Significant Pressor Effect Research Articles

Novel Therapeutic Options in the Management of Reflex Syncope.

Syncope is a symptom associated with a wide range of pathological conditions, ranging from benign to life threatening. The most frequent is the reflex syncope that may be challenging to treat because of the complex and partially unknown pathophysiological mechanism that has to be addressed by the chosen therapy. Head-up tilt testing is so far the only clinical test able to reproduce reflex syncope, but its diagnostic yield has been recently redefined. A new mechanism such as adenosine-sensitive syncope and idiopathic atrioventricular block have been recently described, and the appropriate therapy is not yet established. There is uncertainty on the efficacy of theophylline and on the use of cardiac pacing in these patients. Clinical trial published data and position paper from the main expert groups on fludrocortisone, midodrine, etilefrine, beta-blockers, and cardiac pacing as useful therapies for patients affected by reflex syncope. Theophylline proved in observational trials to be efficient in preventing reflex syncope recurrences in patients with documented spontaneous paroxysmal conduction disorders comparable to cardiac pacing in a subgroup of patients. Reboxetine and sibutramine may elicit a significant pressor and tachycardic effect able to delay the onset of symptoms during head-up tilt testing. Droxidopa has short-term effects on improving the symptoms because of orthostatic hypotension. Cardiac pacing is effective in preventing reflex syncope recurrences with best results when the indication for pacemaker implantation was based on the documentation of bradycardia or asystole during the spontaneous event by a cardiac monitor. External compression using elastic bandage or compressive stockings is able to prevent the decrease in blood pressure in patients with orthostatic hypotension. The optimal management of the complex diagnostic and therapeutic options can be achieved following a standardized and evidence-based approach to the patient with syncope.

Involvement of spinal α2 -adrenoceptors in prolonged modulation of hind limb withdrawal reflexes following acute noxious stimulation in the anaesthetized rabbit.

The role of spinal α 2‐adrenoceptors in mediating long‐lasting modulation of hind limb withdrawal reflexes following acute noxious chemical stimulation of distant heterotopic and local homotopic locations has been investigated in pentobarbitone‐anaesthetized rabbits. Reflexes evoked in the ankle extensor muscle medial gastrocnemius (MG) by electrical stimulation of the ipsilateral heel, and reflexes elicited in the ankle flexor tibialis anterior and the knee flexor semitendinosus by stimulation at the base of the ipsilateral toes, could be inhibited for over 1 h after mustard oil (20%) was applied to either the snout or into the contralateral MG. The heel–MG response was also inhibited after applying mustard oil across the plantar metatarsophalangeal joints of the ipsilateral foot, whereas this homotopic stimulus facilitated both flexor responses. Mustard oil also caused a significant pressor effect when applied to any of the three test sites. The selective α2‐adrenoceptor antagonist, RX 821002 (100–300 μg, intrathecally), had no effect on reflexes per se, but did cause a decrease in mean arterial blood pressure. In the presence of the α2‐blocker, inhibitory and facilitatory effects of mustard oil on reflexes were completely abolished. These data imply that long‐lasting inhibition of spinal reflexes following acute noxious stimulation of distant locations involves activation of supraspinal noradrenergic pathways, the effects of which are dependent on an intact α2‐adrenoceptor system at the spinal level. These pathways and receptors also appear to be involved in facilitation (sensitization) as well as inhibition of reflexes following a noxious stimulus applied to the same limb.

Multiple system atrophy: using clinical pharmacology to reveal pathophysiology.

Despite similarities in their clinical presentation, patients with multiple system atrophy (MSA) have residual sympathetic tone and intact post-ganglionic noradrenergic fibers, whereas patients with pure autonomic failure (PAF) and Parkinson disease have efferent post-ganglionic autonomic denervation. These differences are apparent biochemically, as well as in neurophysiological testing, with near normal plasma norephrine in MSA but very low levels in PAF. These differences are also reflected in the response patients have to drugs that interact with the autonomic nervous system. For example, the ganglionic blocker trimethaphan reduces residual sympathetic tone and lowers blood pressure in MSA, but less so in PAF. Conversely, the α2-antagonist yohimbine produces a greater increase in blood pressure in MSA compared to PAF, although significant overlap exists. In normal subjects, the norepinephrine reuptake (NET) inhibitor atomoxetine has little effect on blood pressure because the peripheral effects of NET inhibition that result in noradrenergic vasoconstriction are counteracted by the increase in brain norepinephrine, which reduces sympathetic outflow (a clonidine-like effect). In patients with autonomic failure and intact peripheral noradrenergic fibers, only the peripheral vasoconstriction is apparent. This translates to a significant pressor effect of atomoxetine in MSA, but not in PAF patients. Thus, pharmacological probes can be used to understand the pathophysiology of the different forms of autonomic failure, assist in the diagnosis, and aid in the management of orthostatic hypotension.

