Biomedical subjects

A K Johnson

Publications and source records attributed to A K Johnson.

At least 73 records · Page 4Linked to original sources

PubMed1998

Relationship between early clinical exposure and first-year students' attitudes toward medical education.

PURPOSE: To determine whether there is a relationship between early clinical exposure and students' attitudes toward medical education. METHOD: At the end of the spring quarter, 1995, 93 first-year students at the University of Washington School of Medicine were asked to complete a one-page, 15-item questionnaire. The 11 items in the questionnaire's first section assessed the students' attitudes toward medical education; each item was rated on a five-point Likert scale (1 = strongly agree, 5 = strongly disagree). The four items in the second section assessed the students' clinical exposures, including type, frequency, and duration. RESULTS: In all, 86 of the students (92%) returned completed questionnaires. The students' participation in clinical experiences was, overall, much higher than expected. A total of 77 students (90%) reported some form of clinical exposure. The clinical-exposure group was defined as those students who had participated in a preceptorship for at least one academic quarter (a half-day per week in clinic) or who had at least five days of clinical experience. Significance tests revealed that the students in the clinical-exposure group were more satisfied with their medical education than were the other students (p = .009). The students' attitudes toward medical education were generally favorable, regardless of their clinical exposures. However, approximately one fourth of the class expressed discontent with the process of medical education, and 40% indicated they were more cynical than when they had started school. CONCLUSION: The results of this study suggest that early clinical experience may contribute to students' satisfaction with medical education.

Adult↗

PubMed1998

Central methysergide prevents renal sympathoinhibition and bradycardia during hypotensive hemorrhage.

Mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were measured in conscious rats during either hemorrhage or cardiopulmonary chemoreceptor stimulation with phenylbiguanide (PBG) after intracerebroventricular injection of the 5-HT1/5-HT2-receptor antagonist, methysergide (40 micrograms). Progressive hemorrhage caused an initial rise (109 +/- 33%) followed by a fall in RSNA (-60 +/- 7%) and a fall in HR (-126 +/- 7 beats/min). Methysergide delayed the hypotension and prevented both the sympathoinhibitory and bradycardic responses to hemorrhage. Systemic 5-HT3-receptor blockade did not influence responses to hemorrhage. The PBG infusion caused transient depressor (-25 +/- 6 mmHg), bradycardic (-176 +/- 40 beats/min), and renal sympathostimulatory (182 +/- 47% baseline) responses that were not affected by central methysergide (-20 +/- 6 mmHg, -162 +/- 18 beats/min, 227 +/- 46% baseline). These data indicate that a central serotonergic receptor-mediated component contributes to the sympathoinhibitory and bradycardic responses to hypotensive hemorrhage in conscious rats. Furthermore, the same central 5-HT-receptor populations involved in reflex responses to hypotensive hemorrhage probably do not mediate the sympathoinhibitory response to cardiopulmonary chemosensitive 5-HT3 receptors.

Animals↗

PubMed1998

Lateral parabrachial nucleus serotonergic mechanisms and salt appetite induced by sodium depletion.

This study investigated the effects of bilateral injections of a serotonin (5-HT) receptor agonist into the lateral parabrachial nucleus (LPBN) on the intake of NaCl and water induced by 24-h water deprivation or by sodium depletion followed by 24 h of sodium deprivation (injection of the diuretic furosemide plus 24 h of sodium-deficient diet). Rats had stainless steel cannulas implanted bilaterally into the LPBN. Bilateral LPBN injections of the serotonergic 5-HT1/2 receptor antagonist methysergide (4 micrograms/200 nl at each site) increased hypertonic NaCl intake when tested 24 h after sodium depletion and after 24 h of water deprivation. Water intake also increased after bilateral injections of methysergide into the LPBN. In contrast, the intake of a palatable solution (0.06 M sucrose) under body fluid-replete conditions was not changed after bilateral LPBN methysergide injections. The results show that serotonergic mechanisms in the LPBN modulate water and sodium intake induced by volume depletion and sodium loss. The finding that sucrose intake was not affected by LPBN serotonergic blockade suggests that the effects of the methysergide treatment on the intakes of water and NaCl are not due to a mechanism producing a nonspecific enhancement of all ingestive behaviors.

Animals↗

PubMed1998

Fos expression in rat brain during depletion-induced thirst and salt appetite.

