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PubMed1992

Cardiovascular effects of acute changes in extracellular ionized calcium concentration induced by citrate and CaCl2 infusions in conscious, chronically instrumented dogs and their interactions with ganglionic blockade.

To assess the hemodynamic effects of acute changes in extracellular ionized calcium concentration, [Ca2+], seven dogs were chronically instrumented to measure heart rate, aortic, left atrial, and left ventricular (LV) pressures, cardiac output, and coronary and renal blood flows. [Ca2+] was lowered 0.35 mmol.l-1 by citrate infusion and then increased 0.35 mmol.l-1 above control level by CaCl2 infusions. This protocol was performed in the conscious dogs with and without ganglionic blockade (chlorisondamine 2 mg.kg-1). LV dP/dtmax decreased at low [Ca2+] and increased at high [Ca2+] during all conditions. The other hemodynamic variables measured were only slightly changed by changing [Ca2+] without ganglionic blockade and surprisingly even less with ganglionic blockade. Therefore, the lesser hemodynamic effects induced by acute changes in [Ca2+] in the conscious compared with anesthetized dogs cannot be explained by the depressant effects of the anesthetics upon the autonomic nervous system. We have suggested that the binding of Mg2+ to citrate may be of importance for the minor hemodynamic effects in the conscious dogs.

Animals↗
PubMed1986

Haemorrhage-induced secretion of active and inactive renin in conscious and pentobarbitone-anaesthetized sheep.

The response of plasma levels of active and inactive renin to haemorrhage was investigated in sheep with indwelling artery and vein catheters. In conscious animals, loss of 10% of estimated blood volume over a 5 min period increased plasma active renin by a mean of 59%, a surprisingly small change. Plasma inactive renin also increased, but only by 86%. Maximum increases in both forms of renin occurred within 1 h of the haemorrhage. The effects of an equivalent blood loss were investigated in pentobarbitone-anaesthetized sheep maintained in an upright posture using padded slings. Anaesthesia per se had no effect on plasma active or inactive renin. In anaesthetized sheep, 3 h after haemorrhage, plasma active renin had increased by 403% and inactive renin by 299% above control values, but a plateau (maximum) response was not reached during this time. In both conscious and anaesthetized animals the haemorrhage-induced increases in active and inactive renin occurred in parallel. It appears that haemorrhage of this intensity is a comparatively mild stimulus to increase plasma renin concentration in conscious sheep but is much more effective in anaesthetized animals. This may be linked to anaesthetic-induced increases in prostaglandin synthesis within the kidney.

Anesthesia, General↗
PubMed1989

Renal sympathetic nerve activity measured by norepinephrine spillover rate in response to changes in blood pressure in conscious rabbits.

1. Renal sympathetic nerve activity (RSNA) in response to changes in mean arterial pressure (MAP) was examined by measuring renal norepinephrine (NE) spillover rate in conscious rabbits. 2. A chronic renal vein catheter was implanted for sampling renal venous blood without stress in conscious animals. 3. RSNA estimated by renal NE spillover rate significantly increased in response to moderate falls in MAP produced by sodium nitroprusside (SNP) infusion and decreased in response to moderate rises in MAP produced by phenylephrine (PE) infusion. 4. The NE spillover method is sufficiently sensitive to detect responses of RSNA to physiological stimuli in conscious rabbits.

Animals↗
PubMed1995

Renal sympathetic and heart rate baroreflex function in conscious and isoflurane anaesthetized normotensive and chronically hypertensive rabbits.

