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Biomedical subjects

M J Brody

Publications and source records attributed to M J Brody.

At least 55 records · Page 3Linked to original sources
PubMed1989

Differential regulation of sympathetic nerve activity by lateral and medial subregions of the rostral ventral medulla.

Microinjections of lidocaine were used to examine the contributions of two subregions of the RVM, RVLM (2 mm lateral to midline) and RVMM (1 mm lateral to midline) to the maintenance of AP and SNA in urethane-anesthetized rats. Lidocaine microinjected into either site reduced AP to similar levels. Blockade of RVLM and RVMM produced a small further reduction in AP and essentially abolished neurogenic maintenance of AP. Blockade of either RVLM or RVMM elicited similar falls in RSNA. In contrast, inactivation of RVLM elicited larger falls in lumbar chain (LSNA) and splanchnic (SSNA) SNA than did inactivation of the RVMM. Combined blockade of RVLM and RVMM essentially eliminated LSNA, while RSNA and SSNA were reduced only 60%. From these data we conclude that (1) RVLM and RVMM contribute equally to the neurogenic maintenance of AP; (2) RVLM and RVMM differentially control the activity of individual sympathetic nerves; and (3) a substantial portion of RSNA and SSNA originates outside the RVM and may not be involved in vasomotor control.

Animals↗
PubMed1989

Characterization of coronary vasoconstrictor site in medullary reticular formation.

The importance of sympathetic neural influences in regulating coronary blood flow has been well established. However, central nervous system pathways responsible for these effects are largely unknown. In a feline model, we have identified a site in medullary reticular formation that may play a role in neural control of the coronary circulation. Changes in heart rate (HR), mean arterial pressure (AP), Doppler coronary flow velocity (CBFV), and femoral flow velocity (FBFV) were measured in 67 anesthetized cats. Electrical stimulation in a specific region of the right medullary lateral reticular formation produced elevations in HR (12 +/- 2% from 156 beats/min), AP (41 +/- 6% from 83 mmHg), CBFV (33 +/- 7%), and femoral vascular resistance index (136 +/- 27%). After beta-adrenergic blockade (propranolol), a transient (5-15 s) stimulus-induced decrease in CBFV was observed in 67% of animals, with a 55 +/- 6% increase in coronary vascular resistance index, not the result of autoregulation. Ipsilateral stellate ganglionectomy or systemic alpha 1-adrenergic blockade abolished the CBFV decrement. Microinjection of L-glutamate into this medullary region failed to elicit either pressor or coronary vasomotor responses. It is concluded that electrical stimulation in a specific site within medullary reticular formation produces neurogenic coronary vasoconstriction as part of a more generalized activation of central sympathetic fibers. This brain stem site may play an important role in reflex or behaviorally mediated coronary responses.

Adrenergic beta-Antagonists↗
PubMed1989

Baroreceptor denervation profoundly enhances cardiovascular responses to central angiotensin II.

The purpose of this study was to examine the influence of arterial baroreflexes on the pressor and regional hemodynamic responses to centrally administered angiotensin II (ANG II) in the conscious rat. Fourteen days after sinoaortic baroreceptor denervation (SAD) or the equivalent sham surgery, the pressor and hindquarters vascular resistance responses to intravenous administration of ANG II were augmented in the SAD group. The pressor and vasoconstrictor responses to intracerebroventricular ANG II were also augmented after SAD; however, the SAD animals were more than 1,000-fold more sensitive than the sham group to the pressor effects of intracerebroventricular ANG II. Further experiments demonstrated that 1) the enhanced pressor response to intracerebroventricular ANG II in the baroreceptor-denervated group was due to similar increases in sympathetic outflow and vasopressin mediated vasoconstriction, 2) the increased sensitivity to central ANG II occurs as soon as 1 h after SAD, and 3) the enhanced pressor effects to intracerebroventricular ANG II also occur with intracerebroventricular hypertonic saline. We conclude that arterial baroreflexes exert a potent central inhibitory effect on the central pressor actions of ANG II that are greater than can be accounted for by the peripheral reflex arc. Finally, because of the rapid onset of the increased responsiveness to central ANG II after SAD, we propose that baroreflex buffering of central pressor stimuli may be tonically involved in circulatory control.