The expression of Fos protein (Fos immunoreactivity, Fos-ir) was mapped in the brain of rats subjected to an angiotensin-dependent model of thirst and salt appetite. The physiological state associated with water and sodium ingestion was produced by the concurrent subcutaneous administration of the diuretic furosemide (10 mg/kg) and a low dose of the angiotensin-converting enzyme (ACE) inhibitor captopril (5 mg/kg; Furo/Cap treatment). The animals were killed 2 h posttreatment, and the brains were processed for Fos-ir to assess neural activation. Furo/Cap treatment significantly increased Fos-ir density above baseline levels both in structures of the lamina terminalis and hypothalamus known to mediate the actions of ANG II and in hindbrain regions associated with blood volume and pressure regulation. Furo/Cap treatment also typically increased Fos-ir density in these structures above levels observed after administration of furosemide or captopril separately. Fos-ir was reduced to a greater extent in forebrain than in hindbrain areas by a dose of captopril (100 mg/kg sc) known to block the actions of ACE in the brain. The present work provides further evidence that areas of lamina terminalis subserve angiotensin-dependent thirst and salt appetite.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1998

Cholecystokinin actions in the parabrachial nucleus: effects on thirst and salt appetite.

The present study investigated the effects of bilateral injections of the nonselective CCK receptor antagonist proglumide or CCK-8 into the lateral parabrachial nuclei (LPBN) on the ingestion of 0.3 M NaCl and water induced by intracerebroventricular injection of ANG II or by a combined treatment with subcutaneous furosemide (Furo) + captopril (Cap). Compared with the injection of saline (vehicle), bilateral LPBN injections of proglumide (50 micrograms . 200 nl-1 . site-1) increased the intake of 0.3 M NaCl induced by intracerebroventricular ANG II (50 ng/1 microliter). Bilateral injections of proglumide into the LPBN also increased ANG II-induced water intake when NaCl was simultaneously available, but not when only water was present. Similarly, the ingestion of 0.3 M NaCl and water induced by the treatment with Furo (10 mg/kg) + Cap (5 mg/kg) was increased by bilateral LPBN proglumide pretreatment. Bilateral CCK-8 (0.5 microgram . 200 nl-1 . site-1) injections into the LPBN did not change Furo + Cap-induced 0.3 M NaCl intake but reduced water consumption. When only water was available after intracerebroventricular ANG II, bilateral LPBN injections of proglumide or CCK-8 had no effect or significantly reduced water intake compared with LPBN vehicle-treated rats. Taken together, these results suggest that CCK actions in the LPBN play a modulatory role on the control of NaCl and water intake induced by experimental treatments that induce hypovolemia and/or hypotension or that mimic those states.

Animals↗

PubMed1998

Multiple receptor subtypes mediate the effects of serotonin on rat subfornical organ neurons.

The subfornical organ (SFO) receives significant serotonergic innervation. However, few reports have examined the functional effects of serotonin on SFO neurons. This study characterized the effects of serotonin on spontaneously firing SFO neurons in the rat brain slice. Of 31 neurons tested, 80% responded to serotonin (1-100 microM) with either an increase (n = 15) or decrease (n = 10) in spontaneous activity. Responses to serotonin were dose dependent and persisted after synaptic blockade. Excitatory responses could also be mimicked by the 5-hydroxytryptamine (5-HT)2A/2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI; 1-10 microM) and could be blocked by the 5-HT2A/2C-receptor antagonist LY-53,857 (10 microM). LY-53,857 unmasked inhibitory responses to serotonin in 56% of serotonin-excited cells tested. Serotonin-inhibited cells were also inhibited by the 5-HT1A-receptor agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT; 1-10 microM; n = 7). The data indicate that SFO neurons are responsive to serotonin via postsynaptic activation of multiple receptor subtypes. The results suggest that excitatory responses to serotonin are mediated by 5-HT2A or 5-HT2C receptors and that inhibitory responses may be mediated by 5-HT1A receptors. In addition, similar percentages of serotonin-excited and -inhibited cells were also sensitive to ANG II. As such the functional relationship between serotonin and ANG II in the SFO remains unclear.

Angiotensin II↗

PubMed1997

Bombesin affects the central nervous system to produce sodium intake inhibition in rats.

