a randomised, double blind crossover design, 14 healthy volunteers were studied twice, receiving cocaine (2 mg/kg intranasally) once and placebo once. Flow cytometric analysis of P-selectin expression (an alpha granule membrane protein found on the surface of activated platelets), quantification of the platelet specific proteins platelet factor 4 and beta thromboglobulin, and measurement of platelet containing microaggregate and platelet microparticle (fragment) formation were used to assess platelet activation. Circulating von Willebrand factor antigen (vWF) was measured to evaluate a possible role of endothelial stimulation concurrent with platelet activation. RESULTS: There was an increase in both platelet factor 4 (mean (SD), 16 (7) to 39 (22) IU/ml, p = 0. 04) and beta thromboglobulin (70 (20) to 98 (26) IU/ml, p < 0.01) at 120 minutes following cocaine administration. Platelet containing microaggregate formation was increased at 40 minutes (from 47 (3.2)% to 54 (2.0)%, p < 0.001) and 80 minutes (55 (2.5)%, p = 0.04). Bleeding time decreased following cocaine from 10 (1) to 9 (1) minutes (p = 0.07). No changes in any of the measured variables were noted following placebo administration. CONCLUSIONS: Cocaine exposure causes platelet activation, alpha granule release, and platelet containing microaggregate formation. These data support the view that cocaine, even at the relatively low doses commonly self administered by occasional abusers, may promote thrombosis and predispose healthy individuals to ischaemic events. Platelet inhibitors should be considered early in any patient with suspected cocaine related ischaemia.

Adult↗
PubMed1999

Fos expression in brain stem nuclei of pregnant rats after hydralazine-induced hypotension.

Fos and dopamine beta-hydroxylase immunoreactivity were evaluated in the brain stems of 21-day pregnant and virgin female rats injected with either hydralazine (HDZ; 10 mg/kg iv) or vehicle. HDZ produced significant hypotension in both groups, although baseline blood pressure was lower in pregnant rats (96 +/- 2.5 mmHg) than in virgin female rats (121 +/- 2.8 mmHg). There were no differences in Fos immunoreactivity in the brain stems of pregnant and virgin female rats after vehicle treatment. HDZ-induced hypotension significantly increased Fos expression in both groups; however, the magnitude of the increases differed in the caudal ventrolateral medulla (CVL), the area postrema (AP), and the rostral ventrolateral medulla (RVL). Fos expression after HDZ in pregnant rats was augmented in noncatecholaminergic neurons of the CVL but was attenuated in the AP and in noncatecholaminergic neurons in the RVL. These results are consistent with differences in the sympathetic response to hypotension between pregnant and virgin female rats and indicate that the central response to hypotension may be different in pregnant rats.

Animals↗
PubMed1998

Neurosteroid modulation of arterial baroreflex-sensitive neurons in rat rostral ventrolateral medulla.

The major metabolite of progesterone, 3 alpha-OH-dihydroprogesterone (3 alpha-OH-DHP), is the most potent endogenous positive modulator of central nervous system GABAA receptors. Acute intravenous administration of 3 alpha-OH-DHP to virgin female rats potentiates arterial baroreflex sympathoinhibitory responses. The current experiments tested the possibility that circulating 3 alpha-OH-DHP potentiates central GABAergic influences in the rostral ventrolateral medulla (RVLM). The unit activity of spontaneously active, spinally projecting, and arterial pressure-sensitive neurons was recorded in the RVLM of urethan-anesthetized rats. Arterial pressure sensitivity of RVLM neurons was tested before (control) and 10 min after bolus injection (44 microliters i.v.) of 3 alpha-OH-DHP (1.12 micrograms/kg, n = 19) or vehicle (40% beta-cyclodextrin, n = 8). Both threshold pressure and saturation pressure for inhibition of RVLM neurons were decreased after acute administration of a physiological dose of 3 alpha-OH-DHP (1.12 micrograms/kg i.v.), which produces plasma concentrations similar to those seen during pregnancy (20-30 ng/ml), suggesting potentiated responsiveness to endogenously released GABA. Following suppression by 3 alpha-OH-DHP, high doses of the inactive stereoisomer 3 beta-OH-DHP (112-224 micrograms/kg i.v.; n = 8) restored unit activity, presumably by displacing 3 alpha-OH-DHP from the neurosteroid binding site on GABAA receptors.