Angiotensin II↗
PubMed1989

Contribution of neurogenic mechanisms to control of intrinsic heart rate.

Altered autonomic tone as well as humoral factors can change the intrinsic rate of the cardiac pacemaker. To study the relationships of neurogenic and humoral factors on intrinsic heart rate (IHR) we used sinoaortic deafferentation (SAD) to increase sympathetic activity, lesion of nucleus ambiguus to reduce central parasympathetic activity, and one-kidney, one-clip (1K1C) renal hypertension to transiently increase the activity of the renin-angiotensin system and the combination of 1K1C hypertension with SAD. In conscious rats, IHR was determined using combined blockade with atropine and propranolol. Rats with 1K1C hypertension (7th day) showed increased mean arterial pressure (MAP), heart rate (HR), and IHR. Rats with SAD (4th day) demonstrated increased MAP and HR, but in contrast, had decreased IHR. Lesion of nucleus ambiguus increased HR and decreased IHR. When 1K1C hypertension was combined with SAD an additional increase in MAP and HR occurred, whereas IHR was reduced compared with renal hypertension alone. These data suggest that IHR is influenced greatly by autonomic tone and that the tachycardia in renal hypertension is linked to increased IHR that is dependent on integrity of the baroreflex.

Animals↗
PubMed1989

Mechanisms of respiration-induced changes in vasomotor control exerted by rostral ventrolateral medulla.

Efferent and afferent mechanisms involved in the differential depressor response to inactivating rostral ventrolateral medulla (RVLM) under conditions of normal (2.5 ml) and reduced (1.5 ml) tidal volume were examined in urethan-anesthetized rats. Under conditions of reduced tidal volume, bilateral microinjection of lidocaine (200 nl, 4%) into RVLM produced an attenuated fall in both mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) despite the fact that base-line levels of both are unchanged. The specificity of the differential response was tested by examination of regional hemodynamics. Microinjecting lidocaine into RVLM produced an attenuated fall in renal, mesenteric, and hindquarter vascular resistances in parallel with the attenuated fall in MAP produced by reducing tidal volume. Microelectrode stimulation of RVLM produced an increase in resistance in all three vascular beds. Of the neural sensory systems examined, both vagal and chest wall afferents appear to be involved in mediating the differential depressor response. These results demonstrate the importance of afferent sensory input to the medulla in determining sites of generation and maintenance of sympathetic vasomotor tone.

Animals↗
PubMed1989

Subregions of rostral ventral medulla control arterial pressure and regional hemodynamics.

The cardiovascular effects of inactivating rostral ventromedial medulla (RVMM) under conditions of normal (2.5 ml) and reduced (1.5 ml) tidal volume were studied in urethan-anesthetized rats. Bilateral microinjection of lidocaine (200 nl, 4%) reduced mean arterial pressure (MAP), renal, mesenteric, and particularly hindquarter vascular resistance. These effects were not significantly altered by reducing tidal volume. Electrical stimulation of RVMM increased MAP and regional vascular resistances, again with the hindquarter change most prominent. The integrated cardiovascular response to stimulating rostral ventrolateral medulla (RVLM) appears to require integrity of RVMM; however, the converse is not true. Overall, these studies indicate that 1) the potential for RVMM to maintain neurogenic control of arterial pressure is as great as RVLM; 2) RVMM is capable of playing a proportionally greater role in the controlling hindquarter vascular resistance; 3) the integrity of RVMM appears to be important for responses elicited from RVLM; and 4) unlike RVLM, neural control of arterial pressure is sustained by RVMM under conditions of reduced tidal volume. We conclude that RVLM and RVMM are functionally and anatomically distinct subregions of rostral ventral medulla with equivalent capacity to maintain vasomotor tone.

Animals↗
PubMed1989

Cardiovascular effects of the N-methyl-D-aspartate receptor antagonist MK-801 in conscious rats.