Bombesin (BN) elicits in the rat important behavioural modifications, including inhibition of food and of water intake. Recently, it has been observed that the peptide also inhibits the intake of sodium chloride. To state whether BN possesses a selective antinatriorexic effect or it elicits only an aspecific depression of ingestive behaviour, we studied the effects of this peptide on the intake of sodium, water or sucrose of Wistar rats after injections into the fourth brain ventricle or into selected brain areas involved in the control of sodium intake, containing BN-like peptides and/or their precursors or specific receptors. We observed that: a) BN (100-200 ng/rat) injected into the fourth brain ventricle inhibits not only the intake of 2% NaCl of sodium depleted rats but also that of water and of 5% sucrose; b) BN (5-50 ng/rat) administered into the nucleus of the solitary tract and the medial amygdala does not influence the intake of these fluids and c) BN (5-50 ng/rat) injected into the paraventricular nucleus does not influence the intake of water and 5% sucrose but potently inhibits that of 2% NaCl. We concluded that the inhibitory effect elicited on salt intake by intracranial administration of BN is selective for this behaviour and is not the expression of an aspecific depression of ingestive behaviour.

Animals↗

PubMed1997

Active site analysis of P450 enzymes: comparative magnetic circular dichroism spectroscopy.

Recent structural studies indicate that the substrate- and O2-binding distal pocket of the P450 enzymes are not identical. Thus, P450terp (CYP108) from the alpha-terpineol-metabolizing Pseudomonad differs from P450cam (CYP-101) (C. A. Hasemann et al., J. Mol. Biol. 236, 1169, 1994). In contrast, the distal pockets of P450terp and P450BMP (CYP102 heme domain; Bacillus megaterium) are more closely similar, including novel hydrogen-bonding interactions between the distal H2O ligand and the I helix (C. A. Hasemann et al., Structure, 3, 41-62, 1995). To evaluate the significance of these differences, we have compared solution magnetic circular dichroism (MCD) spectra of P450terp with spectra of other P450 enzymes (e.g., P450cam, P450BMP, P450BM-3holo, and P450BM1), as well as with spectra of chloroperoxidase and NO synthase. Spectra of native P450terp are more similar to those of P450BMP and those of mammalian P450LM-2 than to those of P450cam. Upon substrate-binding, the MCD spectra of ferric P450terp and all other thiolate-ligated heme systems examined to date display a strong Soret band that is distinctly unique relative to the typical Soret MCD pattern(s) of catalases or other 5-coordinate ferric heme systems. This intense negative MCD feature thus appears diagnostic for cysteinate-linked ferric hemes. In the case of ferrous P450s, the intensity of the Soret-region MCD trough varies between substrate-bound and substrate-free enzymes (despite the fact that the substrate is NOT in direct contact with the heme moiety). A novel finding of particular interest is the clear spectral shifts of the Soret MCD band between the substrate-bound and substrate-free forms of ferrous-CO-P450terp. No such observation has been made previously. Furthermore, the band positions for BOTH types of P450terp are red-shifted from known bands of ferrous-CO-P50cam. These data thus indicate a surprising sensitivity of MCD spectra to active-site polarity and to H2O occupancy, concurring with reports of distal pocket effects on CO-binding rates and equilibrium constants. Comparative analysis of the spectral properties of P450terp with MCD spectra of other P450 enzymes, as well as with chloroperoxidase and NO synthase, demonstrates both the expected similarities and the significant differences that reflect active-site structural features. The detailed spectral analysis of P450terp relative to other P450 enzymes presented herein includes the first observation of a substrate-induced spectral shift for a ferrous-CO-P450. Furthermore, testable structural predictions for P450-BM-1 and for the novel NO synthase enzyme (neither of which has been crystallized to date) are made herein. This work thus provides insights into structurally defined P450s and may also lead to understanding of other P450 enzymes.

Animals↗

PubMed1997

The neuroendocrinology of thirst and salt appetite: visceral sensory signals and mechanisms of central integration.