Cardiovascular Effects of the Essential Oil of Croton Zehntneri Leaves in DOCA-salt Hypertensive, Conscious Rats

This study investigated the cardiovascular effects of the essential oil of Croton zehntneri (EOCZ) in deoxycorticosterone-acetate (DOCA)-salt hypertensive rats. Furthermore, in vitro experiments using isolated thoracic aortic rings were performed to assess the vascular effects of the EOCZ. In conscious hypertensive rats, intravenous (i.v.) injections of EOCZ (1-20 mg/kg) induced rapid (2-4 s) and dose-dependent hypotension and bradycardia (phase 1). The hypotension was followed by a significant pressor effect that was more evident at the higher doses (10 and 20 mg/kg) of EOCZ. Hypotension and bradycardia of EOCZ (phase 1) were abolished and respectively reversed into pressor and tachycardiac effects by methylatropine (1 mg/kg, i.v.) pretreatment. In isolated endothelium-intact aortic preparations, increasing concentrations (1-1000 microg/mL) of EOCZ relaxed the potassium-induced contraction in a concentration-dependent manner with an IC50 (geometric mean [95% confidence interval]) value of 202.0 [92.0-443.7] microg/mL. This vasorelaxant effect remained unaffected by either mechanical removal of functional vascular endothelium (IC50 = 189.0 [159.4-224.7] microg/mL) or the addition of atropine (1 microM) (IC50 = 158.6 [79.8-316.2] microg/mL) in the perfusion medium. These data show that i.v. administration of EOCZ in DOCA-salt hypertensive rats induces a vago-vagal reflex decreases in heart rate and blood pressure (phase 1). EOCZ may induce a second and delayed hypotension due to its direct endothelium-independent vasorelaxant effects, but it seems to be buffered by the pressor component (subsequent to phase 1) of EOCZ. This pattern of blood pressure and heart rate responses to EOCZ seems unaltered by DOCA-salt hypertension, as was similar to that previously reported in conscious normotensive rats.

Nle3,d-Phe6]-γ2-melanocyte-stimulating hormone possesses the renal excretory but not the cardiovascular actions of the native γ2-melanocyte-stimulating hormone in anaesthetized rats

The present study compared the cardiovascular and renal actions of γ(2) -melanocyte-stimulating hormone (γ(2) MSH) with those of the synthetic analogue [Nle(3) ,d-Phe(6) ]-γ(2) MSH (NDP-γ(2) MSH) and explored the effects of high dietary salt intake on the renal actions of NDP-γ(2) MSH. Both peptides were infused systemically (3-1000 nmol/kg) and intrarenally (500 fmol/min) into innervated and renally denervated rats fed either a normal (0.4% NaCl) or high-salt (4% NaCl; HS) diet. Mean arterial pressure (MAP), glomerular filtration rate (GFR), urinary sodium excretion (U(N) (a) V), urinary output (UV) and fractional sodium excretion were determined, as was expression of the melanocortin MC(3) receptor in inner medullary collecting duct (IMCD) epithelial cells. Both renal and systemic infusion of γ(2) MSH increased MAP by 23 ± 2% and 54 ± 4%, respectively, but equivalent doses of NDP-γ(2) MSH had no significant pressor effects. Both peptides had similar natriuretic and diuretic effects in rats fed a normal salt diet. However, NDP-γ(2) MSH increased U(N) (a) V and UV by two- to threefold in rats fed the normal salt diet and by six- to sevenfold in rats fed the HS diet. Furthermore, NDP-γ(2) MSH induced a 3.5-fold increase in GFR only in rats fed the HS diet. These renal effects of NDP-γ(2) MSH were not abolished by prior renal denervation. Rats fed the HS diet also exhibited a 4.5-fold increase in MC(3) receptor expression in IMCD epithelial cells. Intrarenal infusion of NDP-γ(2) MSH induced the natriuretic but not the cardiovascular effects exhibited by γ(2) MSH. The renal activities may be attributed to a direct binding of NDP-γ(2) MSH to MC(3) receptors expressed in IMCD cells, leading to a potent natriuretic effect that is independent of renal innervation.

