Central Cholinergic Receptors in Cardiovascular and Antidiuretic Effects in Rats

1. Cardiovascular and antidiuretic responses to central cholinergic stimulation were investigated in conscious water loaded rats. 2. Pressor responses and antidiuresis were observed after injections of carbachol into the third ventricle. Intraventricular injection of nicotine produced bradycardia but no significant pressor or antidiuretic effects. 3. A prior injection of hexamethonium into the third ventricle abolished the effects of nicotine but did not attenuate the blood pressure increase or antidiuresis to carbachol. A prior injection of atropine into the third ventricle blocked both of these responses to carbachol, indicating the involvement of central periventricular muscarinic receptors in the central mediation of cardiovascular changes and antidiuretic hormone (ADH) release. 4. Analysis of blood levels of ADH after injection of carbachol into the third ventricle indicated the release of ADH in concentrations which were consistent with those seen to intravenous injections of ADH which produced equivalent antidiuresis, supporting the use of the on-line rat antidiuretic assay for measuring endogenous ADH release to central stimuli. 5. To test the possible involvement of catecholaminergic mechanisms in pressor and antidiuretic effect to cholineric receptor stimulation rats, carbachol was injected into the third ventricle of rats before and 10 min after central phentolamine treatment. Both pressor and antidiuretic effects of the carbachol injections were attenuated by phentolamine, indicating a role for a-adrenoreceptors in the mediation of both responses.     

Effects of histamine receptor blockade on cardiovascular changes induced by 35 GHz radio frequency radiation heating

1. The role of histamine in heat-induced cardiovascular changes is uncertain. The purpose of this study was to examine effects of histamine H-1- and H-2-antagonism on heart rate, mean arterial blood pressure (MAP), localized body temperature changes, survival times, and lethal body temperatures that occur during the exposure of anaesthetized rats to 35 GHz radio frequency radiation (RFR). 2. Forty-eight ketamine-anaesthetized Sprague-Dawley rats were exposed, in several different treatment groups (n = 8 in each), to 35 GHz RFR at a level that resulted in significant body heating and subsequent death. During irradiation, a continuous increase in heart rate and a biphasic response in blood pressure (initial increase followed by a decrease) were observed in all groups of animals. 3. An H-1-antagonist, diphenhydramine (1 mg kg(-1) body wt) and an H-2-antagonist, cimetidine (5 mg kg(-1)), administered after sustained RFR exposure, failed to reverse the RFR-induced hypotension. High doses of the drugs (5 and 10 mg kg(-1), respectively) also did not alter the response. Post-RFR survival time was significantly decreased in the high-dose drug-treated group, compared with vehicle-treated (0.9% NaCl, 50% ethanol and 50% D5W) controls. 4. In experiments in which the two drugs were administered prior to RFR exposure, MAP in animals receiving high-dose antihistamines was significantly depressed compared with that of vehicle-treated animals during the first 35 min of RFR exposure. Antihistamine pretreatment, however, did not alter the total RFR exposure time required for death to occur. 5. In summary, pharmacological blockade of H-1 and H-2 receptors is not beneficial in anaesthetized rats made hypotensive by RFR exposure. This indicates that activation of H-1 and H-2 receptors by histamine does not occur to any significant extent and does not mediate the hypotensive response developed in this model of hyperthermia.     

Histamine response and local cooling in the human skin: involvement of H1- and H2-receptors

AIMS: Histamine may contribute locally to cutaneous blood flow control under normal and pathologic conditions. The objective of this study was to observe the influence of skin temperature on histamine vasodilation, and the roles of H1-and H2-receptors using novel noninvasive methods. METHODS: Eleven healthy subjects received, double-blind, single doses of the H1-receptor antagonist cetirizine (10 mg), cetirizine (10 mg) plus the H2-receptor antagonist cimetidine (400 mg), or placebo on separate occasions. Histamine was dosed cumulatively by iontophoresis to the forearm skin at 34 degrees C and 14 degrees C. Laser-Doppler flux (LDF) was measured at the same sites using customised probeholder/iontophoretic chambers with Peltier cooling elements. Finger mean arterial pressure (MAP) was measured and cutaneous vascular conductance calculated as LDF/MAP. RESULTS: Histamine vasodilation was reduced in cold skin. Cetirizine shifted the histamine dose-response at both temperatures: statistically significantly at 14 degrees C only. Combined H1- and H2-receptor antagonism shifted the response significantly at both temperatures. CONCLUSIONS: H1- and H2-receptors mediate histamine-induced skin vasodilation. The sensitivity of these receptors, particularly the H1- receptor, is attenuated at low skin temperature. Whether the reduced effect in cold skin represents specific receptor or postreceptor desensitization, or nonspecific attenuation of cutaneous vasodilation remains to be elucidated.     