This review examines recent advances in the study of the behavioral responses to deficits of body water and body sodium that in humans are accompanied by the sensations of thirst and salt appetite. Thirst and salt appetite are satisfied by ingesting water and salty substances. These behavioral responses to losses of body fluids, together with reflex endocrine and neural responses, are critical for reestablishing homeostasis. Like their endocrine and neural counterparts, these behaviors are under the control of both excitatory and inhibitory influences arising from changes in osmolality, endocrine factors such as angiotensin and aldosterone, and neural signals from low and high pressure baroreceptors. The excitatory and inhibitory influences reaching the brain require the integrative capacity of a neural network which includes the structures of the lamina terminalis, the amygdala, the perifornical area, and the paraventricular nucleus in the forebrain, and the lateral parabrachial nucleus (LPBN), the nucleus tractus solitarius (NTS), and the area postrema in the hindbrain. These regions are discussed in terms of their roles in receiving afferent sensory input and in processing information related to hydromineral balance. Osmoreceptors controlling thirst are located in systemic viscera and in central structures that lack the blood-brain barrier. Angiotensin and aldosterone act on and through structures of the lamina terminalis and the amygdala to stimulate thirst and sodium appetite under conditions of hypovolemia. The NTS and LPBN receive neural signals from baroreceptors and are responsible for inhibiting the ingestion of fluids under conditions of increased volume and pressure and for stimulating thirst under conditions of hypovolemia and hypotension. The interplay of multiple facilitory influences within the brain may take the form of interactions between descending angiotensinergic systems originating in the forebrain and ascending adrenergic systems emanating from the hindbrain. Oxytocin and serotonin are additional candidate neurochemicals with postulated inhibitory central actions and with essential roles in the overall integration of sensory input within the neural network devoted to maintaining hydromineral balance.

Appetite↗

PubMed1997

Behavioral stress alters coronary vascular reactivity in borderline hypertensive rats.

BACKGROUND: Behavioral stress has been proposed to contribute to the occurrence of myocardial ischemia. Objective To investigate the effect of chronic exposure to behavioral stress on the function and structure of the coronary artery of borderline hypertensive rats (BHR). DESIGN: BHR were either exposed to an air-jet stress for 2 h/day for 10 days or kept in their cage for 10 days. METHODS: After 10 days, hemodynamic measurements in conscious animals were recorded, and their hearts were removed for isolation of a left ventricular coronary artery for functional studies or for fixation by retrograde perfusion for study with scanning electron microscopy. Vascular reactivity was measured in isolated coronary arteries (approximately 250 microm) maintained at an intraluminal diameter of 40 mmHg while the intraluminal diameter was recorded continuously. RESULTS: The resting mean arterial pressure and heart rate in conscious, unrestrained BHR were not altered significantly by exposure to 10 days of 2 h/day air-jet stress. Coronary artery relaxation in response to the endothelium-dependent vasodilator acetylcholine was impaired in rats exposed to the air-jet stress compared with that in controls. An attenuated response to exogenous nitric oxide in coronary arteries from stressed BHR was confirmed by the finding of a reduced sensitivity to nitroprusside, which releases nitric oxide independently from the endothelium. However, relaxation of coronary arteries in response to isoproterenol, which acts independently from nitric oxide, was not altered. Coronary artery contraction in response to endothelin-1 and phenylephrine was not altered in vessels taken from BHR exposed to behavioral stress compared with that in vessels from control rats. Scanning electron microscopy of the endothelial surface of the septal coronary artery showed no difference between vessels from control and stressed BHR. CONCLUSION: These results indicate that behavioral stress impairs endothelium-dependent and nitric oxide-mediated coronary relaxation, but does not alter alpha1-adrenoceptor or endothelin-1-mediated contraction. By impairing coronary artery vascular relaxation, chronic exposure to behavioral stress may contribute to myocardial ischemia.

Animals↗

PubMed1997

Stereoselective actions of S-nitrosocysteine in central nervous system of conscious rats.

