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M M Knuepfer

Publications and source records attributed to M M Knuepfer.

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

Dichotomous cardiac and systemic vascular responses to cocaine in conscious rats.

This study examined the effects of cocaine on cardiac output in conscious freely-moving rats. Although pressor responses were similar at all doses, 14 of 32 rats had consistent declines in cardiac output (> 15%) and greater increases in systemic vascular resistance after administration of cocaine (5 mg/Kg, i.v.). Procaine (10 mg/Kg i.v.) did not mimic this effect in either subgroup. We propose that a subpopulation of rats exists with an enhanced susceptibility to cocaine-induced cardiac and systemic vascular alterations at higher doses.

Analysis of Variance↗
PubMed1993

Effects of cocaine on baroreflex control of heart rate in conscious rats.

Cocaine administration elicits a pressor response reportedly dependent upon central and peripheral actions. The present study was designed specifically to determine whether cocaine affects baroreflex sensitivity and whether this is mediated by an action in the CNS. Baroreflex control of heart rate was assessed by noting the change in the duration of the arterial pulse pressure or in the heart rate elicited by administration of pressor and depressor agents. The effects of intracerebroventricular and intravenous cocaine administration were compared. Cocaine (0.1-0.15 mg/kg/min, i.v.) produced a decrease in baroreflex sensitivity that was greater than that produced by an approximately equipressor infusion of phenylephrine (0.5-1.3 micrograms/kg/min, i.v.). Intracerebroventricular (i.c.v.) administration of cocaine (1.5-150 micrograms) or procaine (100 micrograms) had no effect on arterial pressure, heart rate or baroreflex control of heart rate. Furthermore, central administration of yohimbine (3 and 10 micrograms, i.c.v.) was capable of preventing the suppression of the heart rate responses induced by cocaine administration. Propranolol (15 micrograms, i.c.v.) was not able to attenuate the suppression of baroreflex sensitivity elicited by intravenous cocaine administration but higher doses (50-150 micrograms, i.c.v.) could mimic this effect. These data suggest that cocaine suppresses baroreflex control of heart rate by a central alpha 2-adrenergic mechanism. In contrast, the pressor response to intravenous cocaine is not likely to be dependent upon a forebrain periventricular site.

Adrenergic alpha-Antagonists↗
PubMed1993

Calcium channel antagonists reduce the cocaine-induced decrease in cardiac output in a subset of rats.

Intravenous (i.v.) cocaine administration elicits a decrease in cardiac output (CO) in some but not all rats. In the present study, we examined the effects of L-type calcium channel antagonists on cardiovascular responses in conscious freely moving rats with a cocaine-induced decrease in CO. Arterial blood pressure (ABP), heart rate (HR), and CO (pulsed Doppler flowmetry) were measured, and estimates of changes in systemic vascular resistance (SVR), stroke volume (SV), and rate-pressure product (RPP) were calculated from these values. After recovery, rats were treated with cocaine (5 mg/kg, i.v.) to ascertain their myocardial responses. Some rats demonstrated a decrease in CO, usually during the peak pressor response after cocaine administration, whereas others experienced only slight increases in CO. Rats demonstrating a minimum 15% decrement in CO were pretreated with either verapamil or nifedipine before cocaine was readministered. Verapamil (150 micrograms/kg) or nifedipine (100 micrograms/kg) selectively reduced the peak fall in CO and the increase in SVR after cocaine administration, whereas nifedipine (25 micrograms/kg) had little effect on these parameters. Neither drug affected the pressor response to cocaine. These data suggest that calcium channel antagonists can selectively reduce cocaine-induced decreases in CO and increases in SVR without reducing afterload in a subset of rats sensitive to the cardiodepressive effects of cocaine.

Animals↗
PubMed1993

Stress and cocaine elicit similar cardiac output responses in individual rats.

