Hypotensive Phase Research Articles

Effect of diazepam on endocrine and cardiovascular responses to head-up tilt in humans.

Effects of the GABAergic drug diazepam (0.15 mg kg-1, i.v.) on cardiovascular and endocrine responses to 50 degrees head-up tilt were evaluated in seven men. During the initial phase of tilt (normotensive phase), increases in heart rate (HR) and total peripheral resistance (TPR) and decreases in cardiac output were unaffected by diazepam. Also the associated increase in plasma noradrenaline did not change, while response in plasma ACTH was diminished and in plasma cortisol abolished by diazepam (F(1,10) = 6.45; P < 0.03). After 42 +/- 4 min of sustained tilt with saline (control) and 47 +/- 6 min (n.s.) after diazepam, presyncopal symptoms appeared (hypotensive phase) associated with decreases in HR, MAP, and TPR (P < 0.01). This episode induced a 2-3-fold increase in plasma ACTH, beta-endorphin, prolactin, cortisol (< 0.01), and a moderate increase in plasma adrenaline (P < 0.05). Diazepam did not significantly change cardiovascular and endocrine responses to the hypotensive phase of tilt. Results indicate that diazepam attenuates the cortisol part of pituitary-adrenal responses to moderate, but not to severe, central hypovolaemia in humans with no effect on cardiovascular tolerance.

Factors confounding blockade of cardiac afferents by intrapericardial procaine in conscious rabbits.

Intrapericardial procaine has been used by several groups to block cardiac afferent nerves to study effects of cardiogenic reflexes. In eight conscious rabbits, procaine (17-113 mg ipc; median 32) blocked cardiac efferents. Procaine (17-113 mg ipc; median 39) abolished the reflex depressor effects of the cardiac C-fiber excitant 1-phenylbiguanide (PBG), and in four of eight rabbits prevented the hypotensive phase 2 of acute central hypovolemia, which has been attributed to a signal from the heart. However, in three of the rabbits respiratory incoordination and blood gas abnormalities developed. In another study of four rabbits, procaine (165-335 mg ipc; median 235) invariably caused phrenic nerve blockade and underventilation. In three rabbits, after intrapericardial (250 mg) or subcutaneous (50 mg) procaine, plasma procaine levels rose to 9.4 and 4.8 micrograms/ml, respectively. During intravenous infusion of procaine, the PBG chemoreflex was abolished at plasma levels > 3.1 micrograms/ml, and phase 2 of acute hypovolemia at levels > or = 4.3 micrograms/ml. There is a narrow margin between a dose of intrapericardial procaine that blocks cardiac nerves and one that can produce confounding effects from phrenic nerve blockade or absorption into the bloodstream.

Cardioinhibitory-vasodepressor response to head-up tilt without hypoxaemia or myocardial ischaemia.

We evaluated whether hypoxaemia and/or myocardial ischaemia are of importance for development of the bradycardic hypotensive phase (cardioinhibitory-vasodepressor syncope) of central hypovolaemia. Arterial blood gas variables and a twelve-lead electrocardiogram (ECG) were followed during head-up tilt in seven men. During tilt, before presyncopal symptoms appeared, mean arterial pressure (MAP) increased (from 67 +/- 7 to 78 +/- 6 mmHg) (mean +/- SE) as did heart rate (HR) (61 +/- 4 to 99 +/- 8 beats min-1) and total peripheral resistance (TPR) (11 +/- 1 to 17 +/- 1 mmHg min l-1) (P < 0.01), while cardiac output (5.9 +/- 0.5 to 4.6 +/- 0.6 l min-1) and central venous pressure (CVP) (4.2 +/- 0.4 to 1.3 +/- 0.7 mmHg) decreased (P < 0.01). After 40 +/- 7 min of head-up tilt presyncopal symptoms appeared together with a decrease in MAP to 48 +/- 7 mmHg, HR to 71 +/- 11 beats min-1 and TPR to 9 +/- 2 mmHg min l-1 (P < 0.01). Arterial oxygen tension was not changed and there was no ST-segment depression of the ECG. The results indicate that during central hypovolaemia decreases in HR and TPR are elicited during normoxaemia and without electrocardiographic signs of myocardial ischaemia.

