Cardiovascular effects of 1,8-cineole,a terpenoid oxide present in many plant essential oils,in normotensive rats

The cardiovascular effects of i.v. treatment with 1,8-cineole, a monoterpenic oxide present in many plant essential oils, were investigated in normotensive rats. This study examined (i) whether the autonomic nervous system is involved in the mediation of 1,8-cineole-induced changes in mean aortic pressure (MAP) and heart rate (HR) and (ii) whether the hypotensive effects of 1,8-cineole could result from its vasodilatory effects directly upon vascular smooth muscle. In both pentobarbital-anesthetized and conscious, freely moving rats, bolus injections of 1,8-cineole (0.3-10 mg/kg, i.v.) elicited similar and dose-dependent decreases in MAP. Concomitantly, 1,8-cineole significantly decreased HR only at the highest dose (10 mg/kg). Pretreatment of anesthetized rats with bilateral vagotomy significantly reduced the bradycardic responses to 1,8-cineole (10 mg/kg) without affecting hypotension. In conscious rats, i.v. pretreatment with methylatropine (1 mg/kg), atenolol (1.5 mg/kg), or hexamethonium (30 mg/kg) had no significant effects on the 1,8-cineole-induced hypotension, while bradycardic responses to 1,8-cineole (10 mg/kg) were significantly reduced by methylatropine. In rat isolated thoracic aorta preparations, 1,8-cineole (0.006-2.6 mM) induced a concentration-dependent reduction of the contraction induced by potassium (60 mM). This is the first physiological evidence that i.v. treatment with 1,8-cineole in either anesthetized or conscious rats elicits hypotension; this effect seems related to an active vascular relaxation rather than withdrawal of sympathetic tone.     

Cardiovascular effects of the essential oil of Mentha x villosa in DOCA-salt-hypertensive rats.

The present study investigated the effects of chronic treatment with deoxycorticosterone-acetate (DOCA)-salt on cardiovascular responses to intravenous (i.v.) injection of the essential oil of Mentha x villosa (EOMV) in conscious rats. In both DOCA-salt-hypertensive and uninephrectomized control, conscious rats, i.v. bolus injections of EOMV (1 to 20 mg/kg body wt.) decreased mean aortic pressure (MAP) and heart rate (HR) in a dose-dependent manner. Treatment with DOCA-salt significantly enhanced EOMV-induced decreases in MAP, without affecting bradycardia. Likewise, both maximal percent and absolute decreases in MAP elicited by i.v. injection of the ganglion blocker, hexamethonium (30 mg/kg body wt.), were significantly greater in DOCA-salt-hypertensive than in control rats. In DOCA-salt-hypertensive rats, i.v. pretreatment with hexamethonium (30 mg/kg body wt.) reduced the bradycardia elicited by EOMV (1 to 20 mg/kg body wt.) without affecting the enhancement of EOMV-induced hypotension. These results show that i.v. treatment with EOMV decreases blood pressure in conscious DOCA-salt-hypertensive rats dose-dependently, and that this action is enhanced when compared with uninephrectomized controls. This enhancement could be related mainly to an increase in EOMV-induced vascular smooth muscle relaxation, rather than to enhanced sympathetic nervous system activity in this hypertensive model.     

Antihypertensive properties of Allium sativum (garlic) on normotensive and two kidney one clip hypertensive rats

Allium sativum (garlic) is reported to act as an antihypertensive amidst an inconsistency of evidence. In this study, we investigated the cardiovascular effects of aqueous garlic extracts (AGE) on normotensive and hypertensive rats using the two-kidney one-clip (2K1C) model. Mean arterial blood pressure (MAP) and heart rate (HR) were measured in normotensive and 2K1C rat models anesthetized with thiopentone sodium (50 mg/kg body weight i.p.) through the left common carotid artery connected to a recording apparatus. The jugular vein was cannulated for administration of drugs. Intravenous injection of AGE (5-20 mg/kg) caused a significant decrease in both MAP and HR in a dose-dependent manner in both the normotensive and 2K1C models, with more effects on normotensive than 2K1C rat model. The dose of 20mg/kg of AGE significantly reduced systolic (16.7 ± 2.0%), diastolic (26.7 ± 5.2%), MAP (23.1 ± 3.6%) and HR (38.4 ± 4.3%) in normotensive rats. In 2K1C group, it significantly reduced systolic (22.2 ± 2.1 %), diastolic (30.6 ± 3.2%), MAP (28.2 ± 3.1%) and HR (45.2 ± 3.5%) from basal levels. Pulse pressure was significantly elevated (33.3 ±5.1%) in the 2K1C group. Pretreatment of the animals with muscarinic receptor antagonist, atropine (2 mg/kg, i.v.), did not affect the hypotensive and the negative chronotropic activities of the extract. AGE caused a decrease in blood pressure and bradycardia by direct mechanism not involving the cholinergic pathway in both normotensive and 2K1C rats, suggesting a likely involvement of peripheral mechanism for hypotension.     