Cocaine use and behavioral stress elicit variable cardiovascular responses in individuals. In the present study, we examined the effects of cocaine or stress on arterial pressure, heart rate, and cardiac output in conscious rats. Rats were instrumented for determination of ascending aortic blood flow as an index of cardiac output using pulsed Doppler flow-metry. Cocaine administration elicited consistent decreases in cardiac output in some rats, whereas others had increases. In contrast, the pressor and heart rate responses were similar in these two groups of animals. Air jet stress also elicited a decrease in cardiac output only in a subset of conscious rats, yet produced equivalent pressor responses in all rats. Cardiac output responses to cocaine and air jet stress were closely correlated in individual rats, indicating that these stimuli evoke similar hemodynamic responses in individual rats. These observations suggest that the rat may provide a model for understanding differential cardiovascular sensitivity to cocaine and/or stress in humans.

Animals↗
PubMed1992

Adrenergic mechanisms underlying cardiac and vascular responses to cocaine in conscious rats.

The contribution of adrenergic receptors to the cardiovascular responses to cocaine (5 mg/kg i.v.) were examined in conscious, free-moving rats instrumented for continuous measurement of arterial pressure, heart rate and blood flows in the mesentery and hindquarters or ascending aorta. Cocaine elicits an immediate (peak) and sustained pressor response with a concomitant reduction in heart rate. Prazosin (0.1 mg/kg i.v.) pretreatment significantly reduced both the peak and sustained pressor responses by attenuating the increases in systemic, mesenteric and hindquarters vascular resistances. Idazoxan pretreatment (1 mg/kg i.v.) attenuated the peak increase in hindquarters vascular resistance. Whereas propranolol pretreatment (1 mg/kg i.v.) attenuated the peak pressor response, the sustained pressor response was enhanced due to increased hindquarters and systemic vascular resistances. Metoprolol pretreatment (1 mg/kg i.v.) enhanced the sustained pressor response to cocaine, in part due to increased heart rate and mesenteric vascular resistances. Upon examination of the cardiac effects of cocaine, a sustained bradycardic response was observed, whereas stroke volume and cardiac output were relatively unaffected. The bradycardic response to cocaine was attenuated by yohimbine (0.1 mg/kg i.v.), prevented by prazosin and converted to a tachycardia after idazoxan (1 mg/kg) pretreatment. After propranolol pretreatment, cocaine substantially decreased cardiac output and stroke volume. Our results demonstrate that cocaine produces a biphasic pressor response in conscious rats and that the mechanisms underlying the dual responses vary in intensity and mode of action in different vascular beds, but are primarily dependent upon alpha-1 adrenergic receptor-mediated vasoconstriction.

Adrenergic alpha-Antagonists↗
PubMed1992

Cardiovascular responses to cocaine are initially mediated by the central nervous system in rats.

Cocaine produces a pressor response reportedly resulting from both potentiation of peripheral catecholamine activity and a centrally mediated sympathoexcitation. In the present study we sought to differentiate the central nervous system and peripheral contributions to the hemodynamic effects of cocaine. In conscious rats, cocaine (5 mg/kg i.v.) produced a pressor response with two distinct components consisting of a brief, substantial increase in mean arterial pressure (MAP) associated with hindquarters and mesenteric vasoconstriction followed by a sustained, modest response associated with mesenteric vasoconstriction and bradycardia. Pentolinium (7.5 mg/kg i.v.) or adrenal demedullation attenuated the peak increase in MAP by attenuating increases in mesenteric and hindquarters vascular resistance, but did not affect the sustained increase in MAP. Methyl atropine (0.5 or 1 mg/kg i.v.) pretreatment reduced the cocaine-induced increase in systemic vascular resistance and enhanced the hindquarters vasodilation during the sustained MAP response. In contrast, adrenal demedullation abolished the hindquarters vasodilation. The bradycardic response was prevented by pentolinium and reduced by methyl atropine. Sympathetic nerve activity was reduced dramatically after cocaine or procaine administration for several minutes in conscious and in chloralose-anesthetized rats. In several anesthetized rats, the sympathoinhibition was preceded by a brief (3-8 sec) increase in renal sympathetic nerve activity. Procaine or cocaine produced little change in cortical cerebral blood flow as estimated by using a laser Doppler flowmeter. These data suggest that cocaine produces an initial, brief centrally mediated sympathoexcitation, but the sustained, modest pressor response is dependent upon peripheral actions that are diminished by baroreflex activation.