Pathological events in experimental acute pancreatitis prevented by the bradykinin antagonist, Hoe 140

1. In a previous investigation, Hoe 140, a specific and potent bradykinin B2 receptor antagonist, prevented the pancreatic oedema and the hypotension observed during acute experimental pancreatitis; however, it augmented the associated rises in the serum activities of pancreatic enzymes. Therefore, we have now investigated the consequences of the pancreatic oedema for the fate of activated enzymes released into the tissue during the course of acute pancreatitis. 2. Acute oedematous pancreatitis was induced in rats, pretreated with captopril (50 mumol kg-1, i.p.), by hyperstimulation of the exocrine function of the pancreas with the cholecystokinin analogue, caerulein (4 nmol kg-1 h-1, i.v.), for up to 120 min. 3. Pancreatic oedema began to develop 10 min after the start of the caerulein infusion, reached a maximum within about 45 min, and then declined slightly. The development of the oedema parallelled the second phase of the caerulein-induced fall in blood pressure found in earlier experiments. No further extravasation of plasma proteins occurred during the 2nd hour of the caerulein infusion. The oedema formation was completely blocked in animals pretreated with the bradykinin receptor antagonist, Hoe 140 (100 nmol kg-1, s.c.). Pretreatment with aprotinin or soy bean trypsin inhibitor did not result in a significant inhibition of the oedema. 4. The haematocrit of animals with experimental pancreatitis showed a pronounced increase which started 10 min after the start of the caerulein infusion and reached maximal values at 60 min. The changes in haematocrit showed a reduction in total blood volume of 28% due to a 48% loss of plasma. This effect was completely blocked by Hoe 140. 5. In rats with caerulein-induced pancreatitis, there was a time-dependent increase in the activities of amylase and lipase in blood serum as well as in the pancreas. Pretreatment with Hoe 140 greatly augmented the caerulein-induced rise in enzyme activities in blood serum but potently attenuated it in the pancreas. The activities of trypsin in both the blood serum and the pancreas were below or near the limit of detection in all experimental groups.6. It is concluded that the second phase of hypotension in this model of acute pancreatitis is due to the liberation of kinins which cause a massive loss of blood plasma into the pancreas and into the retroperitoneal space. Activated enzymes are trapped in the pancreas, at least in part, by the oedema of the gland. Treatment with Hoe 140 prevents the oedema formation and greatly facilitates the egress of activated enzymes from the pancreas.

Effect of methylene blue on blood pressure in rats.

Methylene blue (MB) is a soluble guanylate cyclase inhibitor, and known as an endothelium-derived relaxing factor (EDRF) inhibitor in vitro. In the present study, it was demonstrated that intravenous administration of MB caused a dose-dependent hypertensive effect in rats. The hypertensive responses to the higher doses (10 and 20 mg/kg) of MB was followed by a reflex hypotension which did not appear in pithed rats. Noradrenaline depletion by reserpine pretreatment did not inhibit MB-induced hypertension, but abolished the hypotensive response. Both hypertensive and hypotensive phases were not altered by indometacin. These results may suggest that in vivo guanylate cyclase inhibition leads to an increase in blood pressure; prostaglandins and noradrenaline release from sympathetic nerve endings do not contribute to MB-induced hypertension and it may be due in part to the inhibition of EDRF.

Modulation of the effect of endothelin-3 on blood pressure by atrial natriuretic peptide in conscious spontaneously hypertensive (SHR) and normotensive (WKY) rats.