1. Baroreflex control of heart rate (HR) has been studied in normotensive (NT) and hypertensive (HT) awake and anaesthetized animals and man, but baroreflex control of sympathetic nerve activity has not been well studied. We investigated baroreflex control of HR and renal sympathetic nerve activity (RSNA) over a wide range of arterial pressure (AP) in conscious and isoflurane (ISO) anaesthetized NT and HT rabbits. 2. Animals were instrumented to record AP, HR and RSNA. Hypertension was accomplished by renal encapsulation. AP-HR and AP-RSNA baroreflex function curves were obtained while awake and after 1.0, 1.5, 2.0 and 2.5% ISO. All baroreflex curves were fit to sigmoid or exponential functions. 3. In conscious rabbits, HT for 3-5 weeks, AP was significantly higher (75.6 +/- 0.8 vs 102.3 +/- 8.9 mmHg); HR significantly lower (218.0 +/- 5.5 vs 189.5 +/- 5.5 beats/min); and RSNA not different than NT rabbits (14.9 +/- 2.2 vs 9.9 +/- 3.2% max RSNA). 4. ISO shifted AP-HR and AP-RSNA baroreflex curves to the left in NT and HT animals, and significantly attenuated baroreflex range and slope. At low ISO concentrations, baroreflex compensation for decreases in AP is limited to small increases in HR and sympathetic nerve activity. At higher ISO concentrations, baroreflex responses to decreases in AP are lost. RSNA responses to increases in AP are preserved with increasing ISO concentrations while HR responses are progressively attenuated. The sole effect of chronic hypertension was to shift the AP-HR and AP-RSNA barocurves to the right along the pressure axis in both conscious and ISO anaesthetized animals with no additional change in range or slope. 5. At this stage of hypertension development, ISO anaesthesia affects baroreflex function equally in normotensive and hypertensive rabbits.

Analysis of Variance↗
PubMed1995

Long-term ouabain administration does not alter blood pressure in conscious Sprague-Dawley rats.

1. We tested the ability of ouabain to cause chronic hypertension by continuously infusing ouabain for 28 days (miniosmotic pump implantation; i.p.). The blood pressure and metabolic effects of sham (150 mmol/L NaCl; n = 12) or ouabain infusion (10 micrograms/kg per day; n = 14; 100 micrograms/kg per day; n = 14) were examined in conscious Sprague-Dawley rats. 2. Plasma ouabain concentrations measured after 28 days of ouabain infusion were as follows: sham, not detectable (n = 11); ouabain 10 micrograms/kg per day, 0.60 +/- 0.07 nmol/L (n = 14); and ouabain 100 micrograms/kg per day, 7.17 +/- 0.57 nmol/L (n = 14; P < 0.001). 3. Sham or ouabain infusion did not alter food intake, bodyweight, water intake or urine output in conscious rats. 4. Blood pressure was not altered by sham treatment. Ouabain at 10 micrograms/kg per day or 100 micrograms/kg per day did not produce consistent rises in blood pressure. Ouabain at 10 micrograms/kg per day increased blood pressure on treatment day 12 only (+6 mmHg; P < 0.05), while at 100 micrograms/kg per day blood pressure increased on treatment days 16 (+9 mmHg; P < 0.05) and day 18 (+8 mmHg; P < 0.05) only. There was no significant difference in blood pressure between sham and ouabain groups. 5. Renal blood flow was decreased in rats infused with ouabain at 10 micrograms/kg per day (2.0 +/- 0.3 mL/min per 100 g bodyweight; n = 5; P < 0.01) and 100 micrograms/kg per day (2.2 +/- 0.4 mL/min per 100 g bodyweight; n = 7; P < 0.05) compared with sham treatment (3.5 +/- 0.2 mL/min per 100 g bodyweight; n = 6). Renal vascular resistance was increased in rats treated with ouabain at 10 micrograms/kg per day (65.5 +/- 12.6 mmHg/mL per min per 100 g bodyweight; n = 5; P < 0.01) and 100 micrograms/kg per day (66.0 +/- 15.6 mmHg/mL per min per 100 g bodyweight; n = 7; P < 0.05) compared with sham treatment (32.6 +/- 2.5 mmHg/mL per min per 100 g bodyweight; n = 6). 6. High plasma concentrations of ouabain do not cause consistent increases in blood pressure in conscious Sprague-Dawley rats.

Animals↗
PubMed1996

Increasing resting vascular tone in conscious dogs does not alter the mesenteric vasoconstrictor responses to ANP.