Adrenal Medulla↗
PubMed1991

Effects of electrical and chemical stimulation of nucleus raphe magnus on responses to renal nerve stimulation.

Electrical stimulation of the nucleus raphe magnus (NRM) inhibits some somatic and visceral input at the spinal level. This study was designed to examine the effects of electrical and chemical stimulation of NRM on neuronal responses to afferent renal nerve (ARN) stimulation. In chloralose-anesthetized rats, electrical stimulation of ARN elicited predominantly excitatory responses in spinal gray neurons. In 10 neurons studied, electrical stimulation of the NRM elicited an inhibition of spontaneous activity of 8 neurons and inhibited evoked responses to ARN stimulation in 6 neurons. Microinjection of glutamate (5-10 nmol in 0.5-1 microliter) into the NRM elicited an inhibition of spontaneous activity in 9 neurons, a facilitation in 6 neurons and no response in 8 neurons receiving ARN input. Responses evoked by ARN stimulation were inhibited in 12 neurons, facilitated in 4 neurons and not affected in 8 neurons. We conclude that renal input can be modulated at the spinal level by activation of the NRM and adjacent tissue. Furthermore, the inhibition of spinal gray neuronal responses elicited by stimulation of the NRM appears to be due, at least in part, to activation of fibers of passage since non-selective electrical stimulation is more efficacious than selective chemical stimulation of neuronal soma and dendrites.

Animals↗
PubMed1991

Cerebrospinal fluid endothelin-1 and endothelin-3 levels in normal and neurosurgical patients: a clinical study and literature review.

Endothelins are a family of structurally related, potent, long-lasting vasoconstrictor peptides. There are no established normal human levels of endothelin-1 or endothelin-3 in the cerebrospinal fluid. We measured cerebrospinal fluid endothelin-1 and endothelin-3 levels in five groups of patients: normal controls, patients with subarachnoid hemorrhage and cerebral vasospasm, patients with severe head injuries, patients undergoing temporal lobectomy for intractable epilepsy, and a patient with a gunshot injury to the thoracic spine. Endothelin-3 levels were significantly elevated in patients with subarachnoid hemorrhage and may participate in cerebral vasospasm and subsequent neurologic deterioration.

Adult↗
PubMed1991

Characterization of the depressor effect of intrathecal endothelin in anesthetized rats.

Intrathecal administration of 1-100 pmol endothelin-1 in urethan-anesthetized rats elicited a dose-dependent decrease in arterial pressure and a modest bradycardia. The depressor response was associated with a sustained hindquarters vasodilation and a modest transient mesenteric vasoconstriction, indicating disparate effects on regional vascular resistance. In contrast, renal sympathetic nerve activity was unaffected except at the highest dose of endothelin-1 (100 pmol). The depressor effect of intrathecal endothelin is unlikely to be due to spinal ischemia produced by vasoconstriction, since a much greater dose of endothelin was needed to produce an increase in spinal vascular resistance compared with the dose necessary to produce hindquarters vasodilation and the depressor effect. Unlike intravenous administration, intrathecal endothelin-1 and endothelin-3 produced indistinguishable effects on arterial pressure, heart rate, renal sympathetic nerve activity, spinal blood flow, and spinal vascular resistance, suggesting that the spinal neuronal endothelin receptors may be less selective than those in the blood vessels. The centrally mediated depressor effect and the selective regional hemodynamic actions of intrathecal endothelin suggest a role of spinal endothelin in regulating cardiovascular function.

Anesthesia↗
PubMed1991

Hemodynamic effects of posterior hypothalamic injection of neuropeptide Y in awake rats.