Endothelin (ET) exerts direct vasoconstrictory effects and stimulates release of vasoactive substances. It has been demonstrated that ET stimulates the release of atrial natriuretic peptide (ANP) both under in vitro and in vivo conditions. The present study aimed at elucidating whether the cardiovascular effects of endothelin-3 (ET-3) in normotensive (WKY) and spontaneously hypertensive (SHR) rats are modulated by ANP. The experiments were performed on 17 conscious WKY and 17 SHR rats. The effects of i.v. administration of 1 microgram of ET-3 on blood pressure (BP) and heart rate (HR) were investigated under control conditions and during ANP infusion (0.3 microgram/kg/min). In both strains ET-3 elicited a transient significant hypotensive effect followed by an increase in BP. BP fall was significantly greater and pressor effect significantly smaller in SHR than in WKY. In WKY, but not in SHR rats, both hypotensive and pressor phases were significantly attenuated during ANP administration. The results are evidence of differential involvement of endogenous blood pressure regulating factors in the cardiovascular effects of ET-3 in WKY and SHR rats during ANP infusion.

Effects of the bradykinin antagonist, HOE 140, in experimental acute pancreatitis.

1. The novel bradykinin antagonist, HOE 140, completely blocked the fall in rabbit blood pressure caused, not only by i.v. bradykinin, but also by i.v. kallikrein. This shows that both the effects of exogenously administered bradykinin and those of endogenously released kinins are antagonized by HOE 140. 2. Acute pancreatitis was induced in rats by i.v. infusion of the cholecystokinin analogue, caerulein. This treatment resulted in massive oedema of the pancreas, increased activities of amylase and lipase in serum and a characteristic, biphasic fall in blood pressure. 3. HOE 140 prevented the caerulein-induced pancreatic oedema and the second phase of hypotension whereas NPC 349, a widely used, but short-acting, bradykinin antagonist did not show a significant inhibition. HOE 140, in contrast to its inhibitory effects on caerulein-induced pancreatic oedema and hypotension, significantly augmented the increases in amylase and lipase activities in serum. 4. It is concluded that in this model of acute pancreatitis, the release of kinins induces pancreatic oedema and hypotension. Prevention by HOE 140 of the kinin-induced oedema allows the pancreatic enzymes to leave the tissue without hindrance and thus will diminish subsequent pathological events. It is suggested that the results obtained with the highly potent and long-acting bradykinin antagonist, HOE 140, provide a pharmacological basis for a clinical trial in acute pancreatitis.

Age, strain and anesthetic dependent differences in the nociceptive responses produced by i.v. 5-HT in the rat

The intravenous (i.v.) administration of serotonin (5-HT) to rats is a noxious visceral stimulus which produces distinct vagal afferent-mediated pseudaffective responses, a passive avoidance behavior, a vagal afferent-mediated inhibition of the tail-flick (TF) reflex and a complex cardiovascular response. In the present study, we examined the effects of age (10 or 16 weeks), strain (Sprague-Dawley, SD; Wistar-Kyoto, WKY; spontaneously hypertensive rats, SHR) and anesthetic (conscious or lightly pentobarbital-anesthetized) on nociceptive (TF reflex and pseudaffective resonses) and cardiovascular responses produced by 5-HT (3–288 μg/kg i.v.). There were no age-related differences in baseline TF latencies in the 3 strains. Further, latencies were generally not significantly different whether rats were tested conscious or lightly anesthetized. There were, however, strain differences. Both conscious or lightly pentobarbital-anesthetized SHR and WKY rats at 10 weeks of agge had significantly faster response latencies than 10 week old SD rats. At 16 weeks of age, only the lightly pentobarbital-anesthetized WKY and SHR showed faster response latencies than SD rats. The WKY and SHR, but not the SD rats, were more sensitive to the nociceptive effect of i.v. 5-HT at 16 weeks of age compared to 10 weeks of age. At both ages, WKY and SHR, but not SD rats, showed an anesthetic-dependent increase in nociceptive sensitivity to i.v. 5-HT. In addition, at both ages regardless of the presence of anesthetic, the order of sensitivity to the nociceptive effects of i.v.5-HT was SD > WKY → SHR. The cardiovascular responses to i.v. 5-HT also were examined at these different strains and in the presence of absence of pentobarbital anesthesia. In general, there were no major differences in the cardiovascular responses to i.v. 5-HT at 10 or 16 weeks of age. The presemce of pentobarbital anesthesia resulted in an increase in the Bezold-Jurisch reflex-mediated hypotension and bradycardia in SD and SHR, but not in WKY, a decrease in the magnitude of the late hypotensive phase in all 3 strains. At all doses of 5-HT tested in lightly anesthetized rats, both the WKY and SHR showed a significantly greater Bezold-Jarisch reflex-mediated hypotension and bradycardia and a less pronounced pressor response compared to SD rats. The magnitude and duration of the late hypottensive phase was similar in SHR and WKY rats, which were greater than SD rats. WKY and SHR showed similar cardiovascular response to i.v. 5-HT except that WKY showed a less pronounced pressor response. In conscious rats, at all doses tested, both the WKY and SHR showed a greater Bezold-Jurisch reflex-mediated hypotension and bradycardia, a less pronounced pressor response and the presence of a late hypotensive phase compared to SD rats. WKY rats showed a greater Bezold-Jurisch reflex-mediated hypotension and bradycardia and a less pronounced pressor response and late hypotensive phase compared to SHR. These results demonstrate that there is a significant influence of strain, age and presence or absencce of pentobarbital anesthetic on the nociceptive actions of i.v. 5-HT and are discussed with respect to strain differences and the developmental aspects of visceral nociception.