1. There is considerable in vitro evidence that, at high concentrations, atrial natriuretic peptide (ANP) acts directly on pre-constricted blood vessels to cause vasorelaxation. Previously, we have seen vasoconstriction rather than vasodilatation in conscious dogs at physiological levels of the peptide. It is possible that the low resting vascular tone in our conscious, unstressed animals prevented the manifestation of the relaxant properties of ANP in vivo. 2. In the present study in conscious, instrumented dogs, we studied the mesenteric vascular responses to 10 min infusions of ANP (10, 25, 50 and 100 ng/kg per min, i.v.) when resting vascular tone was enhanced with a continuous infusion of AVP (75 pg/kg per min, i.v.) and compared these with responses in the normal condition (no added AVP). 3. Mesenteric vascular resistance was increased by ANP (10, 25, 50 and 100 ng/kg per min) by 9 +/- 2, 20 +/- 6, 29 +/- 7 and 32 +/- 9%, respectively. Increased resting vascular tone did not alter the mesenteric vasoconstrictor response to ANP. Thus, the discrepancy between in vitro (vasorelaxation) and in vivo (vasoconstriction) findings may be the result of the widely different concentrations of ANP used, rather than the state of resting vascular tone.

Animals↗
PubMed1997

Circulating Na+/K+-ATPase inhibitors: effects of neuropeptides, volume expansion and salt loading in conscious rats.

1. In mammalian plasma, many different inhibitors of Na+/K(+)-ATPase are present, but it is not clear whether their net effect on NA+/K(+)-ATPase activity changes during the regulation of electrolyte and fluid balance. We studied Na+/K(+)-ATPase inhibition by plasma extracts in conscious rats during short- and long-term body fluid regulation. 2. Male, adult, conscious, freely moving Wistar rats were subjected to one of the following protocols: (i) intracerebro-ventricular (i.c.v.) injections of angiotension II (AngII; 1, 10 and 100 ng), the AngII receptor antagonist losartan (1 microgram), atrial natriuretic peptide (ANP-III; 1 microgram) or isotonic saline (IS); (ii) intra-arterial (i.a.) injections of IS (6 or 10 mL), hypertonic saline (HS; 1.2% NaCl, 5 mL) or hypertonic plasma expander (HPS; 3.5% hetastarch in HS, 5 mL); or (iii) a low salt-high salt-low salt diet sequence (0.18/1.8/0.18% NaCl chow for 5 days each with controls receiving 0.18% NaCl on all days). Bodyweight, the intake of food and water, urine volume and Na+ concentration and weight of faeces were determined daily. Plasma samples were withdrawn repeatedly throughout the respective protocols, extracted on C18-reversed phase columns and assayed for their effect on the activity of different Na+/K(+)-ATPase preparations. 3. The inhibition of rat brain Na+/K(+)-ATPase by plasma extracts was not significantly changed by i.c.v. injection of AngII, losartan, ANP-III and IS within the observation period (30 min from respective stimuli). Similarly, no significant changes occurred after acute volume expansion by i.a. injection of IS or HS within 120 min; upon HPS, however, Na+/K(+)-ATPase inhibition was decreased by approximately 20% (P < 0.05), probably due to passive dilution. During the high-salt diet, fluid retention was effectively counteracted by an adaptive increase of urinary sodium excretion. Throughout the protocol, inhibition of pig brain Na+/K(+)-ATPase by plasma extracts did not differ significantly between groups. 4. It is concluded from these results that the short- or long-term control of body fluids in conscious rats is not associated with systematic changes in Na+/K(+)-ATPase inhibition by plasma factors.

Angiotensin II↗
PubMed1998

Characterization of a major slow oscillation in the mesenteric circulation of conscious rats.