Evidence from microinjection studies in anesthetized rats suggests that central excitatory amino acid pathways using N-methyl-D-aspartate receptors are involved in the regulation of the cardiovascular system. To test the hypothesis that these pathways are tonically involved in the maintenance of or the baroreceptor reflex regulation of cardiovascular function, we have examined the effects of intravenous injection of the centrally acting, noncompetitive N-methyl-D-aspartate receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801), on the mean arterial pressure, heart rate, renal sympathetic nerve activity, and behavior of conscious, freely moving sham-operated and sinoaortic baroreceptor-denervated rats. Administration of MK-801 produced, within 5 minutes, dose-dependent elevations in mean arterial pressure, heart rate, and renal sympathetic nerve activity that were sustained for 0.5 to 2.5 hours. For an equivalent dose, MK-801 produced approximately twice the peak changes in mean arterial pressure and heart rate in the sinoaortic baroreceptor-denervated rats than in the sham-operated rats. Pretreatment results were as follows: 1) The ganglion blocker chlorisondamine markedly attenuated the hypertension and tachycardia in the sham-operated and sinoaortic baroreceptor-denervated rats, 2) pretreatment with the alpha 1-adrenergic receptor antagonist prazosin virtually abolished the hypertension, and 3) the beta 1-adrenergic receptor antagonist atenolol markedly reduced the tachycardia. MK-801 also produced stereotypic behaviors and ataxia in the sham-operated and sinoaortic baroreceptor-denervated rats; however, qualitatively and quantitatively similar changes in behavior were induced in the latter by doses approximately five time lower than required in sham operated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Central vasopressin raises arterial pressure by sympathetic activation and vasopressin release.

Although central administration of arginine vasopressin (AVP) has been reported to increase arterial pressure mediated by activation of the sympathetic system, we found that peripheral blockade of sympathetic transmission did not attenuate this pressor response. To elucidate the mechanism, rats were pretreated with either phentolamine (3 mg/kg), chlorisondamine (2.5 mg/kg), a vasopressin V1 receptor antagonist d(CH2)5Tyr(Me)AVP (AVP-X) (10 micrograms/kg), or the combinations of phentolamine and AVP-X or chlorisondamine and AVP-X. The pressor response to intracerebroventricular injection of AVP in unrestrained conscious rats was reduced but not significantly altered by intravenous injection of phentolamine or AVP-X; however, combined treatment with these agents abolished the response. To determine that the amount of central AVP leaked to the periphery did not contribute to the pressor effect, tritiated AVP and AVP (100 ng total) were injected intracerebroventricularly. Blood samples collected at 0, 3, and 30 minutes after injection showed that radioactivity in plasma was primarily metabolites and that the amount of intact AVP estimated to leak from the brain was too low to produce a pressor effect. Comparative regional hemodynamic studies between intracerebroventricular and intravenous injection of AVP performed in conscious rats instrumented with Doppler flow probes demonstrated a qualitatively similar pattern of increased resistance in the renal, mesenteric, and hindquarters beds. These data suggest that central pressor action of AVP is mediated by both activation of the sympathetic system and release of AVP.

Animals↗
PubMed1989

Lability of arterial pressure after baroreceptor denervation is not pressure dependent.

The mechanisms of increased arterial pressure lability after sinoaortic deafferentation remain unknown. We have shown previously in rats with chronic sinoaortic deafferentation (7-14 days after sinoaortic deafferentation) that ganglionic blockade significantly reduced mean arterial pressure and arterial pressure lability. The present study investigated the possibility that lability is related to the level of arterial pressure. Rats were instrumented chronically and heart rate and mean arterial pressure were sampled every 5 seconds in the conscious, freely moving state. Graded sustained increases in pressure (+10 to +82 mm Hg) produced by constant infusion of angiotensin II, phenylephrine, or vasopressin did not affect lability (standard deviation of 30-minute sampling period); whereas, graded hypotension (-10 to -70 mm Hg) produced by infusions of adenosine, nitroprusside, or nisoldipine appeared to reduce lability. Analysis of covariance and orthogonal polynomial curve fitting demonstrated a significant correlation between the decrease in mean arterial pressure and the decrease in lability produced by nisoldipine but not by adenosine or nitroprusside. Lability does not appear to be solely dependent on the level of arterial pressure because lability was reduced by adenosine when pressure was maintained at control levels by simultaneous infusion of phenylephrine. We conclude that 1) arterial pressure lability is not influenced by elevation of arterial pressure but can be reduced when pressure is lowered by certain vasodilators and 2) pressure alone does not appear to be the major determinant of lability because it can be attenuated by vascular smooth muscle relaxants even when pressure is maintained.

