Hypotension In Rats Research Articles

Alpha- and Beta-Adrenergic Receptors of Noradrenergic Innervation Modulate the Lower Limits of Cerebral and Cerebellar Blood Flow Autoregulation in Spontaneously Hypertensive Rats

The effects of alpha- and beta-adrenergic receptors on the lower limits of cerebral (CBF) and cerebellar blood flow (CeBF) autoregulation were examined in spontaneously hypertensive rats. CBF and CeBF were measured during hemorrhagic hypotension in rats treated with adrenergic blockers, phenoxybenzamine (PBZ) or propranolol (PPL), using a hydrogen clearance method. The lower limits for CBF beyond which blood flow was decreased steeply were 72% of resting values in the control, 44 in the PBZ and 80 in the PPL group. Similar tendency was also observed for CeBF. In the control group, the reducing rates of mean arterial pressure (MAP) to decrease CBF by 15 and 30% of the resting values were 33% (58 mm Hg) of the resting MAP and 46% (80 mm Hg), respectively, and those to reduce CeBF to the same extent were 35% (61 mm Hg) and 52% (92 mm Hg), respectively. In the PBZ group, the respective reducing rates of MAP were 52% (71 mm Hg) and 65% (88 mm Hg), respectively, for CBF and 50% (68 mm Hg) and 65% (88 mm Hg), respectively, for CeBF. In contrast, in the PPL group, those rates were 22% (39 mm Hg) and 32% (56 mm Hg), respectively, for CBF, and 23% (40 mm Hg) and 30% (52 mm Hg), respectively, for CeBF, being significantly smaller than those in the control and the PBZ groups (p less than 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Platelet activating factor antagonists: synthesis and structure-activity studies of novel PAF analogues modified in the phosphorylcholine moiety.

New analogues of platelet activating factor (PAF), in which the phosphate and trimethylammonium moieties were replaced with an acylcarbamoyl moiety and a quaternary cyclic ammonium group, were synthesized. Their biological activities as PAF antagonists were evaluated by the inhibition of PAF-induced rabbit platelet aggregation in vitro and protective effects on PAF-induced hypotension in rats and PAF-induced death in mice. Investigation of structure-activity relationships revealed that PAF antagonist activity is strongly influenced by the acyl substituent of the nitrogen atom on the carbamoyl group and the nature of the polar head group at the 3-position of the glycerin backbone. Among the compounds tested, 2-[[N-acetyl-N-[[2-methoxy-3-[ (octadecylcarbamoyl)oxy]propoxy]-carbonyl]amino] methyl]-1-ethylpyridinium chloride (21, CV-6209) was one of the most potent compounds in the in vitro assay (IC50 = 7.5 X 10(-8) M) and the most potent and long-lasting in the in vivo assays. (R)-(-)-21 and (S)-(+)-21 were also synthesized, and no significant differences were observed in PAF antagonist activity in vitro and an inhibitory effect on PAF induced hypotension in vivo between (RS)-21 and its enantiomers.

Prefrontal stimulus-produced hypotension in rat.

In 41 rats, bipolar electrical stimulation was administered to various regions of the frontal cortex, including the medial prefrontal cortex (MPFC), lateral prefrontal cortex (LPFC), infralimbic cortex, and convexity cortex. Resulting alterations of blood pressure and heart rate were noted. It was observed that hypotension resulted from stimulation administered to either LPFC, infralimbic cortex or ventral portion of MPFC (i.e. prelimbic cortex). Furthermore, stimulation of the LPFC typically produced bradycardia, whereas stimulation of the MPFC or infralimbic cortex had little or no effect on heart rate. Pharmacological and surgical blocks of the vagus nerves failed to attenuate the stimulus produced hypotension (SPH), as elicited from the prefrontal or infralimbic cortices, thus demonstrating that SPH in rats is not mediated by the vagus nerves. However, intraperitoneal injections of norepinephrine, which mimicked a state of increased sympathetic tone, were observed to completely block SPH. Accordingly, it is suggested that SPH may occur as the result of sympathetic inhibition. Furthermore, intravenous injections of naloxone were also observed to also completely block SPH, thus demonstrating that SPH may be mediated via opioid pathways.

Baroreceptor-independent medullary mechanism for release of vasopressin during hypotension in rats.