Long term enhancement of cerebral vascular resistance in spontaneously hypertensive rats produces short term pressor responses and long term re‐modelling of cerebral circulation

Cushing (1901, Bull Johns Hopk Hosp 12, 290‐) discovered that acute increases in cerebral vascular resistance produced hypertension. Based on the Cushing response we propose that hypertension may result from elevated cerebral vascular resistance. We sought to determine the effect of occluding both vertebral and the right common carotid artery (3‐vessel occlusion or 3‐VO) on arterial pressure in spontaneously hypertensive rats (SHR). Given that this strain already has narrowed vertebro‐basilar arteries (Cates et al. 2011; J. Appl. Physiol. 111, 149‐), we hypothesised that the pressor response in the SHR would be larger than that in the Wistar rat. 3‐VO in SHR (n=7) produced a pressor response of 23±3mmHg, which compared with 15±2mmHg in normotensive rats (n=5). Arterial pressure returned to control levels by 8–11 days after 3‐VO. In the SHR there was marked cerebral vessel re‐modelling including dilatation of the right posterior communicating artery (+63%) and ventral spinal artery (+54%) seen from day 11 post 3‐VO. The degree of re‐modelling was associated with the magnitude of the pressure response. 3‐VO in the SHR produces a significant pressor effect and arteriogenesis of cerebral vessels that is associated with a subsequent near normalisation of arterial pressure. Cerebral vascular resistance plays a major role in determining arterial pressure set‐point in the SHR. MRC and BHF funded research.

Effects of Green Tea Ingestion on Postprandial Drops in Blood Pressure in Older Adults

The purpose of this study was to examine whether drinking green tea can prevent postprandial drops in blood pressure in older adults. Participants included 29 older adults who had experienced postprandial drops in systolic blood pressure of more than 15 mmHg in a previous study. During the experimental phase, each participant drank 400 mL of green tea before lunch; during the control phase, participants ate lunch without any tea. Blood pressure and heart rate were measured during both phases before lunch and at 15-minute intervals for 90 minutes after lunch. Drinking green tea before lunch elicited significant pressor effects by increasing systolic and diastolic blood pressure an average of 15.1 mmHg and 5.7 mmHg, respectively. It had no significant effect on heart rate. Drinking green tea before meals is recommended for older adults who experience postprandial hypotension; however, the appropriate volume and time of green tea ingestion to prevent a postprandial drop in blood pressure should be further studied.

VARIABLE EFFECTS OF INHIBITING iNOS AND CLOSING THE VASCULAR ATP-SENSITIVE POTASSIUM CHANNEL (VIA ITS PORE-FORMING AND SULFONYLUREA RECEPTOR SUBUNITS) IN ENDOTOXIC SHOCK

Excess production of NO and activation of vascular ATP-sensitive potassium (K(ATP)) channels are implicated in the hypotension and vascular hyporeactivity associated with endotoxic shock. Using a fluid-resuscitated endotoxic rat model, we compared the cardiovascular effects of an iNOS inhibitor and two distinct inhibitors of the K(ATP) channel. Endotoxin (LPS) was administered to anesthetized, spontaneously breathing, fluid-resuscitated adult male Wistar rats, in which MAP, aortic and renal blood flow, and hepatic microvascular oxygenation were monitored continuously. At 120 min, the iNOS inhibitor, GW273629, and the K(ATP)-channel inhibitors, PNU-37883A and glyburide, were administered separately, and their effects on hemodynamics and oxygenation were examined. We found that GW273629 increased MAP over and above the pressor effect achieved in sham animals. Inhibiting K(ATP) channels via the pore-forming subunit (PNU-37883A and high-dose glyburide) produced significant pressor effects, whereas inhibiting the sulfonylurea receptor with low-dose glyburide was ineffective. No agent reversed the fall in aortic or renal blood flow, the fall in hepatic microvascular oxygenation, or the metabolic acidosis that occurred in LPS-treated animals. We conclude that inhibition of the K(ATP) channel via the pore-forming, but not the sulfonylurea receptor subunit, increases blood pressure in a short-term endotoxic model. However, this was not accompanied by any improvement in macrocirculatory or microcirculatory organ blood flow nor reversal of metabolic acidosis. It therefore remains uncertain whether the iNOS pathway or the K(ATP) channel represents a potential target for drug development in the treatment of endotoxic shock.