Cardiovascular effects of cocaine in anesthetized and conscious rats

This study examined the cardiovascular and respiratory effects of cocaine and procaine in anesthetized and conscious rats. Intravenous cocaine (0.16-5 mg/Kg) elicited a rapid, dose dependent increase in mean arterial pressure of relatively short duration. In pentobarbital anesthetized (65 mg/Kg, i.p.) animals, the pressor phase was generally followed by a more prolonged depressor phase. These effects on arterial pressure were generally accompanied by a significant tachypnea and at larger doses (2.5 and 5 mg/Kg, i.v.), bradycardia. Procaine (0.31 and 1.25 mg/Kg, i.v.) produced similar cardiovascular and respiratory effects (depressor phase, tachypnea) in pentobarbital anesthetized animals. In conscious-restrained animals, both cocaine and procaine (1.25 mg/kg, i.v.) produced pressor responses. The subsequent depressor response was, however, absent in both cases. The cardiovascular effects of cocaine (0.25-1 mg/Kg, i.v.) in urethane anesthetized (1.25 g/Kg, i.p.) animals were essentially similar to those observed in conscious animals. Procaine (1mg/Kg) did not produce any significant cardiovascular effects in urethane anesthetized animals, but did elicit tachypnea. Reserpine pretreatment (10 mg/Kg, i.p.) did not significantly attenuate the pressor response in urethane anesthetized animals. Phentolamine pretreatment (3 mg/Kg, i.v.) did significantly antagonize the pressor effect in urethane anesthetized animals. These results suggest that: the depressor phase is likely due to a interaction between local anesthetic activity (cocaine and procaine) and barbiturate anesthesia, the cardiovascular effects of cocaine in conscious animals are more similar to those observed in urethane anesthetized rats than in pentobarbital anesthetized rats and the pressor effect in urethane anesthetized rats is apparently due to a reserpine resistant catecholaminergic mechanism.     

Nphe1]nociceptin(1-13)-NH2 antagonizes nociceptin-induced hypotension, bradycardia, and hindquarters vasodilation in the anesthetized rat

The purpose of this study was to investigate the effects of [Nphe1]nociceptin(1-13)-NH2 on nociceptin-induced decreases in mean arterial pressure (MAP), heart rate (HR), and hindquarters vascular bed resistance (HVBR) of the anesthetized rat. The results showed that i.c.v. or i.v. [Nphe1]nociceptin(1-13)-NH2 (1.5-12 nmol/kg and 5-120 nmol/kg, respectively) could antagonize the depressor effects of i.c.v. or i.v. nociceptin (3 and 30 nmol/kg, respectively) on MAP and HR. Furthermore, [Nphe1]nociceptin(1-13)-NH2 (5-120 nmol/kg) could reverse nociceptin (30 nmol/kg)-induced decrease of HVBR. However, [Nphe1]nociceptin(1-13)-NH2 had no significant effects on similar effects induced by morphine. Our results suggest that [Nphe1]nociceptin(1-13)-NH2 acts as a selective antagonist of the nociceptin receptor in the cardiovascular system of the rat.     