1. Little is known about spontaneous slow rhythms in regional circulations. The present study was aimed at characterizing low-frequency (LF; 78-269 mHz) oscillations in the mesenteric and hindquarter circulations of conscious rats. 2. Mean arterial pressure (MAP) and indices (pulsed Doppler technique) of mesenteric (n = 25) and hindquarter (n = 23) blood flows were recorded in conscious, freely moving rats during 1 h periods. Fast Fourier transform analysis was applied to beat-to-beat data after resampling at 10 Hz of consecutive 205 s time series. 3. A major oscillation centred at 164 +/- 4 mHz was present in the mesenteric, but not in hindquarter, circulation. Consequently, LF power accounted for approximately 43% of the overall variability of mesenteric blood flow. Cross-spectral analysis performed between MAP and mesenteric blood flow indicated that fractional changes in flow were approximately two-fold of those in MAP, in pressure, at the peak frequency. 4. Acute blockade of the autonomic, renin-angiotensin and vasopressin systems combined with noradrenaline infusion (n = 7) reduced the frequency of the mesenteric blood flow oscillation (115 +/- 6 mHz) but did not change its contribution to overall flow variability (approximately 48%). A clear oscillation was still present after acute inhibition of nitric oxide (NO) synthesis with NG-nitro-L-arginine methyl ester (n = 8), but was virtually absent in chronically guanethidine-sympathectomized rats (n = 12). 5. In conclusion, the mesenteric blood flow of conscious rats exhibits a major slow oscillation that originates in the mesenteric vasculature and is not secondary to the activity of the major pressor systems or to the cyclic release of NO. Because of the strong attenuation of the oscillation in sympathectomized rats, we suggest that adrenergic vasoconstrictor tone plays a permissive role in its genesis.

Animals↗
PubMed1994

The imaginary audience, self-consciousness, and public individuation adolescence.

In this study, we examined the construct of the imaginary audience (Elkind & Bowen, 1979), presumably a precipitant of adolescent egocentrism, as it relates to public individuation and self-consciousness. We hypothesized that the imaginary audience inhibits public individuation and represents a critical form of public self-consciousness. We also argued that the imaginary audience is a normal aspect of early adolescent development that diminishes in the context of secure parental relationships by late adolescence but remains salient if these relationships are insecure. These hypotheses were examined in a cross-sectional study of 850 adolescents in the 7th, 8th, 9th, and 12th grades. Support was generally found for the hypothesized relations. The validity and limitations of the imaginary audience and public individuation constructs are discussed, along with more general theoretical issues concerning adolescent self-consciousness.

Adolescent↗
PubMed1996

Private and public self-consciousness and articulation of the ought self from private and public vantages.

The current research included two studies that examined whether private and public self-consciousness predicts the extent to which individuals schematically articulate the ought self from private and public vantages. Each study assessed private and public self-consciousness, and tested recognition memory of trait adjectives, which participants had rated according to either private/ought (Study 1) or public/ought (Study 2) self-descriptiveness. Across the studies, the convergent and discriminant patterns of false alarms supported the hypotheses that (a) the private and public facets of the ought self resemble bipolar schemas, and (b) private and public self-consciousness, respectively, predicts the extent to which individuals articulate the ought self from either a private or a public vantage.

Adult↗
PubMed1996

When did you first begin to feel it? -- locating the beginning of human consciousness.

In this paper we attempt to sharpen and to provide an answer to the question of when human beings first become conscious. Since it is relatively uncontentious that a capacity for raw sensation precedes and underpins all more sophisticated mental capacities, our question is tantamount to asking when human beings first have experiences with sensational content. Two interconnected features of our argument are crucial. First, we argue that experiences with sensational content are supervenient on facts about electrical activity in the cerebral cortex which can be ascertained through EEG readings. Second, we isolate from other notions of a 'functioning brain' that which is required to underpin the view that a cortex is functioning in a way which could give rise to rudimentary conscious experiences. We investigate the development in the human fetus of the anatomical and chemical pathways which underpin (immature) cortical activity and the growth and maturation of the electrical circuitry specifically associated with sensational content in adult experience. We conclude (tentatively) that a fetus becomes conscious at about 30 to 35 weeks after conception; an answer based on a careful analysis of EEG readings at various stages of cortical development. Finally, we survey the possible ethical ramifications of our answer.

Beginning of Human Life↗
PubMed1998

Renal haemodynamic responses to exogenous and endogenous adenosine in conscious dogs.