Adenosine↗
PubMed1989

Role of renal nerves in experimental hypertension: evaluation of neurogenic mechanisms.

To evaluate neurogenic mechanisms underlying variations in arterial pressure associated with removal of baroreflexes, renal sympathetic nerve activity (RSNA) was recorded in conscious unrestrained rats 1 day and 14 days following sinoaortic deafferentation (SAD) or sham operation. Fluctuations in RSNA and heart rate (HR) were correlated stastistically with moment to moment changes in pressure. One day and 14 days after SAD, the lability of mean arterial pressure (MAP) was increased, whereas the lability of RSNA and HR were reduced at 1 day and unchanged at 14 days. Arterial pressure and RSNA were negatively correlated in sham rats, however in rats with SAD negative correlations were virtually absent and positive correlations appeared only infrequently. These results indicate that SAD reduces variability of both RSNA and HR and that lability of arterial pressure appears to not be driven by variations in sympathetic discharge. To examine the central origins of RSNA in anesthetized rats we blocked neuronal transmission in two vasomotor regions of rostral medulla, rostral ventrolateral medulla (RVLM) and rostral ventromedial medulla (RVMM) using bilateral microinjections of lidocaine. Blockade of either or both RVLM and RVMM produced an equivalent marked reduction in arterial pressure but reduced RSNA to only 40% of control. Ganglionic blockade had little additional effect on arterial pressure but abolished the residual RSNA. These findings suggest that a substantial fraction of RSNA may be non-vasomotor in function and that this activity may originate from spinal sites or from supraspinal sites other than RVLM or RVMM.

Animals↗
PubMed1989

Pharmacological characterization of alpha adrenoceptors involved in the antinociceptive and cardiovascular effects of intrathecally administered clonidine.

The effects on nociception, blood pressure and heart rate of clonidine administered intrathecally to the lumbar level were determined in conscious rats and in rats anesthetized lightly with pentobarbital. In anesthetized rats, intrathecal (i.t.) clonidine (3.2-32.0 micrograms) inhibited the nociceptive tail-flick reflex and had biphasic effects on blood pressure; lesser doses (1.0-10.0 micrograms) produced depressor effects, whereas a greater dose (32.0 micrograms) produced a marked pressor response. Clonidine also produced biphasic effects on blood pressure in conscious rats, with the dose-response function shifted upward and to the left of that observed in anesthetized rats. The depressor and antinociceptive effects of 3.2 micrograms of clonidine were antagonized by pretreatment with yohimbine (30.0 micrograms i.t.) but not by prazosin (30.0 micrograms i.t.) or by yohimbine (0.1 mg/kg i.v.). Thus, these effects of clonidine are mediated by spinal alpha-2 adrenoceptors. The pressor response to 32.0 micrograms of clonidine (i.t., lumbar) was accompanied by marked bradycardia, and similar cardiovascular effects were observed when this dose of clonidine was administered either i.v. or to the cervical level of the spinal cord. The pressor response to 32.0 micrograms of clonidine (i.t., lumbar) was not reduced significantly by i.t. pretreatment with yohimbine (30.0 micrograms) or prazosin (30.0 micrograms), but was diminished significantly by i.v. pretreatment with yohimbine (1.0 mg/kg), prazosin (0.1 mg/kg) or phentolamine (2.0 mg/kg). Neither chlorisondamine (2.5 mg/kg i.v.) or the V1-vasopressin receptor antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid), 2-(o-methyl)tyrosine]Arg8-vasopressin (10.0 micrograms/kg i.v.) reduced the clonidine-produced pressor response. After i.t. injection of 32.0 micrograms of [3H]clonidine, peak levels of radioactivity in the blood were observed at 2 min and corresponded to a blood concentration of 38.8 ng/ml. Injection of an i.v. bolus dose (2.5 micrograms/kg) sufficient to produce these blood levels resulted in a transient pressor response. These results suggest that after i.t. administration of greater doses of clonidine, sufficient amounts of the drug are rapidly redistributed systemically to produce pressor effects by stimulation of vascular alpha adrenoceptors.