八肽胆囊收缩素对大鼠心功能的影响及受体机制

为探讨八肽胆囊收缩素 (CCK 8)对麻醉大鼠心功能的影响及受体机制 ,实验监测了左心室收缩压(LVP)、左心室收缩与舒张期内压变化的最大速率 (±LVdp/dtmax)、心率 (HR)和平均动脉压 (MAP)。结果如下 :小剂量CCK 8(0 4 μg/kg)可引起心动过速 ,MAP、LVP和±LVdp/dtmax轻度上升 ;中剂量CCK 8(4 μg/kg)和大剂量CCK 8(4 0 μg/kg)可引起心动过缓 ,MAP、LVP和±LVdp/dtmax显著增加 ;应用CCK 受体 (CCK R)拮抗剂丙谷胺 (1 0mg/kg)抑制以上变化 ;由逆转录 聚合酶链反应 (RT PCR)检测到心肌组织有CCK A受体 (CCK AR)和CCK B受体 (CCK BR)mRNA表达。以上结果提示 :CCK 8可激活心肌组织的CCK R ,引起剂量依赖性的心功能增加和心率改变。     

Endothelium-derived nitric oxide is involved in the hypotensive and vasorelaxant responses induced by the aqueous fraction of the ethanolic extract of the leaves of Albizia inopinata (Harms) G. P. Lewis in rats.

The acute cardiovascular effects of an aqueous fraction of the ethanolic extract of the leaves (AFL) of Albizia inopinata (Harms) G. P. Lewis (Leguminosae) were studied in rats using a combined in vivo and in vitro approach. In conscious, unrestrained rats, AFL (5, 10 and 20 mg/kg(-1) body wt. i.v., randomly) produced a significant and dose-dependent hypotension associated with increases in heart rate and cardiac output, and with a strong reduction in total peripheral resistances. The hypotensive response to AFL (20 mg/kg(-1) body wt.) was attenuated significantly after nitric oxide (NO) synthase blockade (L-NAME, 20 mg/kg(-1) body wt. i.v.). Furthermore, under these conditions, the associated tachycardia was inhibited completely. In isolated rat aortic rings, increasing concentrations of AFL (10, 20, 40 and 80 microg/ml(-1)) were able to antagonize the effects of phenylephrine- (1 microM) and KCl- (80 mM) induced contractions (IC50 value 65 +/- 4 and 54 +/- 6 microg/ml(-1), respectively). The smooth muscle-relaxant activity of AFL was inhibited similarly either removal of the vascular endothelium or by L-NAME (10 and 100 microM), but was not affected significantly by atropine (1 microM) or indomethacin (10 microM). In isolated rat atrial preparations, AFL (30, 100, 300 and 500 microg/ml(-1)) produced concentration-related negative inotropic and chronotropic effects (IC50 value = 274 +/- 53 and 335 +/- 23 microg/ml(-1), respectively). These results suggest that in rats, the hypotensive effect of AFL is due to a peripheral vasodilation, at least partly secondary to the release of NO by the vascular endothelium. The direct cardio-depressant actions of AFL are of little importance in the systemic effects of the extract.     

Beneficial effects of LK-4, an analog of dextromethorphan on lipopolysaccharide-induced sepsis in rats

Summary Dextromethorphan (DM), an anti-tussive agent, has been claimed to have anti-inflammatory and immunomodulatory effects in vitro. In our preliminary screening test, LK-4, an analog of DM, can afford more protection against circulatory failure induced by LPS than that of DM. Thus, the aim of this study was to evaluate the effects of LK-4 on sepsis induced by intravenous (i.v.) administration of lipopolysaccharide (LPS; 10 mg/kg) in anesthetized Wistar rats and survival rate by intraperitoneal administration of LPS (70 mg/kg) in conscious ICR mice. Results demonstrated that posttreatment with LK-4 (3 and 5 mg/kg, i.v.) significantly attenuated the deleterious hemodynamic changes (e.g., hypotension and tachycardia) in rats treated with LPS. Meanwhile, LK-4 (3 mg/kg) significantly inhibited the elevation of plasma tumor necrosis factor-α, as well as values of GOT and GPT, and BUN and creatinine caused by LPS. The induction of inducible NO synthase and the overproduction of NO and superoxide anions by LPS were also reduced by LK-4. Moreover, infiltration of neutrophils into the lungs and liver of rats 8 h after treatment with LPS was also reduced by LK-4. Furthermore, LK-4 increased the survival rate of mice insulted by toxic dose of LPS. In conclusion, the beneficial effects of LK-4 on LPS-induced sepsis result from its anti-inflammatory and anti-oxidant effects. Thus, LK-4 can be potentially used as a therapeutic agent for sepsis in the future.     