1. Adenosine has been suggested to be the mediator of a metabolic feedback mechanism which transfers acute changes in the tubular load into opposite changes in renal blood flow (RBF). The goal of the present experiments was to assess the importance of endogenously formed adenosine as a 'homeostatic metabolite' during short-term changes in metabolic demand. 2. In nine chronically instrumented conscious foxhounds, both the direct effects of adenosine injections (10, 30 and 100 nmol) into the renal artery and the temporal changes of RBF after short renal artery occlusions (15, 30 and 60 s duration), the most widely used experimental model to study the metabolic feedback mechanism in vivo, were studied. 3. Intrarenal bolus injections of adenosine (10, 30 and 100 nmol) induced dose-dependent decreases of RBF (RBF: -34 +/- 5, -59 +/- 4 and -74 +/- 4 %, respectively). This vasoconstrictor effect of adenosine was significantly larger (RBF: -51 +/- 4, -68 +/- 4 and -83 +/- 3 %, respectively) when the dogs received a low salt diet. 4. The post-occlusive responses were characterized by a transient hyperaemia with no detectable drop of RBF below the preocclusion level. The post-occlusive responses were affected neither by changes in local angiotensin II levels, nor by intrarenal infusions of hypertonic NaCl or blockade of A1 adenosine receptors. 5. When intrarenal adenosine levels were elevated by infusion of the adenosine uptake inhibitor dipyridamole, a transient, although weak, post-occlusive vasoconstriction was detected. 6. In summary, the present data demonstrate that adenosine acts as a potent renal vasoconstrictor in the conscious dog. The endogenous production of adenosine during short-lasting occlusions of the renal artery, however, appears to be too small to induce a post-occlusive vasoconstrictor response of RBF. These results suggest that a metabolic feedback with adenosine as 'homeostatic metabolite' is of minor importance in the short-term regulation of RBF in the conscious, unstressed animal.

Adenosine↗
PubMed1999

Cardiovascular responses to intrathecal dopamine receptor agonists in conscious DOCA-salt hypertensive rats.

Previous studies have demonstrated that in conscious deoxycorticosterone acetate (DOCA)-salt hypertensive rats, the hypotensive action of intravenous (i.v.) bromocriptine, a selective dopamine D2 receptor agonist, was mediated partly by peripheral and partly by spinal dopamine D2 receptor stimulation, and that this effect was greater and longer-lasting than that in uninephrectomized control rats. To determine whether this amplification results partly from a putative spinal hypersensitivity phenomenon, cardiovascular responses to intrathecal (i.t.) administration of apomorphine and quinpirole were studied in conscious, 4-week DOCA-salt hypertensive rats and compared with those in uninephrectomized control rats. In both groups, upper thoracic (T2-T4) i.t. injections of apomorphine (9.1, 45.5 and 91.1 microg/rat) induced immediate and dose-dependent decreases in mean aortic pressure (MAP) and heart rate (HR), while i.t. quinpirole (38.4 microg/rat) induced only bradycardia. Neither magnitude nor duration of these responses was enhanced in DOCA-salt hypertensive rats when compared to control rats. In DOCA-salt hypertensive rats, apomorphine-induced hypotension and bradycardia remained unaffected by i.v. (500 microg/kg) pretreatment with domperidone, a selective dopamine D2 receptor antagonist that does not cross the blood-brain barrier. However, i.t. (40 microg/rat at T2-T4) pretreatment with domperidone significantly reduced apomorphine-induced hypotension, but fully suppressed bradycardia elicited by either apomorphine or quinpirole. These results demonstrated that in conscious DOCA-salt hypertensive rats, intrathecally-injected apomorphine or quinpirole decreased MAP and/or HR through a spinal D2 dopaminergic mechanism, as previously demonstrated in normotensive intact rats. Since both magnitude and duration of these responses were unchanged with respect to uninephrectomized control rats, enhancement of the hypotensive effect of intravenously-administered bromocriptine in DOCA-salt hypertensive rats does not appear to involve spinal dopamine D2 receptors.

Analysis of Variance↗
PubMed1986

The cardiovascular effects of centrally administered 5-hydroxytryptamine in the conscious normotensive and hypertensive rat.