Pituitary-adrenal responses to head-up tilt in humans: effect of H1- and H2-receptor blockade.

Effects of the histamine H1- or H2-receptor antagonists mepyramine (Mep) and cimetidine (Cim) on neuroendocrine and cardiovascular responses to 50 degrees head-up tilt were evaluated in seven human males. Central hypovolemia was characterized by two phases. The first is a normotensive phase with increases in heart rate (HR), total peripheral resistance (TPR), and decrease in cardiac output. Plasma adrenocorticotropic hormone, beta-endorphin, cortisol, catecholamines, and renin activity increased moderately. Normotension lasted 39 +/- 7 min during infusion of saline but was reduced by Mep [18 +/- 3 min, F(2,12) = 9.60, P less than 0.01] and was unaffected by Cim (44 +/- 4 min). The second is a hypotensive phase associated with presyncopal symptoms (hypovolemic shock) and decreases in HR and TPR and a further increase in pituitary-adrenal and sympathoadrenal activity. Decreases in mean arterial pressure and TPR were augmented by Mep, which inhibited release of norepinephrine. Cim inhibited epinephrine release without affecting the development of hypovolemic shock. It is concluded that histaminergic mechanisms are involved in activation of the sympathoadrenal system but not in the pituitary-adrenal axis during central hypovolemia in humans.

Haemorrhagic fever with renal syndrome: clinical aspects.

Based on clinical and pathological features a typical case of haemorrhagic fever with renal syndrome passes through five phases: (1) febrile phase, (2) hypotensive phase, (3) oliguric phase, (4) diuretic phase and (5) convalescent phase. The major manifestations are fever, pain in the back and abdomen, flushed face, prostration, proteinuria, purpura and haemorrhage and acute renal failure. Selective right auricular haemorrhage, marked congestion and haemorrhage in the renal medulla and necrosis of the anterior lobe of the pituitary gland are the three prominent pathological findings. The clinical severity depends upon the causative agents, namely Hantaan virus, Seoul virus and the European form in that order. Specific serological diagnosis of haemorrhagic fever with renal syndrome is made by demonstrating a rise in titre of specific immunofluorescent antibody against Hantaan and related viruses. The management is supportive, based on an understanding of the pathophysiology of the disease.

Regional hemodynamic effects of rilmenidine and clonidine in the conscious spontaneously hypertensive rat