Hindlimb unloading alters nitric oxide and autonomic control of resting arterial pressure in conscious rats

After periods of microgravity or bed rest, individuals often exhibit reduced Vo(2 max), hypovolemia, cardiac and vascular effects, and autonomic dysfunction. Recently, alterations in expression of vascular and central nervous system NO synthase (NOS) have been observed in hindlimb-unloaded (HU) rats, a model used to simulate physiological effects of microgravity or bed rest. We examined the effects of 14 days of hindlimb unloading on hemodynamic responses to systemic NOS inhibition in conscious control and HU rats. Because differences in NO and autonomic regulation might occur after hindlimb unloading, we also evaluated potential differences in resting autonomic tone and effects of NOS inhibition after autonomic blockade. Administration of nitro-L-arginine methyl ester (L-NAME; 20 mg/kg iv) increased mean arterial pressure (MAP) to similar levels in control and HU rats. However, the change in MAP in response to L-NAME was less in HU rats, that had an elevated baseline MAP. In separate experiments, atropine (1 mg/kg iv) increased heart rate (HR) in control but not HU rats. Subsequent administration of the ganglionic blocker hexamethonium (30 mg/kg iv) decreased MAP and HR to a greater extent in HU rats. Administration of L-NAME after autonomic blockade increased MAP in both groups to a greater extent compared with intact conditions. However, the pressor response to L-NAME was still reduced in HU rats. These data suggest that hindlimb unloading in rats reduces peripheral NO as well as cardiac parasympathetic tone. Along with elevations in sympathetic tone, these effects likely contribute to alterations in vascular control and changes in autonomic reflex function following spaceflight or bed rest.     

Cardiovascular responses to intrathecal administration of endomorphins in anesthetized rats

Endomorphins (EMs), the endogenous, potent and selective mu-opioid receptor agonists, have been shown to decrease systemic arterial pressure (SAP) in rats after intravenous (i.v.) administration. In the present study, cardiovascular responses to intrathecal (i.t.) injection of EMs were investigated in urethane-anesthetized rats. It is noteworthy that EMs elicited decreases in SAP and heart rate (HR) in a dose-dependent manner; 10-300nmol/kg were injected intrathecally. Furthermore, these vasodepressor and bradycardic effects were significantly antagonized by naloxone (0.5mg/kg, i.t.). Interestingly, i.t. (5mg/kg) or i.v. (50mg/kg) administrations of N(omega)-nitro-l-arginine methylester (l-NAME) attenuated the vasodepressor and bradycardic effects. Moreover, pretreatment of the rats with muscarinic receptor antagonist atropine (2mg/kg, i.v.) and alpha-adrenoceptor antagonist phentolamine (1mg/kg, i.v.) significantly reduced the vasodepressor effects of EMs. Nevertheless, pretreatment with beta-adrenoceptor antagonist propranolol (2mg/kg, i.v.) could only block the bradycardia effects induced by EMs, but had no significant effects on the hypotension. In summary, all the results suggested that i.t. administration of EMs decreased SAP and HR which were possibly mediated by the activation of opioid receptors in the rat spinal cord. In addition, nitric oxide (NO) release in both the spinal cord and in peripheral tissues might regulate the cardiovascular activities of EMs, and the muscarinic receptor and adrenoceptor played an important role in the regulation of the cardiovascular responses to i.t. administration of EMs.     

Hypotensive mechanism of the extracts and artemetin isolated from Achillea millefolium L. (Asteraceae) in rats