In Vivo Cerebrovascular Effects of Cocaine- and Amphetamine-Regulated Transcript (CART) Peptide

Cocaine- and amphetamine-regulated transcript (CART) and its associated peptides have been implicated in a number of physiologic processes including modulation of the hypothalamo-pituitary-adrenal (HPA) axis and cardiovascular regulation. Recently, we reported that in isolated cerebral arterioles, CART peptide (CARTp) acts directly to produce endothelium-dependent constriction via the endothelin signaling pathway. We used the rat closed cranial window model to determine the in vivo effects of CARTp on pial arteriolar diameter. Intravenous administration of 30 microg/kg CARTp produced a significant pressor effect and constriction of pial arterioles. The pressor response to systemic CARTp was blocked by the beta-adrenergic receptor antagonist propranolol (2 mg/kg IV). Direct application of 0.1 nM-1 microM CARTp to pial arterioles produced a dose-dependent and long-lasting constriction to approximately 88% of baseline diameter. The constriction response to topically applied 100 nM CARTp was blocked by both the endothelin A (ETA) receptor antagonist BQ-123 (10 microM) and the inhibitor of endothelin-converting enzyme, phosphoramidon (100 nM). These results demonstrate for the first time that CARTp constricts cerebral vessels in vivo, an action mediated by its effects on the endothelin system, specifically via activation of ETA receptors. This supports the notion that CARTp plays a physiologic role in cerebrovascular regulation, particularly during times of HPA axis activation.

Effects of big endothelin-1 in comparison with endothelin-1 on the microvascular blood flow velocity and diameter of rat mesentery in vivo

Synthetic big endothelin-1 (ET-1), a 39-residue precursor of ET-1, has been reported to elicit potent contractile action on helical strip specimens obtained from the porcine coronary artery, but its molar potency was found to be 140-fold lower than that of ET-1 [Saito, Y., Nakao, K., Mukoyama, M., Imura, H., 1990. Increased plasma endothelin level in patients with essential hypertension. N. Engl. J. Med. 322, 205]. It has been hypothesized that the increased rate of production and/or release of ET-1 from the vascular endothelium may contribute to the pathogenesis of hypertension. However, the effects of big ET-1 in comparison with ET-1 on the macrocirculation and microcirculation of the rat mesentery have not been well documented. Thus, our main purpose for this study was to examine the effects of both big ET-1 and ET-1 to clarify the role of phosphoramidon in inhibiting the conversion of big ET-1 to ET-1, by investigating the systemic blood pressure, microvascular blood flow velocity, and diameters of arterioles and venules of the rat mesentery. For this purpose, two groups of experiments were performed. In these experiments, the mesentery was arranged for in situ intravital microscopic observation under transillumination. In the first group of experiments, intravenous cumulative injections of big ET-1 or ET-1 were infused through a catheter inserted into the right jugular vein. Infusion of big ET-1 (1–8 nmol/kg) elicited a long-lasting significant pressor effect. Infusion of big ET-1 (1–2 nmol/kg) elicited a significant dose-dependent increase in the microvascular blood flow velocity both in arterioles (20–30 μm) and venules (30–40 μm). Microvascular diameters exhibited a slight but significant vasodilator effect. However, the infusion of big ET-1 (4–8 nmol/kg) elicited a dose-dependent significant decrease in the blood flow velocities, and diameters returned to control measurements. The administration of ET-1 (0.25–2 nmol/kg) induced a dose-dependent significant decrease in the blood flow velocity of arterioles and venules, and their diameters exhibited a vasoconstrictive effect more prominent in arterioles than in venules. In the second group of experiments, cumulative injections of phosphoramidon (30 mg/kg/10 min) were administered 10 min prior to the infusion of big ET-1. Phosphoramidon significantly suppressed the long-lasting significant pressor effect and significantly inhibited the dose-dependent increase and dose-dependent decrease in the microvascular blood flow velocity produced by big ET-1 in the rat mesenteric microcirculation. This study observed differences in the effects big ET-1 and ET-1 have on the rat mesenteric microcirculation and proposes a possible mechanism explaining these differences. Moreover, phosphoramidon markedly inhibited the conversion of big ET-1 to ET-1 in the rat mesenteric microcirculation, which may suggest an inhibition of the enzyme which converts big ET-1 to ET-1.