Rilmenidine is an oxazoline analogue that has antihypertensive properties that resemble those of clonidine. Since rilmenidine has recently been described to have a relatively greater affinity for imidazoline receptors than clonidine, it was of interest to study whether this has functional consequences with regard to the regional hemodynamic responses. We investigated regional hemodynamics in conscious spontaneously hypertensive rats, equipped with miniature Doppler flow probes on the renal and mesenteric arteries and on the abdominal aorta. Clonidine (3-30 micrograms/kg) and rilmenidine (0.2-3 mg/kg) induced similar, dose-dependent reductions in heart rate. Both also induced an early hypertensive response, which was greater with rilmenidine, and similar later blood pressure reductions, which were maintained over 3 h. The early hypertensive response was associated with generalized vasoconstriction. Rilmenidine caused slightly greater mesenteric and hindquarter constriction than clonidine, whereas renal effects did not differ significantly. During the hypotensive phase, rilmenidine was a less potent mesenteric and hindquarter vasodilator than clonidine. During this phase, renal blood flow was at control levels, probably indicating autoregulation of renal flow. The minor differences in regional hemodynamic effects suggest that clonidine and rilmenidine can both be used as potent antihypertensives. The fact that rilmenidine has been suggested to possess less sedative side-effects suggests that, on this basis, it may be superior for antihypertensive drug therapy.

Effects of prostaglandin D2 and its analogue, BW245C, on intraocular pressure in humans

The effects of topically applied prostaglandin (PG) D2 and BW245C, a potent PGD2 agonist, on intraocular pressure (IOP) were studied in normotensive human volunteers. Doses of 5 and 10 micrograms PGD2 induced a mean reduction in IOP of 0.8 and 1 mmHg, respectively. At a dose of 50 micrograms, hypotension was preceded by initial hypertension (4 mmHg at 0.5 h) and the magnitude of the mean IOP reduction during the hypotensive phase was 1.1 mmHg. The application of BW245C (2.5 micrograms) induced an IOP change similar to that observed following treatment with 50 micrograms PGD2. Side effects caused by these compounds included conjunctival hyperemia, itching, and foreign-body and mild burning sensations. However, miosis and signs of intraocular inflammation were not observed. These results indicate that although PGD2 and BW245C are effective in reducing human IOP, their clinical usefulness as anti-glaucoma drugs may be limited by the extraocular side effects.

Cross tachyphylaxis to endothelin isopeptide‐induced hypotension: a phenomenon not seen with proendothelin

1. In anaesthetized rats, an i.v. injection of endothelin-1 (0.25 nmol kg-1) evoked a rapidly appearing (maximal effect within 15 s) and short lasting (3 min) fall in blood pressure with tachyphylaxis occurring so that it was reduced by 50% by the last of 4 injections given 10 min apart. This property was also shared by endothelin-2, endothelin-3 and vasoactive intestinal contractor (VIC). 2. Cross tachyphylaxis between the isopeptides occurred. However, under the same experimental conditions the hypotensive effects of acetylcholine, adenosine, atrial natriuretic peptide (ANP) and substance P were reproducible and not modified in animals in which endothelin-1 no longer lowered blood pressure. Thus, the mechanism of the hypotensive action of endothelin peptides is different from that of acetylcholine, adenosine, ANP, and substance P. 3. In pithed rats, endothelin-1 (0.25 nmol kg-1) and its precursor human proendothelin (h-proendothelin) (0.5 nmol kg-1) induced pressor responses of a similar magnitude, which for h-proendothelin (up to 5.0 nmol kg-1) were not preceded by a hypotensive phase. The pressor effects of endothelin-1, like those of vasopressin, were reproducible upon repeated i.v. injections. 4. Rats given a 10 min infusion (0.1 nmol kg-1 min-1) of endothelin-1 showed no hypotensive response to an i.v. bolus injection of endothelin-1, whereas animals pretreated with an equipressor infusion of h-proendothelin did not develop tachyphylaxis to endothelin-1. 5. In pitched rats, endothelin-1, at a dose inducing the same maximal increase in blood pressure as h-proendothelin, was approximately 3 fold more potent as a mesenteric vasoconstrictor than h-proendothelin. These results suggest that if h-proendothelin is processed to endothelin-1, this transformation is not uniform throughout the vascular system. 6. The pressor response of h-proendothelin in pithed rats was dose-dependently inhibited by phosphoramidon (2.5-5.0mgkg '). However, this compound did not antagonize the effects of endothelin-1(0.25 nmol kg- ) or those of h-proendothelin (0.5 nmol kg- ) once developed. 7. Although some of these results may suggest that h-proendothelin does not undergo in vivo conversion to endothelin-1, the results obtained with phosphoramidon suggest that h-proendothelin is converted into endothelin-1. Therefore, the amount of endothelin-1 so produced can elicit pressor responses or regional vasoconstriction, but is insufficient to lower blood pressure and to inhibit endothelin-1-induced hypotension. 8. The mechanism of the tachyphylaxis does not appear to be depletion of endothelium-derived relaxing factor, since agents coupled to the latter endogenous vasorelaxant substance do not exhibit crosstachyphylaxis with endothelin-1. It is suggested that upon repeated or sustained exposure to endothelin-1, the endothelin-1 receptors mediating hypotension decrease in number and/or undergo conformational changes making them refractory to activation. Alternatively, the depletion of a blood-borne agent responsible for the hypotension could be involved.