Animals↗
PubMed1997

Neurosteroid modulation of [3H]flunitrazepam binding in the medulla: an autoradiographic study.

Neurosteroids bind to unique sites on the GABA(A) receptor complex and modulate receptor function. The effects of neurosteroids on GABA(A) receptors have been well characterized in forebrain regions. However, little is known about their effects on GABA(A) receptors in the medulla, especially those areas involved in autonomic reflex pathways. Stimulation of [3H]flunitrazepam binding to the GABA(A) receptor by two progesterone metabolites, 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha-OH-DHP) and 3beta-hydroxy-5alpha-pregnan-20-one (3beta-OH-DHP), was studied using autoradiographic methods in the medulla and cerebellum of female rats at estrus. [3H]Flunitrazepam binding was enhanced by 3alpha-OH-DHP in every nucleus examined in the medulla and cerebellum. This effect was stereoselective since 3beta-OH-DHP had no effect on binding in any region. No differences were observed in the degree of stimulation of [3H]flunitrazepam binding by 3alpha-OH-DHP among medullary brain regions. However, in the cerebellum, the stimulation of binding was significantly greater in the granular layer than in the molecular layer. Stimulation of [3H]flunitrazepam binding by 3alpha-OH-DHP in nuclei involved in the baroreflex pathways supports previous studies which report that neurosteroids modulate autonomic regulation of blood pressure. These actions may also underlie alterations in autonomic function during pregnancy.

Animals↗
PubMed1997

Effects of pregnancy and progesterone metabolites on arterial baroreflex in conscious rats.

Previous experiments in anesthetized rats suggested that sympathoexcitatory responses were attenuated in pregnant (P) rats. The major progesterone metabolite, 3alpha-hydroxy-dihydroprogesterone (3alpha-OH-DHP), is elevated in pregnancy and reportedly potentiates central gamma-aminobutyric acidergic mechanisms, whereas the 3beta-isomer (3beta-OH-DHP) is inactive. This study obtained baroreflex curves in conscious rats by recording reflex changes in renal sympathetic nerve activity (RSNA) and heart rate (HR) due to perturbations in mean arterial pressure (MAP) [i.v. phenylephrine (PE) and nitroprusside (NTP)] in P rats and in virgin (V) rats before (control) and 15 min after infusion (i.v.) of 3alpha-OH-DHP or 3beta-OH-DHP. Baseline MAP was lower in P rats (P = 102 +/- 2 vs. V = 124 +/- 3 mmHg). Compared with V rats, P rats exhibited less "sympathetic reserve" to respond to a hypotensive challenge, as evidenced by decreased maximum NA and decreased slope of RSNA baroreflex responses to NTP. However, HR baroreflex curves were similar in P and V rats. Acute intravenous administration of 3alpha-OH-DHP to conscious V rats mimicked the effects of pregnancy. Baroreflex sympathoexcitatory responses were decreased, whereas baroreflex control of HR was unaffected. The 3beta-isomer of DHP had no effect on NA or HR baroreflex responses. These results suggest that pregnancy may have differential effects on baroreflex control of sympathetic outflow and HR, and the major metabolite of progesterone, 3alpha-OH-DHP, may contribute to this adaptation of pregnancy.

Animals↗
PubMed1996

Effects of in vivo cocaine administration on human platelet aggregation.