The Effects of Carbidopa Dose and Time and Route of Administration on Systemic L-Dopa Levels in Rats

The effects of carbidopa dose and time and route of administration on systemic plasma levels of parenterally and nonparenterally administered L-dopa were examined in rats. Intravenous coadministration of L-dopa + carbidopa resulted in significant (P < 0.05) carbidopa-dependent increases in both the area under the plasma L-dopa concentration versus time profile (AUC; +27%) and the plasma L-dopa half-life ( . Simultaneous duodenal or rectal carbidopa administration did not alter the L-dopa i.v. pharmacokinetic profile. Carbidopa pretreatment significantly increased the i.v. L-dopa AUC ( + 38 and +82% for i.v. and duodenal pretreatments, respectively) compared to simultaneous administration. Both i.v. and duodenal carbidopa increased duodenal L-dopa AUC to a similar extent ( + 282 and +239% for i.v. and duodenal administration, respectively). Rectal studies indicated poor absorption of both L-dopa and carbidopa, with no demonstrable effect on plasma L-dopa. The results indicate that the timing and route of carbidopa and L-dopa administration are important in determining the extent of i.v. or duodenal L-dopa systemic availability. The rat model affords results similar to those reported in human studies and may be useful for more extensive evaluation of L-dopa and carbidopa interactions.     

No evidence for central histamine-receptor involvement with the hypotensive effect of clonidine in cats

In conscious hypertensive cats, intraventricular (i.c.v.) administration of clonidine (25 μg), induced hypotension and bradycardia. Pretreatment with metiamide (2 mg i.c.v.) did not significantly antagonise either the hypotension or bradycardia induced by clonidine (25 μg), but induced marked behavioural changes. Central pretreatment with mepyramine (200 μg, i.c.v.) or procaine (600 μg i.c.v.), reduced the hypotension evoked by clonidine (25 μg), but no antagonism of the clonidine-induced bradycardia was apparent. Central phentolamine (200 μg, i.c.v.) or tolazoline (200 μg, i.c.v.) antagonised the hypotension and bradycardia evoked by i.c.v. clonidine.     

Cardiovascular effects of nicorandil and nitroprusside in furosemide plus digoxin pretreated dogs

In support of human congestive heart failure (CHF) trials, the cardiovascular effects of the vasodilators nicorandil (NIC) and nitroprusside (NP) were examined in anesthetized and conscious dogs pretreated with the diuretic furosemide (FURO) and the cardiac glycoside digoxin (DIG). In anesthetized control dogs, iv NP (2–19 μg/kg/min) and NIC (24–105 μg/kg/min) maximally reduced mean arterial pressure (MAP) by 43 and 40 mmHg, respectively, with moderate increases in heart rate (HR). These hypotensive responses to NP and NIC were unmodified by iv FURO (2.65 mg/kg) + DIG (0.075 mg/kg) pretreatment (PT). FURO + DIG reduced central venous pressure (CVP) BY 3 mmHg, masking the separate effects of NP and NIC. In a third group, FURO's fluid volume depletion and DIG's plasma concentrations were unaffected by adjunctive NIC infused for 2.5 h at a mean 17 μg/kg/min iv. No untoward interactions were seen with any combination. In conscious dogs, the hypotension and tachycardia seen with iv NP (2–20 μg/kg/min) and NIC (20–160 μg/kg/min) were also unchanged after 5 days of oral FURO (5 mg/kg/day) and DIG (0.0125 mg/kg/day), with no intolerance. Repeated oral NIC (7.5 mg/kg/day × 3 days) in these chronic FURO + DIG dogs ws consistently hypotensive but steadily more tachycardiac. This study offers a prototype of 3-way CHF drug interaction, demonstrates that NIC and NP can be safely combined with acute and chronic FURO and DIG, and shows that these CHF agents minimally affect the cardiovascular responses to NIC and NP in dogs.     

Circulatory Effects of Clonidine after Pre-hypothalamic Section in the Rat

Abstract Clonidine 15 μg/kg intravenously was administered to unanaesthetized rats during recording of blood pressure and heart rate. The rats were either sham operated or sectioned at a level rostral to the hypothalamus. The basal blood pressure and heart rate of the sectioned rats was significantly higher than that of the control rats. The blood pressure increase seen after clonidine in sham operated rats was absent in the rats with a pre-hypothalamic section and after 5–10 min. hypotension was observed. The decrease in heart frequency was more pronounced in the rats with a diencephalic section than in the sham operated rats. The results suggest that the hypertensive effect of clonidine is dependent on intact structures rostral to the hypothalamus.     