The cardiovascular effects of centrally administered 5-hydroxytryptamine (5-HT) have been analysed in conscious normotensive and hypertensive rats. In conscious normotensive rats, 5-HT, (1-30 micrograms) administered intracerebroventricularly (i.c.v.) produced profound and immediate dose-related decreases in heart rate and small increases in blood pressure. The initial pressor responses were followed by secondary secondary depressor responses at high doses of 5-HT. Similar effects were produced by 5-HT i.c.v. in conscious DOCA-salt and spontaneously hypertensive rats, although the magnitude of the pressor responses was substantially greater in hypertensive than normotensive rats. Pretreatment with either N-methylatropine or atenolol intra-arterially reduced the 5-HT-induced bradycardia in normotensive rats; the reduction was enhanced when both antagonists were given in combination. The 5-HT2 antagonist, cyproheptadine (10 micrograms i.c.v.) increased basal blood pressure and heart rate in normotensive rats. Subsequent administration of 5-HT i.c.v. produced biphasic effects on heart rate consisting of an initial tachycardia followed by a marked bradycardia. Methysergide (10 micrograms i.c.v.) pretreatment did not alter resting heart rate, but attenuated the 5-HT induced bradycardia. A higher dose of methysergide, (30 micrograms i.c.v.), decreased resting blood pressure and heart rate. This study has demonstrated, therefore, that the 5-HT induced bradycardia is produced by not only a centrally mediated decrease in sympathetic tone, but also an increase in vagal drive to the heart. The bradycardia is antagonised by centrally administered methysergide, but not by cyproheptadine, which suggests that it is probably mediated through a '5-HT1-like' receptor mechanism.

Animals↗
PubMed1987

Systemic haemodynamic actions of pimobendan (UD-CG 115 BS) and its O-demethylmetabolite UD-CG 212 Cl in the conscious pig.

The cardiovascular effects of the pyridazinone-derivatives pimobendan and its O-demethylmetabolite UD-CG 212 Cl (2-(4-hydroxy-phenyl)-5-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole HCl) were studied in conscious pigs, employing consecutive intravenous 10 min infusions of 10, 25, 50 and 100 micrograms kg-1 min-1 and 2, 4 and 8 micrograms kg-1 min-1 respectively. Pimobendan caused dose-dependent increases in LVdP/dtmax (up to 115%) and heart rate (up to 30%), while cardiac output was slightly elevated (up to 15%) and stroke volume decreased by 12%. Left ventricular end-diastolic pressure decreased in a dose-related manner from 8.7 +/- 1.0 mmHg to 2.7 +/- 1.7 mmHg. Mean arterial blood pressure was not significantly affected because systemic vascular resistance decreased dose-dependently up to 15%. After beta-adrenoceptor blockade, the pimobendan-induced increases in heart rate and cardiac output were attenuated and the increase in LVdP/dtmax almost abolished. The responses of left ventricular end-diastolic and mean arterial blood pressure, systemic vascular resistance and stroke volume were not modified. UD-CG 212 Cl caused dose-related increases in LVdP/dtmax (up to 100%) and heart rate (up to 25%). Cardiac output was minimally elevated (up to 8%) as stroke volume decreased dose-dependently up to 15%. As systemic vascular resistance decreased up to 12%, mean arterial blood pressure was slightly reduced (5%). Left ventricular end-diastolic blood pressure decreased dose-dependently from 9.0 +/- 0.8 mmHg to 3.8 +/- 1.3 mmHg. After beta-adrenoceptor blockade, the UD-CG 212 Cl-induced increases in heart rate and LVdP/dtmax were attenuated and almost abolished and amounted up to 15% and 20%, respectively. The responses of the other systemic haemodynamic parameters were not significantly modified. We conclude that pimobendan and UD-CG 212 Cl are compounds with marked positive inotropic and venodilator properties in the conscious pig. The attenuation of the inotropic effects by pretreatment with propranolol strongly suggests that, in the conscious pig, the beta-adrenergic system is significantly involved in the positive inotropic actions. The lack of effect of beta-adrenoceptor blockade on the vasodilator responses to both compounds suggest a mechanism not related to beta-adrenergic activity.

Animals↗
PubMed1990

Regional and cardiac haemodynamic responses to glyceryl trinitrate, acetylcholine, bradykinin and endothelin-1 in conscious rats: effects of NG-nitro-L-arginine methyl ester.