To evaluate whether cocaine administration to human volunteers in vivo increases platelet aggregation, 12 healthy male volunteers were studied twice in a prospective, double-blinded fashion. There was a decrease in aggregation following cocaine exposure compared to placebo, which was most prominent at high doses of adenosine diphosphate.

Adult↗
PubMed1996

Acute cardiovascular effects of OPC-18790 in patients with congestive heart failure. Time- and dose-dependence analysis based on pressure-volume relations.

BACKGROUND: OPC-18790 is a water-soluble quinolinone derivative that shares the pharmacological properties of vesnarinone and that may be useful for treating heart failure. We studied the contribution and relative dose sensitivities of the inotropic, lusitropic, and vascular effects of OPC-18790 in patients with dilated cardiomyopathy. METHODS AND RESULTS: Pressure-volume (PV) analysis was performed in 17 patients who received either 5 micrograms.kg-1.min-1 (low dose, n = 10) or 10 micrograms.kg-1.min-1 (high dose, n = 7) OPC-18790 by 1-hour IV infusion. Right heart pressures and flow and left heart PV relations (conductance catheter) were measured at baseline and every 15 minutes during infusion. Transient inferior vena caval obstruction was used to determine PV relations. Both doses produced venodilation reflected by a 10% decline in left ventricular end-diastolic volume and a 30% fall in atrial and pulmonary artery pressures. Arterial dilation was four times greater at the high dose, with an approximately 40% fall in effective arterial elastance and systemic resistance. Contractility rose by 25% to 100% (depending on PV index) with both doses. Ventricular-arterial coupling (ratio of ventricular end-systolic to arterial elastances) was approximately 0.25 at baseline and doubled (or tripled) at low (or high) dose, correlating with improved efficiency. Isovolumetric relaxation shortened, whereas the diastolic PV relation was generally unchanged. Heart rate was unaltered. CONCLUSIONS: OPC-18790 has potent venous and arterial vasodilator effects and moderate inotropic and lusitropic effects without a change in heart rate. These combined actions suggest a unique potential of OPC-18790 for heart failure treatment.

Blood Pressure↗
PubMed1996

Converting enzyme inhibitors cause pressure-independent resetting of baroreflex control of sympathetic outflow.

The current study was performed to determine whether baroreflex resetting after acute administration of converting enzyme inhibitors (CEIs) was dependent on the concomitant decrease in mean arterial pressure (MAP). Reflex changes in lumbar sympathetic nerve activity (LSNA) due to increases and decreases in MAP [i.v. phenylephrine (PE) and nitroprusside infusions] were determined in normotensive and renal hypertensive (1-kidney, 1-clip) anesthetized WKY rats 1) before (control), 2) 15 min after intravenous captopril (2 mg/kg) or enalaprilat (300 micrograms), and 3) 15 min after MAP was returned to pre-CEI levels with intravenous PE. CEIs decreased MAP and caused a leftward shift of the MAP-LSNA curve toward a lower operating pressure range in all hypertensive and in one group of normotensive rats. The baroreflex curve remained shifted to the left even after MAP was restored to pre-CEI levels by infusion of PE. Thus CEIs cause a pressure-independent resetting of baroreflex control of sympathetic outflow within 15 min. This effect of CEIs is most likely due to elimination of a central nervous system effect of circulating angiotensin II and could contribute to the antihypertensive actions of this class of compounds.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Effects of cocaine on human platelet aggregation in vitro.