Unilateral microinjection of neuropeptide Y (NPY) into the posterior hypothalamic nucleus was previously found to evoke a sympathoexcitatory-mediated increase in mean arterial pressure (MAP) in urethan-anesthetized rats. In this study, the effect of unilateral injection of NPY into the posterior hypothalamic nucleus on the cardiovascular system of conscious, freely moving rats was determined. Microinjection of NPY (0.2-2.4 nmol) or the cholinergic agonist carbachol (0.5-5.5 nmol) resulted in concentration-dependent increases in MAP. Pretreatment of animals with 7.5 mg/kg iv of the ganglionic blocker pentolinium resulted in a blockade of the increase in MAP evoked by microinjection of NPY (2.4 nmol) or carbachol (3.3 nmol). Despite their similarity of effects on MAP, NPY and carbachol evoked different changes in heart rate. NPY increased heart rate, whereas carbachol evoked a biphasic change in heart rate that consisted of an initial increase followed by a decrease. In addition, carbachol caused increases in both hindquarter and mesenteric vascular resistances, whereas NPY caused a short-lasting increase in mesenteric resistance and a tendency toward an increase in hindquarter resistance. Both NPY and carbachol increased total peripheral resistance while NPY decreased stroke volume. Cardiac output was not significantly affected by either NPY or carbachol, although NPY had a tendency to decrease cardiac output. These results suggest that microinjection of NPY or carbachol into the posterior hypothalamic nucleus of conscious rats evokes an increase in MAP primarily as a result of sympathoexcitation and that NPY and carbachol selectively affect autonomic nervous system control of the cardiovascular system.

Animals↗
PubMed1991

Medial medullary contribution to tonic descending inhibition of visceral input.

In the present study, we sought to define the extent and source of tonic descending modulation of spinal neurons receiving visceral input from the afferent renal nerve (ARN). Spinal gray neurons responding to stimulation of the ARN in 64 chloralose-anesthetized rats were located primarily in laminae IV and V (70%), with fewer neurons located in laminae I and VII. ARN stimulation excited 76 and inhibited 8 neurons. Analysis of response latencies demonstrated that responses were due to activation of A delta- and/or C-fiber afferents. Reversible spinalization with cervical cold block (2-5 degrees C) affected activity in most neurons excited by ARN stimulation without affecting inhibited neurons. Cervical cold block increased the spontaneous activity of (disinhibited) the majority of neurons (54 of 76 neurons) and disfacilitated the spontaneous activity of 14 neurons. The evoked response to ARN stimulation was disinhibited by cold block in 51% and disfacilitated in 17% of the neurons, and there was a good correlation between neurons with disinhibited spontaneous activity and those with disinhibited evoked activity. Microinjections of muscimol (0.5-1 nmol) into the rostral medial medulla affected spontaneous and ARN-evoked activities similarly to cold block in 14 of 15 neurons, although the responses to muscimol were usually smaller in magnitude. We conclude that ARN input is modulated supraspinally and that the nucleus raphe magnus and adjacent neuropil contain neurons that contribute to tonic supraspinal inhibition of renal input in the rat.

Afferent Pathways↗
PubMed1991

Increased sensitivity to arousal in spontaneously hypertensive rats is partially dependent upon the amygdala.

This study was designed to determine the effects of behavioral arousal on baroreflex regulation of heart rate in stroke-prone SHR (spSHR) and to ascertain whether the integrity of the amygdala is necessary to mediate these effects. Heart rate responses to phenylephrine-induced increases in arterial pressure were used as an index of baroreflex sensitivity (BRS). spSHR had reduced BRS compared to WKR. Electrical stimulation of the amygdala suppressed BRS in conscious rats only at intensities that elicited behavioral arousal. When normalized for control bradycardiac responses, the spSHR demonstrated a greater suppression of BRS upon amygdalar stimulation than Wistar-Kyoto rats (WKR). Confrontation with a mouse, used to elicit behavioral arousal, attenuated BRS in both spSHR and WKR. Ablation of the central nucleus of the amygdala and adjacent tissue prevented confrontation-induced suppression of BRS both in WKR and spSHR. These data suggest that spSHR are more sensitive to suppression of BRS due to arousal elicited by stimulation of the amygdala. Furthermore, the amygdala is necessary for arousal-induced suppression of BRS in WKR and spSHR.