Traditional uses of Achillea millefolium L. (Asteraceae) include the treatment of cardiovascular diseases. In the present study, we used anesthetized rats to assess the hypotensive effect of a hydroethanolic extract (HEAM), and its dichloromethane (DCM), ethyl acetate (EA), butanolic (BT), and dichloromethane-2 (DCM-2) fractions, besides the flavonoid artemetin, isolated from A. millefolium. The oral administration of HEAM (100-300 mg/kg), DCM (20 mg/kg), DCM-2 (10-30 mg/kg), but not EA (10 mg/kg) and BT (50 mg/kg) fractions significantly reduced the mean arterial pressure (MAP) of normotensive rats. The phytochemical analysis by NMR ¹H of DCM and DCM-2 fractions revealed high amounts of artemetin, that was isolated and administered by either oral (1.5 mg/kg) or intravenous (0.15-1.5 mg/kg) routes in rats. This flavonoid was able to dose-dependently reduce the MAP, up to 11.47 ± 1.5 mm Hg (1.5 mg/kg, i.v.). To investigate if artemetin-induced hypotension was related to angiotensin-converting enzyme inhibition, we evaluated the influence of this flavonoid on the vascular effects of both angiotensin I and bradykinin. Intravenous injection of artemetin (0.75 mg/kg) significantly reduced the hypertensive response to angiotensin I while increased the average length of bradykinin-induced hypotension. Artemetin (1.5 mg/kg, p.o.) was also able to reduce plasma (about 37%) and vascular (up to 63%) ACE activity in vitro, compared to control group. On the other hand, artemetin did not change angiotensin II-induced hypertension. Our study is the first showing the hypotensive effects induced by the extract and fractions obtained from A. millefollium. In addition, our results disclosed that this effect may be, at least in part, associated with high levels of artemetin and its ability to decrease angiotensin II generation in vivo, by ACE inhibition.     

延髓腹外侧头端区注射肾上腺髓质素对大鼠血压、心率和肾交感神经活动的影响

本研究在 3 4只麻醉Sprague Dawley大鼠观察了延髓腹外侧头端区内微量注射肾上腺髓质素 ( 10μmol/L ,2 0 0nl)对平均动脉压 (MAP)、心率 (HR)和肾交感神经放电 (RSNA)的影响。实验结果如下 :( 1)延髓腹外侧头端区内微量注射肾上腺髓质素可引起MAP、HR、和RSNA明显增加 ,分别由 99 0 9± 3 3 2mmHg ,3 70 78± 7 84bpm和 10 0± 0 %增至 113 5 7± 3 64mmHg (P <0 0 0 1) ,3 83 2 8± 7 3 8bpm (P <0 0 0 1)和 12 3 72±2 74% (P <0 0 0 1) ;( 2 )降钙素基因相关肽受体阻断剂CGRP8 3 7( 10 0 μmol/L ,2 0 0nl)不能阻断肾上腺髓质素的上述效应 ;( 3 )静脉注射NO前体L 精氨酸 ( 10 0mg/kg ,0 2ml)可消除肾上腺髓质素的上述效应。以上结果提示 ,肾上腺髓质素作用于延髓腹外侧头端区可产生显著的心血管作用 ,此作用不是由降钙素基因相关肽受体介导 ,但可被NO所阻断     

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 microg mL(-1)) and higher (300-1000 microg mL(-1)) concentrations of EOCZ. Only the enhancement of phenylephrine-induced contraction was abolished by either the incubation with L-NAME (50 microM) 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.     

Dextromethorphan prevents circulatory failure in rats with endotoxemia

Dextromethorphan (DM), an antitussive agent, has been claimed to have anti-inflammatory and immunomodulatory effects in vitro. Thus, the aim of this study was to evaluate the effects of DM on sepsis induced by intravenous (i.v.) administration of lipopolysaccharide (LPS) in anesthetized Wistar rats and by intraperitoneal administration in conscious ICR mice. Results demonstrated that pretreatment with DM (1,5 and 10 mg/kg, i.v.) significantly attenuated the deleterious hemodynamic changes (e.g., hypotension and tachycardia) in rats treated with LPS. Meanwhile, DM (5 mg/kg) significantly inhibited the elevation of plasma tumor necrosis factor- and interleukin-10 levels, as well as values of GOT and GPT (as an index of liver function), and BUN and creatinine (as an index of renal function) caused by LPS. The induction of inducible NO synthase and the overproduction of NO and superoxide anions by LPS were also reduced by DM. Moreover, infiltration of neutrophils into the lungs and liver of rats 6 h after treatment with LPS was also reduced by DM. In conclusion, the beneficial effects of DM on LPS-induced sepsis result from its anti-inflammatory and antioxidant effects. Thus, DM can possibly be used as a prophylactic agent for sepsis in the future.     