Acute Effect of Black and Green Tea on Aortic Stiffness and Wave Reflections

Objective: While most studies have shown an inverse relation between tea consumption and cardiovascular risk, other studies have shown opposite results. Aortic stiffness and wave reflections are markers of cardiovascular disease and prognosticators of cardiovascular risk.Methods: The acute effect of black and green tea on aortic stiffness and wave reflections was assessed in 29 healthy volunteers in a randomized, single-blind, sham-procedure controlled, cross-over design. In the black tea sub-study, 16 subjects received 6 gm of tea, caffeine (175 mg), or hot water in 3 different sessions. In the green tea sub-study, 13 subjects received 6 gm of tea, caffeine (125 mg), or hot water. Carotid-femoral pulse wave velocity and wave reflection indices were measured at baseline and for 3 hours after consumption.Results: Black tea increased pulse wave velocity during the first 90 min (increase by 0.49 m/sec, P < 0.05), showing a rapid return towards baseline values thereafter (P = 0.07 for the whole study period); in contrast, green tea had no effect. Both black and green tea increased augmentation index (by 5.0% and by 6.6%, P < 0.01 and P < 0.001, respectively) throughout the study. These changes were less than the respective changes produced by caffeine. Both black and green tea had a significant pressor effect. No change in oxidant status was found with both types of tea.Conclusions: Both black and green tea increases acutely wave reflections and only black tea increases aortic stiffness. Tea flavonoids may play a role in the attenuation of the effects of caffeine contained in tea.

Cardiovascular effects of the essential oil of Croton zehntneri leaves and its main constituents, anethole and estragole, in normotensive conscious rats

Cardiovascular effects of the essential oil of Croton zehntneri (EOCZ) were investigated in conscious rats. In these preparations, intravenous (i.v.) injections of EOCZ (1–20 mg kg − 1 ) and its main constituents anethole and estragole (both at 1–10 mg kg − 1 ) elicited brief and dose-dependent hypotension and bradycardia (phase I) that were followed by a significant pressor effect associated with a delayed bradycardia (phase II). The initial hypotension and bradycardia (phase I) of EOCZ were unchanged by atenolol (1.5 mg kg − 1 , i.v.) or l-NAME (20 mg kg − 1 , i.v.) pretreatment, but were respectively reversed into pressor and tachycardic effects by methylatropine (1 mg kg − 1 , i.v.) pretreatment. The subsequent pressor effect and the delayed bradycardia (phase II) remained unaffected by atenolol, but were abolished by l-NAME and methylatropine pretreatment, respectively. In rat endothelium-containing aorta preparations, the vasoconstrictor responses to phenylephrine were enhanced and reduced, respectively, by the lower (1–30 μg mL − 1 ) and higher (300–1000 μg mL − 1 ) concentrations of EOCZ. Only the enhancement of phenylephrine-induced contraction was abolished by either the incubation with l-NAME (50 μM) or in the absence of the endothelium. These data show, for the first time, that i.v. administration EOCZ induces an initial hypotension followed by a pressor response, two effects that appear mainly attributed to the actions of anethole and estragole. The EOCZ-induced hypotension (phase I) is mediated by a cholinergic mechanism and seems to result mainly from the concomitant bradycardia. The pressor response of EOCZ (phase II) seems to be caused by an indirect vasoconstrictive action of EOCZ most likely through inhibition of endothelial nitric oxide production.

Critical role for the alpha-1B adrenergic receptor at the sympathetic neuroeffector junction.