Amygdala↗
PubMed1991

A comparison of the hemodynamic effects of endothelin-1 and sarafotoxin S6b in conscious rats.

The hemodynamic effects of sarafotoxin S6b (SRT) and endothelin-1 (ET-1) were studied in conscious, freely moving rats. Intravenous bolus administration of ET-1 produced an initial transient depressor response and skeletal muscle (hindquarters) vasodilation. This depressor activity was not observed after i.v. SRT except at a high dose. The initial fall in blood pressure was followed by a sustained pressor response and an increase in total peripheral resistance which were mediated, at least partially, by visceral (mesenteric) and skeletal muscle (hindquarters) vasoconstriction. The durations of the pressor responses and times required to achieve the peak pressor effects (peak time) were greater for ET-1 as compared to SRT. The results of qualitatively similar sustained hemodynamic effects and the strong correlation between the amplitude of the responses to ET-1 and SRT in individual rats suggest that the sustained pressor responses to these peptides are mediated by the same receptors, although the potency was significantly greater for ET-1 than for SRT. Furthermore, the initial depressor and sustained pressor responses appear to be mediated by distinct receptor subtypes inasmuch as the same dose of ET-1 was required for both vasodilator and vasoconstrictor activity but a higher dose of SRT was required to elicit its vasodilator as compared to constrictor effects. Thus, SRT may have relatively lower affinity for receptors mediating its initial hemodynamic responses whereas ET-1 binds with equal affinity to both receptors. These potent and vascular specific hemodynamic actions suggest a role of endothelin in regulating cardiovascular function.

Animals↗
PubMed1990

Splanchnic input to thoracic spinal neurons and its supraspinal modulation in the rat.

The urinary responses of 62 T8-T11 spinal neurons were recorded extracellularly following electrical stimulation of the greater splanchnic nerve (GSN) in chloralose-anesthetized rats. Recorded neurons were found in both the dorsal and ventral horns. Fifty-seven neurons increased their firing rate in response to GSN stimulation; 8 of these exhibited biphasic responses consisting of excitations followed by inhibitions. Excitatory responses to GSN stimulation consisted of either one or two bursts with latencies consistent with activation by either A delta or C fibers. GSN stimulation inhibited 5 neurons. The effects of reversible spinalization on spontaneous activity and on both synchronous and non-synchronous (afterdischarge) GSN-evoked responses were investigated using a cooling probe on the spinal cord between C1 and C2. Of 19 neurons tested in this way, 9 exhibited opposite directional changes in their spontaneous activities and their GSN-evoked responses upon spinalization. Differential effects of cold-block on first and second bursts, or on A delta- and C-fiber mediated responses, were not usually observed. However, differential effects of cold-block on synchronous and non-synchronous portions of the overall GSN-evoked response were often observed in that their magnitudes often changed independently of one another. Supraspinal pathways contributed to GSN-evoked responses of several neurons because their responses were diminished during cooling while spontaneous activity was increased or unchanged. These decreases in the magnitude of the GSN-evoked response were not always accounted for by decreases in the synchronous portions of the responses. However, most neurons did exhibit decreases in the number of non-synchronous responses, or afterdischarges, during spinal cooling, exhibiting in some cases biphasic responses. This study provides evidence for strong supraspinal regulation of splanchnic afferent input to the spinal cord of the rat. Further, this regulation exhibits some specificity toward different portions of splanchnic-evoked responses in spinal neurons.

Afferent Pathways↗
PubMed1990

Endothelin and sarafotoxin S6b have similar vasoconstrictor effects and postsynaptically mediated mechanisms.