Bronchodilating Plasma Concentrations of Enprofylline and Theophylline have Minor Cardiovascular Effects in Man

Abstract: The cardiovascular effects with bronchodilating plasma concentration of theophylline (3.8–12.6 mg/l) and enprofylline (0.8–3.0 mg/l) were studied in six healthy male subjects by means of non-invasive procedures. With these plasma concentrations only minor effects were noted with regard to heart rate, blood pressure and systolic time intervals. However, both xanthines seem to have a vasodilating ability and a weak positive inotropic effect on the heart.     

Studies on the Effect of Histamine in Isolated Human Pulmonary Arteries and Veins

Abstract: The effect of histamine (0.01–200 μM) was studied in isolated human pulmonary vessels. Histamine induced concentration dependent contractions in both arteries and veins. In veins the maximal response to histamine was lower than in arteries. Histamine and 2-methyl-histamine had a dual action in both arteries and veins clearly demonstrated in vessels precontracted with potassium. In these vessels histamine and 2-methyl-histamine induced relaxation at low concentrations and contractions at high concentrations. Veins were more sensitive to the relaxant effect of histamine than arteries. Mepyramine eliminated the dual action of 2-methyl-histamine and histamine and unveiled a mepyramine resistant relaxation at the highest histamine concentrations used which was resistant to the effect of cimetidine and metiamide. The H₂ receptor agonist dimaprit (10–400 μM) induced a slight relaxation in both arteries and veins that could be eliminated by metiamide (100 μM). The results show that histamine has a dual action in human pulmonary vessels which includes a contractile effect mediated via H₁ receptors and a relaxant response partly mediated through H₁ receptors and partly via unspecific mechanisms. However, an H₂ mediated relaxant effect cannot be excluded.     

Cardiovascular Effects of Zimelidine and Tricyclic Antidepressants in Conscious Rats *

Abstract: Blood pressure, heart rate and electrocardiograms were recorded in conscious rats during intravenous injections of consecutively increasing doses of zimelidine, amitriptyline, clomipramine, desipramine and imipramine. The tricyclic antidepressants (TCA's) increased blood pressure from low doses and induced shortlasting decreases in blood pressure at higher doses. Heart rate was initially increased by amitriptyline while the other TCA's tended to decrease heart rate dose-dependently. The TCA's prolonged the QRS and QT intervals dose-dependently from low doses and the PR interval from intermediate doses. Zimelidine did not affect blood pressure or heart rate until high doses were given. The PR interval was not affected by zimelidine. Moderate to high doses of zimelidine prolonged the QT length and high doses widened the QRS complex. The results indicate a good cardiovascular tolerance for zimelidine.     

Enhanced antinociceptive effects of morphine in histamine H2 receptor gene knockout mice

We have previously shown that antinociceptive effects of morphine are enhanced in histamine H1 receptor gene knockout mice. In the present study, involvement of supraspinal histamine H2 receptor in antinociception by morphine was examined using histamine H2 receptor gene knockout (H2KO) mice and histamine H2 receptor antagonists. Antinociception was evaluated by assays for thermal (hot-plate, tail-flick and paw-withdrawal tests), mechanical (tail-pressure test) and chemical (formalin and capsaicin tests) stimuli. Thresholds for pain perception in H2KO mice were higher than wild-type mice. Antinociceptive effects of intracerebroventricularly administered morphine were enhanced in the H2KO mice compared to wild-type mice. Intracerebroventricular co-administration of morphine and cimetidine produced significant antinociceptive effects in the wild-type mice when compared to morphine or cimetidine alone. Furthermore, zolantidine, a selective and hydrophobic H2 receptor antagonist, enhanced the effects of morphine in all nociceptive assays examined. These results suggest that histamine exerts inhibitory effects on morphine-induced antinociception through H2 receptors at the supraspinal level. Our present and previous studies suggest that H1 and H2 receptors cooperatively function to modulate pain perception in the central nervous system.     

Cardiovascular effects of 3-mercaptopropionic acid and levels of GABA in regions of the brain of guinea-pigs

3-Mercaptopropionic acid (3-MP), an inhibitor of the synthesis of gamma-aminobutyric acid (GABA), was administered to anesthetized rats and guinea-pigs in order to examine the relationship between the effect of this agent on regional levels of GABA in the brain and cardiovascular function. After a latent period, 3-mercaptopropionic acid (0.16 ml/kg, i.p.) produced initial increases in blood pressure and heart rate in rats followed by vagal bradycardia and hypotension. Guinea-pigs treated with 3-mercaptopropionic acid developed one of three patterns of cardiovascular changes. The type I response consisted of a period of sympathetically-mediated hypertension and tachycardia followed by vagal bradycardia. Type II animals exhibited increased arterial pressure and heart rate, but no vagal activation. Type III and control animals exhibited no significant cardiovascular changes following administration of 3-mercaptopropionic acid or appropriate vehicle. Regional levels of GABA in brain, measured at 90 min after treatment were significantly lower than control in type I and II animals in 3 of 4 areas of the brain measured, but not in type III guinea-pigs. When decreases in levels of GABA were compared to the changes in cardiovascular parameters for individual animals, the decrease in heart rate at the time of sacrifice was directly correlated with the decrease in medullary levels of GABA in type I animals. Conversely, in type II guinea-pigs, decreases in hypothalamic levels of GABA correlated inversely with heart rate at sacrifice. These results suggest that activation of cardiac sympathetic and parasympathetic nervous pathways following the administration of 3-mercaptopropionic acid may result from decreased levels of GABA in different regions of the brain.     