Neonatal capsaicin treatment abolishes the nociceptive responses to intravenous 5-HT in the rat

The intravenous (i.v.) administration of serotonin (5-HT) to lightly pentobarbital-anesthetized rats is known to produce a triad of reflex cardiovascular responses, distinct afferent-mediated pseudaffective reactions, and a vagally mediated inhibition of the nociceptive tail-flick (TF) reflex consistent with 5-HT acting as a noxious stimulus. In the present experiments we examined the involvement of capsaicin-sensitive afferents in mediating these responses. Lightly pentobarbital-anesthetized 16-week-old male Sprague-Dawley rats which had been treated as neonates (in the first 48 h of life) with capsaicin (50 μg/kg. s.c.) were compared to age-matched neonatal vehicle-treated controls. Whereas the i.v. administration of 5-HT produced a dose-dependent (6–96 μg/kg, i.v.) inhibition of the nociceptive TF reflex (ED 50 = 48.1 ± 113 μg/kg; n = 7) and distinct pseudaffective responses (usually by 24–48 μg/kg) in vehicle-treated rats. 5-HT (6–192 μg/kg, i.v.) failed to significantly alter TF latency or produce pseudaffective behaviors in the capsaicin-treated rats (n = 10). There was no difference in baseline TF latencies between the two groups. There were essentially no differences between vehicle- and capsaicin-treated rats with respect to the initial cardiopulmonary vagal afferent-mediated (Benzold-Jarish reflexes) decrease in heart rate and arterial blood pressure or the subsequent pressor phase. However, the magnitude of the late hypotensive phase was significantly greater in capsaicin-treated rats. Capsaicin-treated rats were significantly heavier than vehicle-treated rats (482.0 ± 12.4g vs439.3 ± 12.1.g) and also exhibited small cutaneous lesions around the nostrils, on the skin in and around the vibrissae, behind and on the back of the ears, on the throat, and on the underside of the belly. Radioimmunoassay showed that there was a significant (P < 0.05) depletion of substance P (58.3%) and calcitonin gene-related peptide (50.7%) in the lumbar spinal cord of neonatal capsaicin-treated rats (n=8) compared to vehicle-treated rats (n=5). These results demonstrate that the 5-HT-induced, vagally-mediated inhibition of the TF reflex and pseudaffective responses are mediated by capsaicin-sensitive afferents. This strongly suggests that (1) afferent fibers subserving the nociceptive response are predominantly unmyelinated C-fiber vagal afferents and (2) these afferents are different from those vagal afferents that mediate the cardiovascular responses to i.v. 5-HT.

Vagal afferent-mediated inhibition of a nociceptive reflex by intravenous serotonin i the rat. I. Characterization