In the isolated perfused mesenteric vascular bed, porcine endothelin (ET) and sarafotoxin S6b produced direct vasoconstriction and potentiated nerve stimulation-induced vasoconstriction. ET also enhanced the vasoconstrictor response to exogenous norepinephrine (NE). Basal or stimulated endogenous NE release was not affected either by ET or sarafotoxin S6b. Qualitatively similar responses to ET and sarafotoxin S6b were always observed, although, in many cases, the response to ET was greater and longer lasting than to sarafotoxin S6b. These results indicate that vasoconstrictor responses to ET or sarafotoxin S6b are mediated primarily by postsynaptic mechanisms. No initial vasodilator response to ET or sarafotoxin S6b was observed in this mesenteric vascular preparation.

Animals↗
PubMed1990

Afferent connections of the nucleus centralis amygdalae. A horseradish peroxidase study and literature survey.

The central nucleus of the amygdala has been shown to be involved in cardiovascular regulation and the integration of arousal. In this study, the afferent input was investigated in cat by microinjecting horseradish peroxidase (HRP) into the central nucleus and examining retrogradely-labelled cells in the brain. Retrograde labelling was found in the cortex next to the sulcus ectosylvius anterior, fissura lateralis Sylvii, sulcus rhinicus anterior and posterior, sulcus suprasylvius, and pyriform and entorhinal cortices as well as in the insula and claustrum. Each of the sub-nuclei of the amygdaloid complex exhibited retrogradely-labelled perikarya. Labelled cells were also found in the diagonal band of Broca, nucl. lateralis septi, and nucl. proprius striae terminalis (bed nucl. of stria terminalis). In the hypothalamus the area preoptica medialis and lateralis, nucl. dorsomedialis, paraventricularis, periventricularis, arcuatus and mammilaris medialis were labelled. The nucl. subthalamicus, zona incerta, peripeduncular system, substantia nigra, and nucl. interpeduncularis contained HRP-marked cells. In the thalamus labelled cells were observed in the nucl. reuniens, nucl. centroposterior lateralis, nucl. latero-posterior, nucl. posterior, nucl. centro-anterior, antero-dorsalis, antero-medialis, antero-lateralis, centrum mdianum, nucl. reticularis, nucl. rhomboideus, nucl. parafascicularis and subfascicularis. The area tegmentalis Tsai and the corpora geniculata also contained labelled cells. In the brain stem, HRP-marked cells could be detected in the brachium colliculi inferioris, aqueductal grey matter, locus coeruleus, nucl. parabrachialis, in various nuclei of the formatio reticularis, in the nucl. retrofascialis, nucl. solitarius, nucl. commissuralis, nucl. ambiguus and nucl. dorsalis n. vagi. The results were compared to other neuroanatomical studies and to functional studies of the amygdala.

Afferent Pathways↗
PubMed1990

Cardiac and vascular actions of sarafotoxin S6b and endothelin-1.

Snake venom-derived sarafotoxin S6B (SRT) and porcine endothelium-derived endothelin-1 (ET) have striking structural similarities. In conscious, freely-moving rats, ET (0.67 nmol/kg) produced a transient tachycardia and fall in arterial blood pressure which was followed by a long-lasting increase in arterial pressure, bradycardia, decrease in cardiac output (CO) and marked increase in total peripheral resistance. In contrast, SRT (0.67 nmol/kg) produced only the sustained cardiovascular responses. The sustained cardiovascular effects of SRT or ET were similarly attenuated by nifedipine. SRT and ET (30 nM) produced vasoconstriction in the isolated perfused mesenteric vascular bed without initial vasodilation. SRT and ET had potent positive inotropic and negative chronotropic effects on isolated perfused hearts and induced toxic reactions including coronary vasospasm, arrhythmias, A-V block and ventricular fibrillation. In addition to SRT lacking the initial depressor response in vivo, several differences in the activities of the peptides were also observed. ET produced greater and longer-lasting actions than SRT in producing pressor and vasoconstrictor responses in all 3 preparations, and in its ability to induce toxic effects on the heart.

Animals↗