胍丁胺对Dahl盐敏感型高血压大鼠和Dahl盐抵抗型大鼠血流动力学的影响

在麻醉Dahl盐敏感型(DS)高血压大鼠和Dahl盐抵抗型(DR)正常血压大鼠,研究了静注胍丁胺(agmatine,AGM)对血流动力学的影响.结果显示(1)静注AGM(1,10,20mg/kg)可剂量依赖性地降低DS和DR大鼠的HR,MAP,LVP,±LVdp/dtmax,CI和TPRI.在DS高血压大鼠,MAP,LVP,±LVdp/dtmax和TPRI较DR正常血压大鼠下降幅度要大;而HR和CI在两种大鼠下降幅度无差异.需特别提出的是,DS高血压大鼠在静注高剂量AGM(20mg/kg)后,各项血流动力学指标出现先降低而后升高的现象,这一结果在DR正常血压大鼠并未出现.(2)预先静注咪唑啉受体(IR)和α2-肾上腺素能受体阻断剂(α2-AR)idazoxan(2.5mg/kg)可部分阻抑AGM的血流动力学效应.(3)预先静注α2-肾上腺素能受体阻断剂yohimbine(4mg/kg)同样可部分阻抑AGM的效应.(4)预先静注咪唑啉受体(I1)和α2-肾上腺素能受体阻断剂efaroxan(2.5mg/kg)则完全阻断AGM的血流动力学效应.以上结果表明,AGM可显著降低麻醉DR和DS大鼠的HR,MAP,LVP,±LVdp/dtmax,CI和TPRI;此效应似主要由I1-IR所介导,并有I2-IR和α2-AR参与.     

Systemic responses to carotid occlusion in the anesthetized rat.

We evaluated the effects of four standard anesthetization regimens on the systemic cardiovascular responses to bilateral common carotid artery occlusion in 28 adult male rats. Rats were randomly assigned to anesthesia groups: thiopental sodium (PT; 100 mg/kg ip), alpha-chloralose (CH; 100 mg/kg iv), ketamine hydrochloride plus acepromazine (KA; 135 mg/kg and 1.5 mg/kg sc), and pentobarbital sodium (PB; 50 mg/kg ip). PT and PB animals had similar baseline heart rates (HR; 333 and 345 beats/min, respectively) and arterial pressures (MAP; 126 and 118 mmHg, respectively), whereas both were lower in CH and KA (314 and 288 beats/min, 92 and 85 mmHg). During bilateral carotid occlusion, PT demonstrated the largest change in MAP (dMAP; +27 mmHg) but the smallest change in HR (dHR; +8 beats/min). CH and PB demonstrated similar dHR (+24 and +16 beats/min) and dMAP (+20 and +19 mmHg). KA demonstrated a significant dHR (+14 beats/min), but the average dMAP was not statistically significant (+3 mmHg). Therefore, carotid occlusion in rats anesthetized with PT, PB, or CH consistently elicits a systemic arterial pressor response comparable with that reported for conscious animals. When the magnitude and stability of baseline HR and MAP are also considered, PT and PB anesthetization seem to be the most reliable for evaluation of the carotid occlusion pressor response in rats.     

Pressor effects of systemic administration of methionine and leucine enkephalin in the conscious rat

Experiments were designed using conscious Sprague-Dawley rats to determine the blood pressure (BP) and heart rate (HR) responses to intravenous doses of (1) the adrenal catecholamines noradrenaline (NA) and adrenaline (A), (2) adrenal pentapeptides methionine enkephalin (ME) and leucine enkephalin (LE), (3) combination (i.v.) injections of both ME or LE with NA or A that modulate the hemodynamic responses when the adrenal catecholamines were given alone, and (4) the possible receptor mechanisms mediating the resultant BP and HR response to i.v. pentapeptide administration. NA (0.48 and 2.4 nmol) and A (0.3 and 1.5 nmol) given i.v. evoked potent, dose-related pressor responses associated with reflex bradycardia. ME and LE (1.6 - 48 nmol) elicited transient (10-20 s) increases in mean arterial pressure (MAP), which was associated either with no change in mean heart rate (MHR), such as ME, or with slight bradycardia (i.e., LE). Combining ME or LE (16 nmol) with NA (2.4 nmol) or A (0.3 or 1.5 nmol) did not change MAP and MHR from when these respective doses of NA or A were given alone. However, 16 nmol of ME or LE with a low dose of NA (0.48 nmol) increased the pressor response compared with NA (0.48 nmol) given alone. Other experiments whereby specific receptor blockers (naloxone, diprenorphine, atropine, propranolol, phentolamine or guanethidine) were given i.v. 5 min before subsequent i.v. administration of LE or ME (16 nmol) indicated that only phentolamine or guanethidine could completely suppress the pressor responses of LE and ME. Naloxone and diprenorphine pretreatment attenuated the pressor response of LE but did not affect the BP response to ME.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular responses to V1-vasopressinergic antagonism in conscious versus anesthetized rats