BACKGROUND: A temporal relationship has been established between cocaine ingestion and myocardial infarction, and a cocaine-induced increase in platelet aggregation has been suggested as a possible explanation. However, the mechanisms of cocaine associated coronary thrombosis have yet to be completely elucidated. For this reason, we examined the in vitro effect of cocaine and its metabolites on platelet aggregation. METHODS: Platelet aggregation was tested by obtaining platelet rich plasma from 42 healthy volunteers and incubating the platelet rich plasma in six concentrations of cocaine (ranging from 1.47 to 2940 nmol) for 10 minutes prior to aggregation with ADP 1 microM. The same procedure was used to test the effect of two cocaine metabolites, benzoylecgonine and ecgonine methyl ester, on platelet aggregation. Abnormal results were confirmed by inducing aggregation with ADP at higher concentrations (2.4 and 10 microM) and with arachidonic acid (624 microM). RESULTS: At increasing concentrations, cocaine progressively inhibited ADP and arachidonic acid induced platelet aggregation. No effect was seen with benzoyl ecgonine or ecgonine methyl ester as compared to saline. CONCLUSIONS: These data suggest that under certain conditions cocaine may negatively affect hemostasis by decreasing platelet aggregation.

Adenosine Diphosphate↗
PubMed1996

Effects of cocaine on anterior pituitary and gonadal hormones.

Acute and chronic cocaine administration has been reported to change endocrine and neurochemical functions in animals and human drug abusers. This study examined the effects of acute cocaine administration on anterior pituitary and gonadal hormones in male human volunteers without a history of drug abuse. Using a double-blind, randomized study design, luteinizing hormone, follicle-stimulating hormone (FSH), prolactin and testosterone levels were measured in 12 healthy men before and after intranasal administration of 2 mg/kg cocaine or placebo. Each subject was studied twice, serving as his own control. Compared to placebo, both luteinizing hormone, and, to a lesser degree, follicle-stimulating hormone levels increased significantly after cocaine, reaching a peak value 60 min after the administration of the study drug. This pattern is consistent with a possible cocaine induced rise in gonadotropin-releasing hormone and subsequent rise in luteinizing hormone and follicle-stimulating hormone due to stimulation of gonadotroph cells in the pituitary gland. Neither cocaine nor placebo induced a change in testosterone levels. Prolactin levels showed a decrease from base line after both placebo and cocaine administration, with a significantly more pronounced decrease after cocaine. This likely reflects the combination of the physiologic diurnal variation in prolactin secretion and an added inhibitory effect on prolactin due to cocaine. These findings show that the acute administration of cocaine significantly alters anterior pituitary hormonal release patterns.

Administration, Intranasal↗
PubMed1995

Hemodynamic and energetic comparison of bucindolol and metoprolol for the treatment of congestive heart failure.

Although beta blockers have demonstrated a salutary effect on ventricular function in patients with heart failure, it is unclear whether a nonselective third-generation beta blocker produces different hemodynamic and energetic effects than a second-generation beta 1 selective agent. In 30 male patients with heart failure, we retrospectively analyzed hemodynamic data from 2 protocols examining the effects of a nonselective beta antagonist bucindolol (n = 15), and a highly selective beta 1 antagonist metoprolol (n = 15). Both studies were conducted in a similar fashion with patients undergoing cardiac catheterization before and after receiving 3 months of beta blockade. Both groups were matched at baseline in terms of ventricular function. beta blockade resulted in similar reductions in heart rate and similar improvements in ejection fraction, ventricular volumes, stroke and minute work, peak +dP/dt, and isovolumic relaxation in both groups. Only patients taking bucindolol had a significant within-group decrease in resting left ventricular end-diastolic pressure. The metoprolol group had a greater decrease in coronary sinus blood flow and myocardial oxygen consumption. Bucindolol increased cardiac index more than metoprolol, but did not increase stroke volume index more than metoprolol. The bucindolol group had an increase in systolic elastance, whereas the metoprolol group had a parallel left shift in this relation. Thus, metoprolol reduces coronary blood flow and myocardial oxygen consumption more than bucindolol, whereas bucindolol produces slightly more favorable improvements in resting cardiac index and end-diastolic pressure. Otherwise, these 2 agents produced similar hemodynamic changes.

Adrenergic beta-Antagonists↗
PubMed1995

Predictors of systolic and diastolic improvement in patients with dilated cardiomyopathy treated with metoprolol.