The effect of intravenous (i.v.) serotonin (5-HT) on nociception and blood pressure in male Sprague-Dawley rats. Intravenous 5-HT produced a dose-dependent (6–192 μg/kg, i.v.) inhibition of the nociceptive tail-flick (TF) reflex in lightly pentobarbital-anesthetized ( ED50 = 40 μg/kg) and conscious rats ( ED50 = 44 μg/kg). In the lightly pentobarbital-anesthetized rat, the blood pressure response to i.v. 5-HT was typically a triphasic response with a marked Bezold-Jarisch reflex-induced decrease in pressure (associated with a brief period of apnea) followed by a pressor phase and a subsequent delayed hypotension. In the conscious rat, the response was typically biphasic with the late hypotensive phase absent. A variety of anatomical and pharmacological manipulations were to characterize the 5-HT-induced inhibition of the TF reflex and associated changes in blood pressure. Prevention of 5-HT-induced reflex apnea by artificial ventilation did not affect inhibition of the TF reflex produced by 5-HT. Pharmacological manipulations were performed to mimic, as closely as possible, the acute increases and decreases in blood pressure associated with i.v. 5-HT. Nitroprusside (8 μg/kg, i.v.) produced a decrease in blood pressure of similar magnitude and rate as that associated with the Bezold-Jarish reflec-induced decrease in pressure produced by 72 μg/kg 5-HT, but did not change TF latency from baseline. Similarly, acute increases in pressure produced by phenylphrine (8 μg/kg, i.v.), intended to mimic the secondary pressor effect of 5-HT, did not change TF latency. The short-acting ganglion blocker trimethaphan (5 mg/kg, i.v.) closely mimicked the late hypotensive phase produced by 5-HT but again resulted in no change in TF latency. Pretreatment with the ganglion blocker chlorisondamine (2.5 mg/kg) abolished all depressor responses to 72 μg/kg 5-HT, but did not significantly affect the TF reflex. These results indicate that acute changes in blood pressure and respiration associated with i.v. 5-HT do not contribute to inhibition of the TF reflex. This conclusion was confirmed in experiments in which bilateral vagotomy abolished approximately 70% of the 5-HT-induced inhibition of the TF reflex (and all depressor responses), and resulted in a significantly greater pressor response. Finally, low thoracic spinal cord transection (T 9–10) abolished the inhibition of the TF reflex produced by i.v. 5-HT. Therefore, 5-HT stimulates vagal afferents and inhibits the TF reflex by activating descending inhibitory system from the brainstem. Taken together with the behavioral responses observed, these results support the notion that 5-HT, when administered i.v., is a noxious stimulus.

Inhibition by indomethacin of the increased facility of outflow induced by adrenaline

Topical adrenaline lowers intraocular pressure (IOP) in the rabbit largely due to an increase in facility of outflow of aqueous humour. This paper studies the inhibition by indomethacin or piroxicam of the adrenaline-induced rise in facility of outflow. Topical indomethacin is shown to reduce the acute IOP changes induced by adrenaline in conscious rabbits; both the early rise and the prolonged fall in pressure were inhibited. In anaesthetized rabbits, indomethacin pretreatment prevented the large rise in facility of outflow which normally follows topical adrenaline. Indomethacin did not block the mydriasis induced by adrenaline, nor did it significantly alter aqueous humour protein levels. Piroxicam, a cyclo-oxygenase inhibitor which, unlike indomethacin, does not block Ca 2+ movements in some tissues, also blocked the adrenaline-induced rise in facility of outflow, suggesting that this increased facility depends on cyclo-oxygenase and not on Ca 2+ movements. Verapamil, a drug which blocks Ca 2+ channels, was shown to inhibit the brief ocular hypertensive effect of adrenaline in the conscious rabbit, but to leave the hypotensive phase unchanged. It is concluded that the hypotensive mechanism of adrenaline may depend on synthesis of a prostaglandin, since inhibition of the adrenaline-induced rise in facility is achieved by inhibitors of cyclooxygenase. Despite previous reports that a prostaglandin may be responsible for the brief hypertensive phase, the present evidence suggests that Ca 2+ movements may be involved, perhaps in activation of the extraocular muscles.