1. Conscious Long Evans rats, chronically instrumented for cardiovascular measurements, were challenged with i.v. bolus doses of glyceryl trinitrate (40 nmol kg-1), acetylcholine (1.2 nmol kg-1), bradykinin (3.2 nmol kg-1), or endothelin-1 (0.25 nmol kg-1). Under control conditions these doses produced similar falls in mean arterial blood pressure (glyceryl trinitrate, -20 +/- 3 mmHg; acetylcholine, -24 +/- 2 mmHg: bradykinin, -21 +/- 3 mmHg; endothelin-1, -25 +/- 3 mmHg), associated with renal, mesenteric and hindquarters vasodilatations (except for endothelin-1 which caused mesenteric vasoconstriction). 2. In the presence of NG-nitro-L-arginine methyl ester (L-NAME, 10 mgkg-1), a potent inhibitor of nitric oxide biosynthesis and endothelium-dependent vasorelaxation in vitro, the hypotensive responses to glyceryl trinitrate, acetylcholine, and endothelin-1 were increased, although that to bradykinin was not. However, comparing the differences between the response to glyceryl trinitrate and that to any other agonist in the absence and presence of L-NAME showed that there were relative attenuations of the hypotensive responses to bradykinin and endothelin-1, but not to acetylcholine, in the presence of L-NAME. 3. This comparative analysis showed that the renal and hindquarters vasodilator responses to bradykinin and endothelin-1 were attenuated in the presence of L-NAME, but the renal, mesenteric and hindquarters vasodilator responses to acetylcholine were not. However, when L-NAME was administered in the presence of pentolinium, captopril and the vasopressin V1-receptor antagonist, d(CH2)5[Tyr-(Et)]DAVP, (to abolish baroreflex and neurohumoral mechanisms), there was attenuation of the renal and mesenteric vasodilator effects of acetylcholine relative to those seen with glyceryl trinitrate. Under those conditions only the renal vasodilator effects of bradykinin and endothelin-1 were attenuated. 4. In separate experiments in conscious Long Evans rats, direct measurement of cardiac haemodynamics showed that the hypotensive responses to glyceryl trinitrate, acetylcholine, bradykinin and endothelin-l were entirely attributable to rises in total peripheral conductance since both in the absence and presence of L-NAME there were no reductions in cardiac index in response to these substances. 5. The results indicate that measurement of systemic arterial blood pressure alone in conscious rats does not permit reliable quantitation of the influence of L-NAME on regional vasodilator responses to glyceryl trinitrate, acetylcholine, bradykinin or endothelin-1. Furthermore, these substances exert effects in different vascular beds that may be differentially influenced by baroreflex mechanisms, neurohumoral mechanisms, or both. Moreover, except in the case of the renal vasodilator response to endothelin-1 (which was abolished in the presence of L-NAME), even when L-NAME caused attenuation of the vasodilator effects of acetylcholine or bradykinin (relative to glyceryl trinitrate), substantial responses remained. It is feasible that such responses in vivo are nitric oxide-independent.

Acetylcholine↗
PubMed1990

Effect of capsaicin-sensitive sensory nerves on plasma glucose and catecholamine levels during 2-deoxyglucose-induced stress in conscious rats.

1. Sensory fibres innervate the adrenal medulla but their function is not known. In this paper we have studied the effect of capsaicin-sensitive sensory fibres on the adrenal catecholamine (CA) response and blood glucose response to 2-deoxyglucose (2-DG)-induced glucopenic stress in conscious rats. 2. 2-DG at 500 mg kg-1 (i.v.) induced a 2.5 fold increase in plasma glucose levels, a 3.5 fold increase in inferior vena caval (i.v.c.) plasma noradrenaline (NA) levels and a 7 fold increase in i.v.c. plasma adrenaline (Ad) levels over 60 min. The hyperglyaemia in response to 2-DG was attenuated by pentolinium and by left splanchnicotomy plus right adrenalectomy. These procedures also caused a complete inhibition of the increase in plasma CA. 3. The hyperglycaemia in response to 2-DG was attenuated by pretreatment of rats with capsaicin as neonates, suggesting that capsaicin-sensitive sensory fibres are required for regulation of plasma glucose in response to glucopenic stress. 4. The increase in i.v.c. plasma CA levels in response to 2-DG during the early phase of glucopenia (first 30 min) in the conscious rats pretreated with capsaicin was the same as in the rats pretreated with vehicle alone. During the later phase of glucopenia (after 45 min), the increase in plasma CA levels in rats pretreated with capsaicin was higher than in the rats pretreated with vehicle alone. 5. In vehicle-pretreated rats and capsaicin-pretreated rats the tissue NA and Ad levels in the adrenal medulla after 8 h of stress were depleted to the same extent. However, tissue CA levels in the capsaicin group recovered faster over 24 h than in the vehicle group. 6. These results indicate that capsaicin-sensitive sensory fibres are not required to maintain adrenal CA secretion during glucopenic stress in the conscious rat but are required for maintenance of blood glucose levels.