OBJECTIVES: The aim of this study was to determine which patients will have systolic and diastolic improvement after beta-blockade with metoprolol. BACKGROUND: Beta-adrenergic blocking agents improve systolic and diastolic function in patients with heart failure. However, it is unclear which patients will respond best to therapy. METHODS: We retrospectively examined baseline characteristics of 24 patients who underwent double-blind then open-label treatment with metoprolol to determine which characteristic predicted improvement in systolic and diastolic function. Degree of improvement in systolic function (22 patients) was defined by the change in left ventricular ejection fraction after 3 months of therapy. Degree of improvement in diastolic function (15 patients) was defined as the change in left ventricular end-diastolic pressure and change in the slope of the isovolumetric relaxation rate-end-systolic pressure relation. RESULTS: Both systolic blood pressure at baseline (r = 0.54, p = 0.009) and the maximal positive value of the first derivative of left ventricular pressure with respect to time (peak +dP/dt) at baseline (r = 0.39, p = 0.07) correlated with improvement in ejection fraction after metoprolol treatment. Stepwise logistic regression demonstrated that only peak systolic pressure was an independent predictor of systolic improvement. Baseline heart rate, ventricular volumes, ejection fraction and adrenergic activation, as reflected by coronary sinus norepinephrine, did not predict response. Patients with the most diastolic impairment at baseline had the most favorable diastolic improvement. Those with the lowest myocardial respiratory quotient (most fatty acid utilization) at baseline also had the most marked reduction in left ventricular end-diastolic pressure. CONCLUSIONS: These data suggest that those patients with the highest peak systolic pressure, highest left ventricular end-diastolic pressure and most prolonged isovolumetric relaxation at baseline will respond best to therapy with metoprolol. However, other patients without these characteristics may also benefit.

Adult↗
PubMed1995

Effects of cocaine on cortisol secretion in humans.

The effects of acute cocaine administration on the pituitary adrenal axis in humans without a history of drug abuse are unknown. The authors studied 12 male volunteers twice in a double-blinded, placebo-controlled, randomized fashion. After intranasal administration of 2 mg/kg cocaine, cortisol levels were significantly higher than after placebo administration. The authors concluded that acute administration of cocaine to humans increases cortisol secretion.

Administration, Intranasal↗
PubMed1995

Effects of pregnancy and progesterone metabolites on regulation of sympathetic outflow.

1. Pregnancy is characterized by a 40% increase in blood volume and cardiac output, a decrease in arterial blood pressure and thus a substantial decrease in total peripheral resistance. The aims of the experiments described in this manuscript were: (i) to determine if pregnancy resulted in alterations in baroreflex control of sympathetic outflow; and (ii) to evaluate possible mechanisms for pregnancy-induced changes in control of sympathetic outflow. 2. Arterial baroreflex control of efferent renal sympathetic nerve activity was examined in female pregnant and non-pregnant normotensive Sprague-Dawley and Wistar-Kyoto rats. In both rat strains, pregnancy was associated with a decrease in baseline arterial pressure, a shift in the baroreflex function curve to a lower operating pressure range and an attenuated ability to reflexly increase sympathetic outflow above baseline levels during a hypotensive challenge. Pregnant Sprague-Dawley rats retained their ability to respond to a hypertensive challenge, whereas pregnant Wistar-Kyoto rats exhibited a decreased sensitivity to hypertensive as well as hypotensive challenges. 3. The inhibitory amino acid transmitter, GABA, mediates baroreflex sympatho-inhibition within the rostral ventral lateral medulla (RVLM) of the brainstem. Since 3 alpha-OH dihydroprogesterone (3 alpha-OH-DHP), a major metabolite of progesterone, is elevated in pregnancy and has been reported to potentiate central nervous system GABAA inhibitory responses, experiments were performed to determine if effects of this metabolite of progesterone could contribute to the pregnancy associated changes in control of sympathetic outflow.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