This study examined whether the stereoselective actions of S-nitrosocysteine (SNC) in the central nervous system involves the activation of stereoselective SNC recognition sites. We examined the effects produced by intracerebroventricular injection of the L- and D-isomers of SNC (L- and D-SNC) on mean arterial blood pressure, heart rate, and vascular resistances in conscious rats. We also examined the hemodynamic effects produced by intracerebroventricular injections of 1) L-cystine, the major non-nitric oxide (NO) decomposition product of L-SNC, 2) the parent thiols L- and D-cysteine, and 3) the bulky S-nitrosothiol L-S-nitroso-gamma-glutamylcysteinylglycine [L-S-nitrosoglutathione, (L-SNOG)]. Finally, we examined the decomposition of L- and D-SNC and L-SNOG to NO on their addition to brain homogenates. The intracerebroventricular injection of L-SNC (250-1,000 nmol) produced falls in mean arterial pressure, increases in heart rate, and a dose-dependent pattern of changes in hindquarter, renal, and mesenteric vascular resistances. The intracerebroventricular injections of D-SNC, L-cystine, and L-SNOG produced only minor effects. The intracerebroventricular injection of L-cysteine produced pressor responses and tachycardia, whereas D-cysteine was inactive. L- and D-SNC decomposed equally to NO on addition to brain homogenates. L-SNOG decomposed to similar amounts of NO as L- and D-SNC. These results suggest that SNC may activate stereoselective SNC recognition sites on brain neurons and that S-nitrosothiols of substantially different structure do not stimulate these sites. These recognition sites may be stereoselective membrane-bound receptors for which L-SNC is the unique ligand.

Animals↗

PubMed1997

Frequency-response characteristics of autonomic nervous system function in conscious rats.

To characterize the efferent pathway from the hypothalamic paraventricular nucleus (PVN) to peripheral autonomic neurons and finally to selected effector organs, we stimulated the PVN in 10 conscious rats at frequencies ranging from 0.05 to 2.0 Hz. Simultaneously, blood pressure, heart rate, splanchnic sympathetic nerve activity, and mesenteric artery blood flow were measured. The sinus node of the heart responded to PVN stimulation via the parasympathetic pathway (during beta 1-adrenergic blockade) up to a stimulation frequency of 2.0 Hz, whereas the sympathetically mediated response (during muscarinic blockade) was limited to stimulation frequencies < 0.5 Hz. The splanchnic nerve responded to PVN stimulation with synchronous discharges up to stimulation frequencies of 2.0 Hz, whereas the oscillatory component of the vasoconstrictor response of the mesenteric artery was negligible beyond stimulation frequencies of 1.0 Hz. We conclude that sympathetic transmission to the heart is at least four times slower than parasympathetic transmission. In addition, the time-limiting step in sympathetic transmission from the hypothalamus to vascular smooth muscle contraction and pacemaker activity of the sinus node may be located at the site of synaptic transmission to the adrenergic receptors.

Animals↗

PubMed1997

Effects of subfornical organ lesions on sympathetic nerve responses to insulin.

Although insulin exerts potent excitatory effects on the sympathetic nervous system, the mechanisms of insulin-induced activation remain unclear. To demonstrate a central nervous system site of sympathoexcitation, we recently found that destruction of tissues surrounding the anteroventral third ventricle region abolishes elevations in sympathetic nerve activity to intravenous insulin administration. Anteroventral third ventricle lesions may eliminate sympathoexcitation by destroying cell bodies in the lesioned area or by interrupting fibers of passage from the subfornical organ. To determine whether the lesions abolish sympathetic increases by disrupting efferent fibers from the subfornical organ, we measured lumbar sympathetic activity in anesthetized anteroventral third ventricle-lesioned (n = 4) and subfornical organ-lesioned (n = 12) rats before and during intravenous insulin at 0.13 U/h while maintaining euglycemia. Additional sham-lesioned rats received infusion of insulin (n = 10) and the vehicle for insulin (n = 10). Insulin administration in sham-lesioned rats elevated lumbar activity from 100% to 171 +/- 14% (+/-SE), whereas vehicle infusion did not alter sympathetic activity (100% to 113 +/- 11%). In anteroventral third ventricle-lesioned rats, insulin failed to increase sympathetic nerve activity (100% to 119 +/- 14%). Importantly, rats with subfornical organ lesions had increases in nerve activity that were indistinguishable from increases observed in insulin-infused sham-lesioned rats (100% to 163 +/- 21%). These findings indicate that whereas the anteroventral third ventricle region itself is crucial for sympathoexcitation to insulin, the subfornical organ and fibers originating from the subfornical organ traversing the anteroventral third ventricle area are not essential in mediating elevations in lumbar sympathetic nerve activity to hyperinsulinemia.

Analysis of Variance↗

PubMed1997

The interaction of meal-related, rhythmic and homeostatic mechanisms and the generation of thirst and drinking.