Adrenal Medulla↗
PubMed1993

Effects of 5-HT-receptor and alpha 2-adrenoceptor ligands on the haemodynamic response to acute central hypovolaemia in conscious rabbits.

1. We set out to elucidate the pharmacological mechanisms by which alpha 2-adrenoceptor and 5-HT-receptor ligands affect the haemodynamic response to acute central hypovolaemia in conscious rabbits. 2. Acute central hypovolaemia was produced by inflating an inferior vena caval cuff so that cardiac output fell at a constant rate of approximately 8.5% of its baseline level per min. 3. Drugs were administered into the fourth cerebral ventricle in either 154 mM NaCl (saline) or 20% w/v 2-hydroxypropyl-beta-cyclodextrin (beta-CDX). After vehicle treatments, the haemodynamic response to acute central hypovolaemia had the usual two phases. During Phase I, systemic vascular conductance fell in proportion to cardiac output so that mean arterial pressure fell by only 8 mmHg. Phase II commenced when cardiac output had fallen to approximately 60% of its baseline level, when vascular conductance rose abruptly and arterial pressure fell to < or = 40 mmHg. The haemodynamic response was not dependent on the vehicle used (saline or beta-CDX). 4. Methysergide delayed the occurrence of Phase II in a dose-dependent manner, and prevented it at a dose of 30- 600 nmol (geometric mean = 186 nmol). The effects and potency of methysergide were not dependent on the vehicle used, indicating that beta-CDX can be used as a vehicle for fourth ventricular administration of lipophilic drugs to conscious rabbits. Clonidine (10 nmol) reversed the effects of a critical dose of methysergide. 5. Phase II was also prevented by 8-hydroxy-2-(di-n-propylamino)tetralin (5-HT1A-selective agonist, geometric mean critical dose (range) = 13.1 (10-30) nmol), sumatriptan (5-HT1D-selective agonist, 72.1 (10-300) nmol), mesulergine (5-HT2/1C-selective antagonist, 173 (30-1000) nmol), idazoxan (alpha 2-adrenoceptor-selective antagonist, 548 (100-3000) nmol), and mianserin (5-HT2/1C-selective antagonist, 548 (100-3000) nmol). It was not affected by MDL 72222 (5-HT3-selective antagonist, 300 nmol) or ketanserin (5-HT2/1C-selective antagonist, 3000 nmol). 6. To characterize the nature of alpha 2-adrenoceptors in rabbit brainstem, we examined the binding of [3H]-rauwolscine to membrane homogenates of whole brainstem. [3H]-rauwolscine bound to a population of sites with the characteristics of alpha 2A-adrenoceptors. 7. From these results we suggest that activation of 5-HT1A receptors in the brainstem can prevent Phase II of the response to acute central hypovolaemia in conscious rabbits. Our results do not support the notion of an endogenous 5-hydroxytryptaminergic mechanism mediating Phase II. The mechanism by which the alpha 2-adrenoceptor antagonists yohimbine and idazoxan prevent Phase II remains to be elucidated. However, their potency relative to other 5-HT-receptor ligands indicates that an agonist action at 5-HT1A-receptors is more likely than an antagonist action at alpha 2-adrenoceptors.

2-Hydroxypropyl-beta-cyclodextrin↗