The alpha-1 adrenergic receptors (alpha(1)ARs) are critical in sympathetically mediated vasoconstriction. The specific role of each alpha(1)AR subtype in regulating vasoconstriction remains highly controversial. Limited pharmacological studies suggest that differential alpha(1)AR responses may be the result of differential activation of junctional versus extrajunctional receptors. We tested the hypothesis that the alpha(1B)AR subtype is critical in mediating sympathetic junctional neurotransmission. We measured in vivo integrated cardiovascular responses to a hypotensive stimulus (induced via transient bilateral carotid occlusion [TBCO]) in alpha(1B)AR knockout (KO) mice and their wild-type (WT) littermates. In WT mice, after dissection of the carotid arteries and denervation of aortic baroreceptor buffering nerves, TBCO produced significant pressor and positive inotropic effects. Both responses were markedly attenuated in alpha(1B)AR KO mice (change systolic blood pressure 46+/-8 versus 11+/-2 mm Hg; percentage change in the end-systolic pressure-volume relationship [ESPVR] 36+/-7% versus 12+/-2%; WT versus KO; P<0.003). In vitro alpha(1)AR mesenteric microvascular contractile responses to endogenous norepinephrine (NE; elicited by electrical field stimulation 10 Hz) was markedly depressed in alpha(1B)AR KO mice compared with WT (12.4+/-1.7% versus 21.5+/-1.2%; P<0.001). In contrast, responses to exogenous NE were similar in alpha(1B)AR KO and WT mice (22.4+/-7.3% versus 33.4+/-4.3%; NS). Collectively, these results demonstrate a critical role for the alpha(1B)AR in baroreceptor-mediated adrenergic signaling at the vascular neuroeffector junction. Moreover, alpha(1B)ARs modulate inotropic responses to baroreceptor activation. The critical role for alpha(1B)AR in neuroeffector regulation of vascular tone and myocardial contractility has profound clinical implications for designing therapies for orthostatic intolerance.

Influence of the presence of doctors-in-training on the blood pressure of patients: a randomised controlled trial in 22 teaching practices

Until now, no information is available about the effect of the presence of a doctor-in-training on a patient's blood pressure. We tested the hypothesis that the presence of a last year medical student might increase the blood pressure of the patient, in addition to the possible pressor response to the doctor-trainer. Normotensive and hypertensive patients with a minimum age of 25 years, visiting for any reason, were recruited at 22 teaching general practices. Patients were randomised into a 'trainee' group (n=133) and a 'no trainee' (n=129) group. The blood pressure was measured at two subsequent contacts. In the 'trainee' group, a student was present at the first visit only. In the 'no trainee' group, both visits were without student. Both groups had similar anthropometric characteristics at entry. At the first visit, systolic pressure was higher in the 'trainee' group than in the control group (139.5 vs 133.1 mmHg, P=0.004), with a similar trend for diastolic pressure (80.2 vs 77.8 mmHg, P=0.07). From the first contact to the follow-up visit, blood pressure decreased in the trainee group by 4.8 mmHg systolic (P<0.001) and 1.7 mmHg diastolic (P=0.03), whereas the corresponding changes in the control group were -0.1 mmHg (P=0.90) and +1.5 mmHg (P=0.03). Thus, the between group differences in these trends averaging 4.7 mmHg (CI 1.5-7.9, P=0.005) systolic and 3.2 mmHg (CI 1.1-5.3, P=0.003) diastolic were statistically significant. We conclude that in teaching-practices, the presence of a doctor-in-training has a significant pressor effect when an experienced general practitioner measures a patient's blood pressure. If confirmed, our findings imply that doctors should be cautious to initiate or adjust antihypertensive treatment when blood pressure readings are obtained in the presence of a student.

Blood pressure effects of intravenous apomorphine in conscious deoxycorticosterone-acetate salt-hypertensive rats.

The present study reports the effects of apomorphine (APO) on blood pressure and the principal site of action of this agonist in 4-week deoxycorticosterone-acetate (DOCA)-hypertensive conscious rats. In these preprations, intravenous (i.v.) administration of APO (0.50-1 mg/kg) induced short-lasting and dose-dependent decreases in mean arterial pressure. The hypotensive response to APO (0.3 mg/kg) was reversed into a significant pressor effect by i.v. hexamethonium (30 mg/kg), whereas it was enhanced by i.v. pretreatment with the vasopressor antagonist of arginine vasopressin (AVP) d(CH2)5Tyr(Me)AVP (10 microg/kg) and/or prazosin (1 mg/kg). This depressor effect was suppressed by the central and peripheral dopamine D2 receptor antagonist metoclopramide (5 mg/kg i.v.), unaffected by the selective dopamine D1 receptor antagonist SCH 23390 (0.2 mg/kg i.v.), partly reduced by intrathecal domperidone (40 microg per rat at T9-T10 level), a dopamine D2 receptor antagonist which does not cross the blood-brain barrier, and reversed into a significant pressor effect by i.v. domperidone (0.5 mg/kg). The latter pressor effect was fully abolished by combined i.v. pretreatment with the vasopressor antagonist of AVP and prazosin. These results show that, in conscious DOCA salt-hypertensive rats, APO induced a brief, initial depressor effect, which is opposed to a central pressor component. The depressor component is related to an inhibition of norepinephrine transmission through activation of dopamine D2 receptors, some of which are located in the spinal cord and some of which are located in the peripheral circulation. The central pressor component, which became manifest after peripheral dopamine D2 receptor blockade, appears to be related to an increase in vasopressin release and sympathetic tone through activation of brain dopamine D2 receptors.