Adrenergic alpha-Antagonists↗
PubMed1988

Regional hemodynamic responses to central administration of corticotropin-releasing factor (CRF).

Central administration of corticotropin-releasing factor (CRF) produces a marked increase in both mean arterial pressure and heart rate. These increases appear to be mediated almost exclusively by an activation of the sympathetic nervous system. We studied the hemodynamic mechanisms of the response by determining the contribution of the major vascular beds to the increase in arterial pressure. Experiments were done in conscious, freely moving, male Sprague-Dawley rats. Animals were prepared for measurement of regional blood flow using miniaturized pulsed Doppler flow probes placed on the renal, mesenteric and abdominal aortic arteries. Intracerebroventricular injection of CRF (28.5-570 pmol) produced a dose-dependent increase in both mean arterial pressure and heart rate. A significant increase in vascular resistance was observed in the mesenteric and renal but not in the hindquarter vascular bed at the highest dose of CRF. These data indicate that vasoconstriction in the renal and mesenteric circulations contributes to the centrally mediated pressor effect of CRF.

Animals↗
PubMed1988

Autonomic, sensory, and motor dysfunction following intrathecal administration of three substance P antagonists.

Antagonists of the putative peptide neurotransmitter substance P have been found to produce pronounced cardiovascular effects when administered into the spinal subarachnoid space. These previous studies have not, however, provided any direct evidence that these effects result from interaction with substance P receptors. The present study was designed to characterize the modification of cardiovascular function resulting from administration of these compounds, and evaluate their effects on the integrity of spinal cord function. Intrathecal administration of two substance P antagonists produced a depressor response accompanied by a reduction of hindquarter vascular resistance. Following administration of a substance P antagonist, the integrated cardiovascular responses to electrical stimulation of the renal afferent nerves and ventrolateral medulla were markedly attenuated. Intrathecal administration to conscious rats of three substance P antagonists led to a variety of sensory and motor dysfunctions, including loss of spontaneous motor function, responsiveness to mechanical and thermal stimuli, and bladder function. No such effects were produced by administration of substance P, luteinizing hormone releasing hormone (LHRH), or LHRH antagonist. These effects from administration of a substance P antagonist were associated with a dose-dependent necrosis of spinal cord tissue. The necrosis may be secondary to ischemia since pretreatment with the vasodilator adenosine significantly delayed or blocked the sensory and motor dysfunctions. This conclusion was supported by the demonstration that cerebrovascular smooth muscle (pial vessels) was constricted by a SP antagonist. Taken together, these data suggest that substance P antagonists appear to non-specifically block transmission in the spinal cord, by mechanisms which may involve reduction of blood flow to the spinal cord.

Animals↗
PubMed1988

Studies on neural and humoral contributions to arterial pressure lability.

The mechanisms of arterial pressure lability in rats following sinoaortic deafferentation (SAD) remain unknown. In this paper, we review several studies that have investigated the potential mechanisms of this lability. Combined ganglionic and alpha-adrenergic receptor blockade reduced lability but not to control levels, indicating that the sympathetic nervous system plays a major role but is not the only mechanism involved in the generation of lability. When ganglionic blockade was combined with blockade of an endogenous humoral vasoconstrictor (vasopressin or angiotensin), lability was returned to control levels in SAD rats; however, humoral blockade alone did not alter lability. Infusion of phenylephrine or endogenous vasoconstrictors in the presence of combined neural and humoral blockade increased arterial pressure lability to levels similar to those found in rats with SAD. The neurogenic contribution to lability was further investigated by recording renal sympathetic nerve activity in conscious freely moving intact rats and rats with SAD. These studies demonstrated that one day after SAD, there was little direct correlation between transient changes in renal sympathetic nerve activity and arterial pressure lability. Thus, the evidence presented in this paper is consistent with the hypothesis that arterial pressure lability is not the direct result of unbuffered variations in sympathetic discharge but rather is produced by an interaction between neural and humoral components.