Plasma vasopressin (AVP) levels were measured at rest (mean arterial pressure 80-85 mmHg) and during hypotension (mean arterial pressure 38-45 mmHg) induced by ganglionic blockade (trimethaphan) in halothane-anaesthetized respirated rats with end-tidal pCO2 maintained at 34-40 mmHg. Hypotension (15 min) produced a 310% increase in plasma AVP (+/- 60% S.E.M.) which was not reduced significantly by prior baro- and chemoreceptor denervation. The hypotension-induced rise in AVP was blocked by bilateral microinjections (40 nl) of the GABA-mimetic agent muscimol (151 pmol) into the ventrolateral medulla at obex level and significantly attenuated by injections of the same amount in the nucleus tractus solitarius. The rise in AVP was unaffected by microinjections in the pontine locus coeruleus. It was also blocked by bilateral microinjections of the glutamate-receptor antagonist kynurenate (40 nl, 1.8 nmol) into the ventrolateral medulla but unaffected by microinjections of the inactive analogue xanthurenic acid (40 nl, 1.8 nmol). A significantly smaller rise in plasma AVP (88%) was observed following bilateral nephrectomy. It is concluded that, in this preparation, hypotension produces the release of AVP via a mechanism largely independent of baro- and chemoreceptors, which requires the activation of neurones located in the caudal medulla oblongata. The same or closely related neurones may be activated by a neural or hormonal signal generated by the kidney.

Inhibition of gastric motility changes following PAF-acether and endotoxin by L-652, 731

Evidence from three types of experiments indicates that platelet activating factor (PAF) is an important mediator of endotoxin-induced hypotension in rats. a) Endotoxin infusion stimulates the time-dependent appearance of PAF in the blood. b) PAF infusion results immediately (<30 sec) in hypotension while endotoxin-induced hypotension takes 3–5 min to occur, allowing time for PAF production. c) Infusion of the specific PAF-receptor antagonist kadsurenone (2.2 μmole/kg bolus, 0.9 μmoles/min/kg continuous infusion), which inhibits PAF-induced hypotension by 67%, causes a 67% reversal of endotoxin-elicited hypotension. An additional finding of this study is that rats respond hypotensively to each of a series of low-dose PAF infusions but only to the first low-dose endotoxin infusion. These endotoxin-refractory rats do respond to subsequent PAF infusions.

Structure-activity relationship in PAF-acether. 4. Synthesis and biological activities of carboxylate isosteres.

The synthesis and biological characterization of some 3-carboxylate isosteres of PAF-acether structurally modified in positions 1 (ether, carbamate), 2 (acetoyl, ethoxy), and 3 (chain length and polar head group) are reported. All derivatives present antagonist activities against PAF-acether-induced effects in vitro (platelet aggregation) and in vivo (bronchoconstriction and thrombocytopenia in guinea pig and, to a lesser extent, hypotension in rat). The functional modifications presented here do not modify dramatically the potency of antagonist activities, and there is no enantioselectivity. All of the isosteres are specific PAF-acether antagonists, except the 1-carbamoyl analogue, which is also potent against acetylcholine-induced hypotension and bronchoconstriction.

Effects of LG 30435 on different platelet activating factor-induced responses.

LG 30435 is a new potential anti-asthmatic agent with multiple sites of action. It can inhibit the bronchoconstriction induced by various agonists, including platelet activating factor (PAF). The effects of this compound on PAF-induced biological responses have now been investigated. LG 30435 inhibited both serotonin release from, and aggregation of, rabbit washed platelets evoked by PAF, being four times more potent on release than on aggregation. In contrast, it did not inhibit a number of the biological effects of PAF which are not platelet-mediated, such as contraction of guinea-pig lung parenchymal strips, hypotension in rats and lethality in mice. It may be concluded that, unless platelet PAF receptors are different from those in other tissues, LG 30435 is capable of inhibiting platelet-mediated effects of PAF by interfering with secondary mechanisms activated by this autacoid and not by direct antagonism of PAF at receptor sites.

Platelet‐activating factor‐induced cellular and pathophysiological responses in the cardiovascular system

AbstractRecent findings in several laboratories have demonstrated the important interactions of platelet‐activating factor (PAF) with vascular endothelial cells, and thus the potential role of this lipid mediator in the pathophysiology of the cardiovascular system. PAF potently and specifically stimulates the in situ and in vivo release of tissue‐type plasminogen activator from the vascular endothelium [Emeis and Kluft, 1985]. Several lines of evidence indicate that PAF may play a critical role in the neutrophil adhesion to endothelial cells stimulated with thrombin or leukotrienes [Zimmerman et al., 1985]. PAF is a potent stimulator of Ca+2 efflux from endothelial cells, which thus might be an early step in the suspected involvement of the endothelium in in vivo responses to PAF, such as hypotension and increased vascular permeability [Brock and Gimbrone, 1986]. In our own laboratory, we have developed a specific and potent PAF receptor antagonist, L‐652,731, in order to determine the role of PAF in different animal models of disease. Utilizing this receptor antagonist as well as other criteria, PAF is indicated to be a major mediator of the endotoxin‐induced hypotension in rats and soluble immune complex‐induced hypotension and extravasation, also in rats. The immune complex‐induced increased plasma glucosaminidase is partially mediated by PAF, whereas the immediate and complete neutropenia is not indicated to involve PAF.