Reflex release of vasopressin and renin in hemorrhage is enhanced by autonomic blockade

We determined the relationships during hemorrhage between nominal blood volume (BV) and 1) plasma arginine vasopressin (AVP), 2) plasma renin activity (PRA), and 3) mean arterial pressure (MAP). Conscious rabbits were studied under normal conditions and during total autonomic blockade (TAB) at bleeding rates of 2 and 4 ml/min. Normally, MAP was well maintained until BV had been reduced to approximately 65% of control (termed 65% BV) after which it fell abruptly. The threshold for a rise in AVP was 80-75% BV, followed by exponential rises to levels of 14 and 24 times control at the slow and fast rate of bleeding. PRA rose earlier in hemorrhage, but this rise was more gradual, to values at 60% BV of 5.5 and 7 times control at the two rates of bleeding. During TAB, MAP fell rapidly and both BV concentration curves were shifted to the left with the rises in AVP and PRA/unit delta BV greater than normal; at 75% BV at each rate of hemorrhage, AVP and PRA had risen, respectively, to approximately 40 and 8 times control. Normally, the rises in the AVP and PRA (i.e., angiotensin II) concentrations were modest during the nonhypotensive phase, consistent with their minimal constrictor action observed in a parallel study. During the hypotensive phase, both reached high levels in the constrictor range. During TAB, high concentrations were reached with small BV loss, representing a model of near-maximum release of PRA and AVP.

Autonomic, hormonal, and local circulatory effects of hemorrhage in conscious rabbits

Conscious instrumented rabbits were bled at a constant rate of congruent to 3% of the blood volume (BV) per minute. We determined the BV-response relationships for mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), mesenteric and hindlimb blood flows, and for the corresponding conductances. We studied the responses 1) under normal conditions; 2) after pretreatment with captopril, arginine vasopressin (AVP) antagonist, or both; 3) during total autonomic blockade (TAB); and 4) during neurohumoral blockade (NHB, i.e., TAB + captopril + AVP antagonist). We determined the direct local response component from the responses obtained during NHB. The local chronotropic effects congruent to 0, so that the reflex rise in HR was entirely autonomically mediated. The local vascular response consisted of vasodilatation and provided the base line for assessing the estimated constrictor component from the net response from control, with the former ranging from 2 to 16 times the conventional estimates based on the net responses. In normal rabbits, the phase of good maintenance of MAP was entirely governed by autonomic mechanisms, which minimized the fall in CO and offset the local vasodilator component. During the hypotensive phase immediately after hemorrhage, when congruent to 30-35% BV had been removed, the constrictor effects of AVP and angiotensin II (ANG II) became important, whereas the role of autonomic mechanisms diminished. During TAB, the constrictor effects of AVP and ANG II were prominent even with small BV losses.

Cardiovascular effects of ethanol in anaesthetized, conscious and pithed rats

The influence of ethanol (2.0 g/kg p.o.) on heart rate and blood pressure in anaesthetized, conscious and pithed rats was studied. In anaesthetized rats we observed an increase in heart rate and a marked and very sudden decrease in blood pressure. In pithed rats blood pressure decreased more slowly than in anaesthetized and conscious animals and there were no changes in heart rate. These results show that the central nervous system may be responsible for the increase in heart rate and early phase of hypotension caused by acute ethanol administration. The slower decrease (up to 1 h) in blood pressure may be caused by central and different indirect peripheral mechanisms.

Effect of Naloxone on Blood Pressure Responses and Plasma Catecholamine Levels Following Clonidine Injection in Conscious, Unrestrained Rats

Intravenous injection of clonidine produces a biphasic blood pressure response, a transient increase followed by a prolonged decrease. Significant increases in plasma norepinephrine (NE), epinephrine (EPI), and dopamine (DA) levels occur 5 min following injection, corresponding to the hypertensive phase. Thirty minutes after clonidine injection, blood pressure, NE, EPI, and DA levels had returned to control levels. However, at 60 min, when the blood pressure had decreased to below control levels, a significant decrease in plasma NE was found. This finding confirms that clonidine decreases blood pressure, in part, by reducing sympathetic nerve activity. Naloxone, an opiate antagonist, when given prior to clonidine, abolished the hypotensive phase as well as preventing the decrease in plasma NE levels. The hypertensive phase was potentiated. Naloxone, when given alone, increased plasma NE levels at 15, 40, and 70 min following injection, indicating that naloxone increases sympathetic nerve activity peripherally, and may prevent clonidine's hypotensive phase by also increasing sympathetic activity in the central nervous system through blockade of opiate receptors. Therefore, the hypotensive effect of clonidine may involve interactions with endogenous opiate peptides.