One of the primary goals of the study of thirst is to understand why drinking occurs under ad libitum or natural conditions. An appreciation of the experimental strategies applied by physiologists studying thirst from different perspectives can facilitate progress toward understanding the natural history of drinking behavior. Drinking research carried out using three separate perspectives-homeostatic, circadian rhythms, and food-associated-generates types of information about the mechanisms underlying drinking behavior. By combining research strategies and methods derived from each of these approaches, it has been possible to gain new information that increases our appreciation of the interactions between homeostatic mechanisms and circadian rhythms in the modulation of water intake and how these might be related to drinking associated with food intake under near natural conditions.

Animals↗

PubMed1996

Commissural nucleus of the solitary tract lesions reduce food intake and body weight gain in rats.

This study investigated the effects of an electrolytic lesion of the commissural subnucleus of the nucleus of the solitary tract (commNTS) on body weight, daily food and water intake, and plasma glucose and insulin in rats. In the first 6 days following brain surgery, commNTS lesioned rats reduced daily food intake by 80% compared to rats with sham lesions. After this period rats with lesions of commNTS started recovering food intake, but intake remained significantly reduced until the 12th day after surgery. A reduction in body weight was observed 4 days after surgery and reached a maximum on the 12th day. After this, a partial recovery of body weight was observed, but weight remained significantly reduced compared to weights of rats with sham lesions through the conclusion of the study. Food intake and body weight gain in other rats with partial lesions of the commNTS or with lesions outside the commNTS did not differ from rats with sham lesions with regard to those variables. Daily water intake and plasma glucose and insulin were not changed by the commNTS lesions. These results suggest that commNTS is involved with mechanisms that control food intake and body weight in rats.

Animals↗

PubMed1996

Anteroventral third ventricle lesions attenuate pressor responses to serotonin in anesthetized rats.

When administered intravenously, serotonin (5-hydroxytryptamine; 5-HT) evokes a triphasic blood pressure response, consisting of the Bezold-Jarisch-associated depressor response, a pressor action, and long-lasting depressor response. Because the pressor response may, in part, be caused by central nervous system (CNS) activation by 5-HT, we predicted that destruction of the anteroventral third ventricle (AV3V) region, an area rich in 5-HT receptors, would attenuate increases in blood pressure to intravenous 5-HT. In anesthetized sham-lesioned and AV3V-lesioned Sprague-Dawley rats, we measured mean arterial pressure (MAP), heart rate (HR), and lumbar sympathetic nerve activity (SNA) to increasing bolus doses of intravenous 5-HT (1, 2.5, 5, 10, 25 mu g/kg), before and after blockade of bradycardia using methylatropine (200 mu g/kg). In all rats, bolus injections of 5-HT elicited bradycardia accompanied by a fall in lumbar SNA and an initial hypotension followed by a pressor response and a longer lasting hypotensive response. The bradycardia, reduction in lumbar SNA, and both depressor responses were equivalent in sham-lesioned and AV3V-lesioned groups. Importantly, AV3V lesions attenuated pressor responses to increasing doses of 5-HT (3 +/- 1, 6 +/- 4, 6 +/- 4, 17 -/+ 4 35 +/- 3 mmHg) compared to sham-lesioned controls (6 +/- 3, 16 +/- 7, 33 +/- 5, 54 +/- 4, 51 +/- 6 mmHg; P < 0.0001). This attenuation was conserved following blockade of bradycardia with methylatropine (P < 0.01). In summary, pressor responses to intravenous 5-HT are diminished by AV3V lesions. These data indicate that the pressor component of the blood pressure response to intravenous 5-HT is partly dependent upon interaction with the CNS.

Animals↗

PubMed1996

Stimulation of lumbar sympathetic nerves may produce hindlimb vasodilation via the release of pre-formed stores of nitrosyl factors.