Regional changes in brain noradrenergic activity elicited by a decrease in blood pressure.

Using high performance liquid chromatography with electrochemical detection, the level of 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), an index of noradrenaline release, was determined in regions of the brainstem and hypothalamus of rats after acute hypotension induced by hydralazine. In hypotensive rats, an increase in MHPG concentrations was observed in the posterior hypothalamus, while no significant changes were seen for all the other regions. These results suggest that hypotension results in an enhancement of noradrenaline release in the posterior hypothalamus in rats.

Evidence for discrete alterations in central cardiovascular catecholamine and neuropeptide Y immunoreactive neurons in aged male rats and in genetically hypertensive male rats of the Lyon strain.

A computer-assisted morphometrical and microdensitometrical analysis has been performed on cardiovascular noradrenaline (NA), adrenaline (A) and neuropeptide (Y (NPY) neurons in adult and 24-month-old male rats and on hypotensive (LL), normotensive (LN) and hypertensive (LH) male rats of the Lyon strain using the indirect immunoperoxidase procedures. It was found that in NPY/phenylethanolamine-N-methyltransferase (PNMT) costoring neurons of the CI area of the rostral medulla oblongata NPY-like immunoreactivity showed a more marked reduction than the PNMT immunoreactivity. Furthermore, within the parvocellular part of the paraventricular hypothalamic nucleus. NPY immunoreactive nerve terminal profiles were much more affected than the PNMT immunoreactive profiles during aging as revealed by a marked reduction in the number of profiles and by a marked reduction of absorbency values in the microdensitometrical analysis. Thus, in the NPY/PNMT costoring neurons of the A C1 group of the ventrolateral medulla projecting, for example, to the hypothalamus, the peptide transmission line may have a special vulnerability to the aging processes which may contribute to the development of hypertension in old people in view of a vasodepressor role of many central NPY/PNMT neurons. An extensive morphometrical and microdensitometrical analysis of the various catecholamine (CA) cell groups of the medulla oblongata of the LL, LN and LH rats of the Lyon strain was performed. In a comparison between LL and LH rats the A2 cell group of the LH strain showed a trend for an increase in the mean tyrosine hydroxylase (TH) immunoreactive cell body area and the C3 group showed a significant increase in the number of PNMT immunoreactive profiles.(ABSTRACT TRUNCATED AT 250 WORDS)

Triazolodiazepines are potent antagonists of platelet activating factor (PAF) in vitro and in vivo.

The triazolodiazepines brotizolam, triazolam and alprazolam inhibited PAF-induced human platelet aggregation in vitro (IC50 = 0.54, 7.6 and 13.7 microM, respectively) but showed only a weak or no effect against other aggregating agents (ADP, adrenaline, collagen, serotonin, arachidonic acid). In comparison, flunitrazepam and diazepam, two diazepines without the triazole ring, showed IC50-values of 42 and 260 microM, respectively. Flunitrazepam does not possess the specificity shown by the other compounds. Brotizolam and triazolam also inhibited PAF-induced human neutrophil aggregation in vitro, with IC50-values 0.21 and 6.6 microM, respectively. In anesthetized guinea pigs, brotizolam (2.5 to 10 mg/kg p.o. or 0.1 to 0.5 mg/kg i.v.) or triazolam (20 to 100 mg/kg p.o.) inhibited dose-dependently the intrathoracic accumulation and aggregation of 111Indium labelled platelets induced by an i.v. infusion of PAF (30 ng/kg X min). Brotizolam at doses of 1 to 10 mg/kg p.o. and 0.1 to 0.5 mg/kg i.v. inhibited dose-dependently the reduction in tidal volume (bronchoconstriction), the systemic hypotension and the lethal effect due to i.v. PAF in guinea pigs. Triazolam inhibited these effects of PAF at doses of 50 to 200 mg/kg p.o. PAF-induced systemic hypotension in rats can be reversed by cumulative i.v. doses (0.05 to 1.0 mg/kg) of brotizolam. In conclusion, these results show that triazolodiazepines, like brotizolam and triazolam, are potent inhibitors of PAF-induced effects in vitro and in vivo.