Animals↗
PubMed1988

A simple method for chronic cannulation of the portal vein in intact unrestrained rats.

A simple new method is described for chronic cannulation of the portal vein in rats. A Silastic catheter (0.64 mm OD) with an internal metallic leader is directly inserted in the junction of the two small ileal veins. The catheter is advanced into the mesenteric vein to the portal vein. Then the leader is removed and the catheter tunneled out the back of the neck. This method allows for the measurement of portal vein pressure, direct injection of substances in the portal vein, or blood samples for at least 1 wk in intact unrestrained rats. Validation included the presence of elevated portal vein pressure in portal hypertensive rats compared with normal rats and the absence of clot development in the portal vein. This method should help provide a better understanding of hepatic physiology and pharmacology in normal and disease states.

Animals↗
PubMed1988

Continuous monitoring of portal vein and hepatic artery hemodynamics in unrestrained rats.

Continuous measurement of portal vein and hepatic artery blood flows during physiological experimental conditions, even in large animals, poses difficult problems. We report the successful use of miniaturized flow probes and pulsed Doppler flowmetry for chronic monitoring of hepatic artery and portal vein flows in intact unrestrained rats and describe the probe construction and implantation. Proportionality between portal vein velocity and portal flow was made possible by a technique for stabilizing the diameter of the venous segment from which velocity is recorded. The accuracy of the method in detecting changes in portal vein flow was established by the high statistically significant correlation between changes in velocity recorded simultaneously from portal vein and superior mesenteric artery in a series of rats with ligated celiac and inferior mesenteric arteries. In these preparations all portal vein flow is derived from the superior mesenteric artery. Complex dynamic changes in the hepatic circulation of conscious unrestrained rats were recorded in response to systemic injections of glucagon and angiotensin II. In the resting state several characteristic velocity patterns were recorded from the portal vein. Oscillations linked to respiration were not observed while the animals rested quietly but were noted during sleep and anesthesia. Two hitherto unrecognized patterns produced respectively by the pulsations of the superior mesenteric artery and by spontaneous contractions of the portal vein were also observed. The method described here provides the first opportunity to study hepatic circulation in chronically instrumented rats during physiological experimental conditions.

Animals↗
PubMed1988

Central interactions between aldosterone and vasopressin on cardiovascular system.

Although the presence of mineralocorticoid binding sites have been demonstrated in brain, little is known about their physiological role. The purpose of this study was to evaluate possible interactions between a relatively short 2-day central infusion of aldosterone (5 ng/h) and a diverse group of centrally acting pressor agents. The intracerebroventricular infusion of aldosterone selectively attenuated the pressor response produced by the injection of arginine vasopressin (AVP, 10-400 ng) into the lateral ventricle without altering the responses to ventricular administration of 50-200 ng angiotensin II (ANG II), 150 ng carbachol, and 0.5 and 1 M hypertonic sodium chloride. No aldosterone-vasopressin interaction occurred in rats receiving a simultaneous central infusion of aldosterone and RU 28318 [7 beta-hydroxy-3-oxo-7 alpha-propyl(17 alpha)-pregn-4-ene-21-potassium carboxylate], a specific mineralocorticoid receptor antagonist. Baroreflex reactivity and the pressor response to intravenous AVP were not modified by the aldosterone treatment, indicating that overall cardiovascular reactivity was not depressed. Because the vascular reactivity of the mesenteric artery to AVP and norepinephrine remained unchanged after 2 days of central aldosterone infusion, and because plasma levels of aldosterone were not altered, the selective inhibition by this mineralocorticoid of the central AVP response appears to be purely central in origin. This specific central effect of aldosterone is mediated through interaction with mineralocorticoid receptors.

Aldosterone↗