Blockade of spinal dopamine D2 receptors enhances the pressor effect of intravenous quinpirole in normotensive, conscious rats.

The present investigation was undertaken to examine whether in conscious intact rats blockade of spinal dopamine D2 receptors enhances the pressor effect of intravenous quinpirole. In saline-pretreated rats, intravenous quinpirole (1 mg/kg) induced a significant pressor effect, which reached a maximum (17.71+/-0.60 mmHg) within the first min. after injection. Pretreatment with intravenous (0.5 mg/kg) or intrathecal (40 microg/rat at T9-T10) domperidone, a dopamine D2 receptor antagonist that does not cross the blood-brain barrier, significantly enhanced the maximal pressor response to quinpirole (25.60+/-1.52 and 24.00+/-1.72 mmHg, respectively). The pressor effect of quinpirole was also significantly enhanced after combined pretreatment with intravenous and intrathecal domperidone, and its maximum (31.60+/-2.31 mmHg) was significantly higher than that recorded in animals pretreated with intrathecal or intravenous domperidone alone. Intravenous pretreatment with metoclopramide (5 mg/kg) fully abolished the quinpirole-induced pressor effect. These results show that in conscious intact rats, blockade of spinal dopamine D2 receptors enhances the pressor response to systemic quinpirole, suggesting that this agonist can decrease blood pressure through a spinal dopaminergic mechanism. Thus, our previous hypothesis that the entire effect of intravenous quinpirole on blood pressure in conscious rats can be composed of a central pressor action, a peripheral sympathoinhibitory depressor effect and also a spinal depressor effect is strongly supported by the present findings.

Long-Lasting Cardiovascular Effects of Liposome-Entrapped Angiotensin-(1-7) at the Rostral Ventrolateral Medulla

The aim of this work was to evaluate the potential of liposomes as a tool for the sustained release of the short half-life peptides of the renin-angiotensin system in a specific site of the brain. Angiotensin (Ang)-(1-7) was selected for this study because of its known cardiovascular effects at the level of the rostral ventrolateral medulla (RVLM) and because of the considerable interests in elucidating its physiopathological role as a neuromodulator. Ang-(1-7)-containing liposomes (LAng) were microinjected unilaterally in the RVLM of Wistar rats, and the effects on blood pressure (MAP) and heart rate were evaluated by telemetry. Empty liposomes (Lemp) were used as control. LAng elicited a significant pressor effect during daytime and bradycardia during nighttime that lasted for 5 and 3 days, respectively. These cardiovascular effects resulted in a significant attenuation of the circadian variations of MAP and heart rate. In the case of MAP, a significant inversion of the circadian rhythm was observed on day 2 after LAng microinjection. None of these effects were observed following microinjection of Lemp. Using this novel technique, it was possible to establish, in chronic conditions, the pressor effect of Ang-(1-7) at the RVLM. Moreover, our data unmasks a new physiological role for Ang-(1-7) at the level of the RVLM: modulation of the circadian rhythms of MAP and heart rate.

The effects of endothelin-1 on ischaemia-induced ventricular arrhythmias in rat isolated hearts