Isolation and identification of hypotensive principles in red-mold rice.

During an initial search for pharmacologically active principles in red-mold rice, two hypotensive compounds were isolated and identified. The active principles, A-3 and B-1, were fractionated and purified from the EtOH extract of red-mold rice prepared with Monascus pilosus through extraction with H2O, Amberlite CG-120 column chromatographies and high-performance liquid chromatography on an ODS column. A-3 was identified as acetylcholine chloride by comparison with an authentic sample, and B-1, colorless needles of mp 203-205 °C, was proved to be identical with authentic γ-aminobutyric acid. Intravenously administered A-3 (0.5 μg/kg) and B-1 (250μg/kg) produced potent depression of the carotid arterial blood pressure in spontaneously hypotensive rats, as did the corresponding authentic samples.

BAY k 8644, a calcium channel agonist, reverses hypotension in endotoxin-shocked rats

The hypotension and depressed myocardial function frequently observed in endotoxin-induced shock are difficult to overcome pharmacologically. In this paper we demonstrate that the calcium channel agonist BAY k 8644 potently elevates blood pressure in endotoxin-shocked rats. A one time dose as low as 10 μg/kg of BAY k 8644 significantly elevated mean arterial pressure (MAP) in endotoxin-treated hypotensive rats while having minimal effects in normal rats. The maximum BAY k-induced percentage increase in MAP was greater in endotoxin-treated rats when compared with saline-treated control (153% vs. 120% increase respectively). BAY k 8644 also caused a dose-dependent decrease in heart rate of 37% in endotoxin-treated rats and 39% in control rats (NS vs. control). No differences in the regulatory properties of [ 3H]nitrendipine binding sites were discerned comparing control and endotoxin-treated rats. Thus, the enhanced activity of BAY k 8644 in hypotensive rats was not due to augmented affinity for the cardiac dihydropyridine binding site. These results demonstrate that the use of calcium channel agonists might represent a unique pharmacologic approach in pathologic states characterized by hypotension and diminished cardiac function.

Naloxone fails to reverse hemorrhagic hypotension.

The effect of opiate antagonist therapy with naloxone on hemorrhagic shock was examined. An equivalent intravenous bolus of naloxone or normal saline had the same pressor effect in conscious, unrestrained, hypovolemic hypotensive rats. The proposal that opiate antagonists are of therapeutic value in the treatment of hemorrhage is questioned.

Naloxone and haemorrhagic hypotension in rats. Evidence against sympathetic nervous system as the primary mediator of improved cardiovascular haemodynamics.

Release of endogenous opiate-like substances seem to occur in different forms of stress. Earlier studies have shown that the opiate antagonist, naloxone, has a positive effect on cardiac performance and blood pressure in animals with haemorrhagic shock. In the present study, we have examined the involvement of the sympathetic nervous system in this response. Two groups of anaesthetized normotensive Wistar-Kyoto rats were studied. Both groups were bled rapidly (about 5 min) down to an arterial pressure of 50 mmHg and were kept at that level for 30 min. At the end of the 30-min bleeding period, naloxone 1, 2, or 5 mg kg-1 was injected i.v. in a small volume of saline. In the first group of rats (n = 6), the aortic pressure was kept constant at 50 mmHg by further bleedings after naloxone. In the other group (n = 7), the arterial pressure was allowed to rise after naloxone. As reported earlier, haemorrhagic hypotension caused a pronounced inhibition of renal sympathetic nerve activity. Naloxone injected after 30 min of hypotension caused an immediate rise in blood pressure, followed 1-2 min later by a rise in sympathetic nerve activity (SNA). In animals in which pressure was held constant by further bleeding after naloxone, only small and insignificant changes in SNA were observed. The conclusions are the following: injection of naloxone increases blood pressure in rats exposed to severe haemorrhage (Faden & Holiday 1979). The rise in aortic pressure is followed 1-2 min later by a rise in SNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Spinal cord noradrenergic neurons are activated in hypotension

Although norepinephrine-containing nerve terminals in the spinal cord synapse in the vicinity of sympathetic preganglionic cells, their effect on sympathetic outflow has remained unclear. Since survival during hypotension necessitates sustaining maximal sympathetic activity, we used experimental hypotension as a physiological stimulus to determine whether such activity is associated with an increase or a decrease in spinal cord norepinephrine turnover. Male Sprague-Dawley rats (500 g) were anesthetized with chloralose and urethane and their left carotid arteries were cannulated for blood pressure measurements and blood removal. Control animals remained normotensive during the 1-h study period; hypotensive animals were bled to a 50 mm Hg systolic pressure. Catecholamine release, as indicated by methoxyhydroxyphenylethyleneglycol sulfate (MHPG-SO 4) concentrations, was greater in spinal cords of hypotensive rats than in normotensive controls. Apparent catecholamine synthesis also increased: norepinephrine concentrations did not change even though those of MHPG-SO 4 doubled and the accumulation of dihydroxyphenylalanine (in other animals pretreated with NSD 1015) also doubled. These studies show that catecholamine-containing neurons in the spinal cord are stimulated in hypotension, and suggest that they may function physiologically to increase sympathetic outflow and thus blood pressure.