The physiological activation of lumbar sympathetic nerves by air-jet stress produces a hindlimb vasodilation in conscious rats. Although the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester markedly reduces the duration of this air-jet stress-induced vasodilation, it does not prevent the initial fall in resistance. These data suggest that the vasodilation is initiated by the release of an as yet unidentified factor, whereas the vasodilation is sustained by the release of nitric oxide or newly synthesized nitrosyl factors such as S-nitrosothiols. At present, the possibility that neurogenic vasodilation may be initiated by the release of pre-formed pools of nitrosyl factors from storage sites within the hindlimb vasculature has not been addressed. We reasoned that if nitrosyl factors do exist in storage pools, then we should be able to demonstrate a "use-dependent" loss of vasodilation after nitric oxide synthesis inhibition which would be the result of a gradual depletion of the releasable pools of these nitrosyl factors. In the present study, we examined the effects of repeated episodes of direct electrical stimulation of the lumbar sympathetic chain on ipsilateral hindlimb vascular resistance in pentobarbital-anesthetized rats prior to and following administration of the nitric oxide synthesis inhibitors N(G)-nitro-L-arginine methyl ester (10, 25 or 100 mumol/kg i.v.) or N(G)-nitro-L-arginine (50 mumol/kg i.v.). Three episodes of electrical stimulation of 3.2 +/- 0.4 V (20 Hz, 5 ms duration, 5 ms delay for 10 s given 5 min apart) produced pronounced and reproducible reductions in hindlimb vascular resistance in the ipsilateral hindlimb (-56 +/- 5%, -55 +/- 5% and -53 +/- 6%, respectively), but no changes in mean arterial pressure. Three episodes of electrical stimulation at 4.8 +/- 0.4 V also caused reproducible decreases in hindlimb resistance (-59 +/- 7%, -61 +/- 9% and -64 +/- 12%) and minor but reproducible decreases in blood pressure. The vasodilation produced by the first electrical stimulation at 3.2 +/- 0.4 V was completely abolished by a 25 mumol/kg dose of N(G)-nitro-L-arginine methyl ester (-11 +/- 9%). The initial episode of electrical stimulation at 4.8 +/- 0.4 V produced a pronounced fall in ipsilateral hindlimb resistance in the N(G)-nitro-L-arginine methyl ester-treated animals whereas the second and third stimulations produced progressively smaller vasodilations (-55 +/- 4%, -34 +/- 3% and -19 +/- 2%, respectively). The 10 mumol/kg dose of N(G)-nitro-L-arginine methyl ester was not effective whereas the 100 mumol/kg dose produced similar effects as the 25 mumol/kg dose. The 50 mumol/kg dose of N(G)-nitro-L-arginine produced similar effects as the higher doses of N(G)-nitro-L-arginine methyl ester. Those results suggest that lower intensity electrical stimulation of the lumbar sympathetic nerves produces vasodilation via the release of nitric oxide or newly synthesized nitrosyl factors such as S-nitrosothiols. In contrast, the vasodilation produced by higher intensity electrical stimulation may involve the mobilization and release of pre-formed pools of nitrosyl factors which undergo a "use-dependent" depletion in the absence of nitric oxide synthesis. These pre-formed pools of nitrosyl factors may exist within the sympathetic nerves themselves. In addition, they may be stored within the vascular endothelium and released by neurogenically-derived neurotransmitters/neuromodulators.

Adrenergic Fibers↗

PubMed1996

Characterization of endothelium-dependent vasodilation and vasoconstriction in coronary arteries from spontaneously hypertensive rats.

Coronary artery disease often occurs in patients with hypertension. The present study was designed to evaluate coronary vascular function in isolated coronary arteries of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats and to determine the effect of antihypertensive treatment on coronary vascular responsiveness. Male SHR and WKY rats (12 to 14 weeks old) were divided into control and hydralazine-treated (120 mg/L drinking water for 10 days) groups. After 10 days, arterial pressure and heart rate were recorded while rats were conscious and unrestrained. Left ventricular coronary arteries (200 to 300 microns diameter) were isolated and intraluminal diameter was continuously recorded while vessels were maintained at a constant intraluminal pressure of 40 mm Hg. Relaxation of coronary arteries to both acetylcholine and nitroprusside was slightly, but significantly, enhanced in vessels from SHR compared to WKY rats. The enhanced relaxation was a specific effect, since isoproterenol induced similar relaxation in coronary arteries from SHR and WKY rats. Contraction to phenylephrine, but not endothelin-1, was augmented in coronary arteries from SHR compared to WKY rats. Treatment with hydralazine significantly lowered arterial pressure in SHR and WKY rats, but did not alter the enhanced contraction to phenylephrine or the enhanced relaxation to acetylcholine and nitroprusside in coronary arteris from SHR. These results indicate that coronary arteries of 12 to 14 week-old SHR do not have impaired endothelium-dependent relaxation, but to exhibit enhanced alpha-adrenoceptor-mediated contraction that is not reduced by lowering arterial pressure.

Adrenergic alpha-Agonists↗