We have shown previously that a small bolus dose of endothelin-1, given intravenously before coronary occlusion, exerts a marked antiarrhythmic effect in anaesthetised rats. The aim of the current study was to determine whether or not this is due to a direct effect of endothelin-1 on the heart by assessing the antiarrhythmic effect of endothelin-1 against occlusion-induced arrhythmias in rat isolated hearts. Rat isolated hearts were perfused in Langendorff mode (constant flow) and subjected to coronary artery occlusion for 30 min. Coronary perfusion pressure and a surface electrocardiogram (ECG) were monitored throughout the experiment. In the first series of studies, the effects of three 5-min infusions of endothelin-1 (0.1–10 nM), given prior to coronary occlusion, were assessed. A second series of hearts was given a single bolus dose of endothelin-1 (10 pmol) 5 min prior to ischaemia. A third series of experiments was performed using a modified (low K +) Krebs Henseleit solution to increase the incidence of ischaemia-induced ventricular fibrillation (VF). In these hearts, endothelin-1 (0.1 or 2 pmol) was administered as a bolus injection 5 min before ischaemia. Infusion of endothelin-1 prior to ischaemia did not modify the incidence or severity of arrhythmias at any of the concentrations used. Bolus administration of endothelin-1 (10 pmol) in hearts perfused with Kreb's Henseleit solution containing normal K + (4.4 mM) was found to cause a small rise in coronary perfusion pressure, with no preceding depressor response. Under these conditions, endothelin-1 exerted only a very moderate reduction in arrhythmias, by reducing the arrhythmia count in the 21–30-min post-occlusion period. Furthermore, in hearts perfused with low K + solution, bolus injection of endothelin-1, in a dose that either had no effect on coronary perfusion pressure (0.1 pmol) or produced a significant vasodilator effect with no significant pressor effect (2 pmol), had no effect on ventricular fibrillation. Thus, in concentrations that are sufficient to exert effects on the coronary vasculature, endothelin-1 fails to modify arrhythmias in an isolated heart preparation. These results suggest that the antiarrhythmic effects of endothelin-1 previously observed in vivo are not due to a direct effect on either the myocardium or the coronary blood vessels.

Role of the solitary tract nucleus in mediating nociceptive evoked cardiorespiratory responses

We compared the cardiorespiratory reflex responses evoked by noxious stimulation of the forelimb and cornea. Due to the depressant effects of anaesthesia on visceral reflexes we compared data from an unanaesthetised decerebrate rat model — the working heart–brainstem preparation (WHBP), with the anaesthetised rat. In both experimental models stimulation of the forelimb (mechanical pinch) evoked a tachycardia (WHBP: 19±2 bpm) and a decrease in respiratory cycle length (WHBP: from 4.1±0.2 to 2.3±0.1 s). The magnitude of response in anaesthetised animals depended on anaesthetic depth. Mechanical stimulation of the cornea evoked a bradycardia (−49.2±4.8 bpm) and an increase in respiratory cycle length from 4±0.36 to 5.88±0.2 s which was only present in the WHBP. In the WHBP activation of forelimb and corneal nociceptors both elicited significant pressor effects; in anaesthetised rats there were inconsistent changes in arterial pressure. To determine a role for the nucleus of the solitary tract (NTS) in mediating nociceptive evoked responses in the WHBP, synaptic transmission was blocked reversibly following bilateral microinjections of cobalt chloride. The heart rate responses evoked from either forelimb or corneal nociceptors were attenuated by approximately 50% ( P<0.05). A similar effect was observed using isoguvacine, a GABA A receptor agonist, to hyperpolarise NTS neurones. In conclusion, activation of forelimb and corneal nociceptors evoked contrasting patterns of cardiorespiratory response in the WHBP while in the anaesthetised rat the magnitude of the cardiorespiratory response to forelimb stimulation was quantitatively dependent on anaesthetic dose. In the WHBP, NTS neurones appear important for mediating the cardiac component of the reflex response following stimulation of nociceptive reflex pathways.

Significant interaction between clozapine and cocaine in cocaine addicts

Because clozapine may be prescribed to cocaine abusing patients with schizophrenia, we studied cocaine–clozapine interactions in a controlled setting. Eight male cocaine addicts underwent four oral challenges with ascending doses of clozapine (12.5, 25 and 50 mg) and placebo followed 2 h later by a 2-mg/kg dose of intranasal cocaine. Subjective and physiological responses, and serum cocaine levels were measured over a total 4-h period. Clozapine pretreatment increased cocaine levels during the study and significantly increased the peak serum cocaine levels in a dose dependent manner. In spite of this elevation in blood levels, clozapine pretreatment had a significant diminishing effect upon subjective responses to cocaine, including ‘expected high’, ‘high’ and ‘rush’, notably at the 50 mg dose. There was also a significant effect upon ‘sleepiness’, ‘paranoia’ and ‘nervous’. Clozapine caused a significant near-syncopal episode in one subject in the study, requiring his removal from the study. Clozapine had no significant effect on baseline pulse rate and systolic blood pressure, but it attenuated the significant pressor effects of the single dose of intranasal cocaine. These data suggested a possible therapeutic role for clozapine in the treatment of cocaine addiction in humans, but also suggests caution due to the near-syncopal event and the increase in serum cocaine levels.