Studies of platelet activating factor (PAF) antagonists from microbial products. II. Pharmacological studies of FR-49175 in animal models.

Platelet activating factor (PAF) antagonistic action of FR-49175 was studied using in vivo models designated as PAF-induced bronchconstriction, hypotension and vascular permeability increase. This compound (0.1 mg/kg, i.v.) significantly inhibited PAF-induced bronchoconstriction in guinea-pigs. However, it did not prevent PAF-induced hypotension in rats or vascular permeability increase in mice. Furthermore, the effect of this compound against a systemic anaphylaxis model in guinea-pigs was examined, but it did not show any inhibition of antigen-induced mortality at the dose of 10 mg/kg, i.v.

Structures and Hypotensive Effect of Flavonoid Glycosides in Unshiu Peeling. II.

We describe the structures and hypotensive effects of three additional glycosides (1, 2 and 3) obtained through further investigation on unshiu peelings. The structures 3-hydroxy-3', 4', 5, 6, 7, 8-hexamethoxyflavone 3-β-D-glucoside (1), limocitrin 3-O- [5-α-glucosyl-3-hydroxy-3-methylglutaryl (1→2)] -β-glucoside (2) and narirutin-4'-glucoside (3) were established by UV, 1H-NMR and 13C-NMR spectroscopy, and chemical evidence. Compounds 1 and 3 showed strong depressive effects, when intravenously injected with stroke-prone spontaueously hypotensive rats (0.51.0mg dose/100g body weight). Among these compounds, 1 was a new flavonoid glycoside, and 2 anal 3 were found for the first time in unshiu.

Tyrosine accelerates catecholamine synthesis in hemorrhaged hypotensive rats

Tyrosine, the amino acid precursor of catecholamines, increases blood pressure (BP) in rats made hypotensive by hemorrhage. Since this amino acid also accelerates catecholamine synthesis in and release from frequently-firing neurons, we tested the hypothesis that tyrosine's pressor action resulted from this mechanism. Male Sprague-Dawley rats (500 g) were anesthetized with chloralose (50 mg/kg) and urethane (500 mg/kg) and tracheostomized. The carotid artery was cannulated allowing BP to be recorded continuously. Blood was removed until systolic BP fell to half of each animal's starting value; 45 min later, animals received tyrosine or other treatments in volumes of 1 ml/kg. Tyrosine (100 mg/kg) increased BP by 58%, while saline caused an insignificant increase. Pretreatment with carbidopa, which inhibits tyrosine's conversion to catecholamines, blocked the amino acid's effect. Tyrosine also failed to increase BP in rats made hypotensive with phentolamine, suggesting that it acts via catecholamine receptors. Adrenal epinephrine significantly (P < 0.02) and splenic norepinephrine slightly (P < 0.07) increased in rats receiving tyrosine after 1 h of hypotension when compared with tissue-catecholamine contents in similar rats. These observations show that tyrosine increases BP during hemorrhagic hypotension by accelerating catecholamine synthesis.

Platelet activating factor (PAF) involvement in endotoxin-induced hypotension in rats. studies with paf-receptor antagonist kadsurenone

Evidence from three types of experiments indicates that platelet activating factor (PAF)1 is an important mediator of endotoxin-induced hypotension in rats. a) Endotoxin infusion stimulates the time-dependent appearance of PAF in the blood. b) PAF infusion results immediately (less than 30 sec) in hypotension while endotoxin-induced hypotension takes 3-5 min to occur, allowing time for PAF production. c) Infusion of the specific PAF-receptor antagonist kadsurenone (2.2 mumole/kg bolus, 0.9 mumoles/min/kg continuous infusion), which inhibits PAF-induced hypotension by 67%, causes a 67% reversal of endotoxin-elicited hypotension. An additional finding of this study is that rats respond hypotensively to each of a series of low-dose PAF infusions but only to the first low-dose endotoxin infusion. These endotoxin-refractory rats do respond to subsequent PAF infusions.