Experiments were performed to compare the possible effect of endogenous arginine vasopressin on renal hemodynamics between anesthetized, surgically stressed rats and conscious rats. Animals were instrumented with arterial and venous catheters as well as with a pulsed Doppler flow probe on the left renal artery. The rats were studied under the following conditions: (1) conscious and unrestrained; (2) anesthetized only; (3) anesthetized with minor surgical stress; and (4) anesthetized with major surgical stress. Two anesthetic agents were also compared, a mixture of ketamine (110 mg/kg i.m.) and acepromazine (1 mg/kg i.m.), and sodium pentobarbital (50 mg/kg i.p.). Baseline mean arterial blood pressure was significantly higher in pentobarbital-anesthetized rats following surgical stress compared with conscious animals, but blood pressure was not affected by ketamine-acepromazine anesthesia. After baseline measurements of blood pressure, heart rate, and renal blood flow, a specific V1-vasopressinergic antagonist (d(CH2)5Tyr(Me) arginine vasopressin, 10 mg/kg i.v.) was administered to each group. Mean arterial blood pressure, heart rate, and renal blood flow were monitored for an additional 15 min. Mean arterial blood pressure and renal blood flow decreased after V1 antagonism in ketamine-acepromazine-anesthetized rats with major surgical stress, but were not affected in pentobarbital-anesthetized animals. Heart rate and renal vascular resistance were not affected following V1 blockade with either anesthetic agent. These data suggest that arginine vasopressin plays a role in maintaining blood pressure and renal perfusion in ketamine-acepromazine-anesthetized rats following surgical stress, but does not have a significant effect on renal hemodynamics under pentobarbital anesthesia.     

Hemodynamic actions of endothelin in conscious and anesthetized dogs

The newly described endogenous peptide, endothelin, was administered to five chronically instrumented conditioned dogs. Endothelin produced significant and simultaneous increases in both heart rate (HR) and mean arterial pressure (MAP) in conscious dogs. Endothelin also produced significant increases in MAP in anesthetized animals. Ganglionic suppression induced by hexamethonium (10 mg/kg) and atropine (0.1 mg/kg) blocked HR responses and markedly inhibited the pressor responses to endothelin in conscious animals. These results suggest that endothelin in part acts to elevate blood pressure and heart rate through modification of autonomic nervous system tone. When endothelin and angiotensin II were administered in mole equivalent doses, angiotensin II produced a pressor response of greater magnitude than did endothelin in conscious animals.     

CV-3988 - a specific antagonist of platelet activating factor (PAF)

CV-3988, rac-3-(N-n-octadecylcarbamoyloxy)-2-methoxypropyl 2-thiazolioethyl phosphate was shown to be a specific inhibitor of platelet activating factor (PAF). This compound in concentrations of 3 x 10(-6) to 3 x 10(-5)M inhibited aggregation of rabbit platelets induced by PAF (3 x 10(-8)M), while it had no effect on the aggregation induced by arachidonic acid, ADP, collagen or A-23187. CV-3988 alone even at a concentration of 10(-3)M had no effect on platelet aggregation. The inhibitory action of CV-3988 on the PAF-induced aggregation was independent of the formation of micelles. The PAF (0.1 to 1.0 micrograms/kg, i.v.)-induced hypotension in anesthetized rats was also inhibited dose-dependently by the i.v. administration of CV-3988 (1 and 10 mg/kg), while the hypotensive actions induced by the i.v. administration of acetylcholine (1 micrograms/kg), arachidonic acid (1 mg/kg), bradykinin (10 micrograms/kg), isoproterenol (1 microgram/kg) and histamine (100 micrograms/kg) were not altered by CV-3988 (10 mg/kg, i.v.). All these findings indicate that CV-3988 specifically inhibits the action of PAF in vitro and in vivo. This is the first report of a PAF antagonist which can specifically inhibit the PAF-induced hypotension as well as the PAF-induced platelet aggregation.