乌榄叶水提物对应激性高血压大鼠降压作用的研究

目的探讨乌榄叶水提物对应激性高血压大鼠血压和心率的影响.方法用电击足底与噪声结合刺激大鼠4周,建立应激性高血压模型.采取用颈总动脉插管法,通过MedLab生物信号采集处理系统,检测大鼠平均收缩压、舒张压和心率.结果乌榄叶水提物对应激性高血压大鼠有显著的降压作用,其中以舒张压下降最为明显,降压幅度较正常大鼠显著(P＜0.01),作用维持时间更长,同时具有减慢心率作用.结论乌榄叶含有丰富而强效的降压活性成分;降压效果与大鼠基础血压相关.     

Steady-State Pharmacokinetics and Pharmacodynamics of Benazeprilat in Spontaneously Hypertensive Rats (SHR) and Wistar–Kyoto (WKY) Rats

The effects of the simultaneous steady-state intravenous infusion of benazeprilat, the active metabolite of benazepril HC1, and angiotensin I (AI) on mean arterial blood pressure were investigated in the conscious, unrestrained spontaneously hypertensive rat (SHR) and its normotensive parent strain, the Wistar–Kyoto (WKY) rat. A competitive inhibition model is applied and the limits of its validity are discussed. Deviations from the model are apparent at high drug infusion rates and may relate to the effect of benazeprilat on the clearance of AI. The strains differ in the amounts of angiotensin converting enzyme (ACE) or responsiveness to angiotensin II (AII), the drug clearances, and either the pharmacology or the distribution of the drug. Since the latter two differences are drug dependent, prediction between strains is rendered difficult. This steady-state approach relates the hypertension in the SHR to the amount of ACE or responsiveness to AII and renal function.     

Peripheral haemodynamic effects of smoking in habitual smokers. A methodological study

Summary The effect of smoking on forearm haemodynamics was studied in four groups of healthy subjects, who had all smoked cigarettes (10–15 cigarettes/day) on average for 10 years. Changes in heart rate, blood pressure, forearm blood flow, forearm vascular resistance and pulse wave velocity were determined before and every 15 min for 75 min after smoking two cigarettes within 10 min. The inhaled nicotine was about 2.2 mg. There was no significant difference between the four groups in any haemodynamic variable before or after smoking, which indicated adequate reproducibility of the parameters studied and so made it possible to pool the results from all 30 subjects.Smoking significantly increased blood pressure, heart rate and pulse wave velocity and decreased forearm blood flow. Forearm vascular resistance remained unchanged. The rises in systolic blood pressure and pulse wave velocity were transient and both peaked (7% and 28%, respectively) 15 min after smoking. In contrast, heart rate and diastolic blood pressure remained significantly elevated and forearm blood flow was significantly decreased throughout the 75 min follow-up. The maximal changes were: heart rate +34%, diastolic blood pressure +17%, and forearm blood flow –24%. It is concluded that smoking produces statistically significant changes in forearm haemodynamics affecting both small and large arteries. The reproducibility of the study design means that it can be used to evaluate substances which may antagonize the haemodynamic effects of tobacco smoking.     

Cardiovascular responses to orthostatic and other stressors in men and women are independent of sex

1. Cardiovascular responses to the stress of orthostasis, forearm (FA) ischaemia (reactive hyperaemia) and FA exercise (postexercise hyperaemia) are well described. Although sex differences in responses to orthostatic stress have been reported, few studies have examined the impact of sex on reactive hyperaemia and none has commented with regard to postexercise hyperaemia. 2. We investigated 11 men (mean (+/-SEM) age 18.5 +/- 0.3 years) and 10 women (18.8 +/- 0.8 years), all of whom were sedentary, with women being studied in the mid-follicular phase of their menstrual cycle. We measured blood pressure (BP), heart rate (HR) and forearm blood flow (FBF) in response to a fixed sequence of orthostatic, ischaemic and exercise stressors. 3. Orthostatic stress (10 min at -50 mmHg lower body negative pressure; LBNP) induced presyncopal signs in one man and three women. In all other subjects, BP was well maintained, with FBF decreasing and HR increasing similarly in both sexes. The tachycardia was earlier in onset in men and reached significantly higher absolute levels in women during the final 5 min of LBNP, but the percentage changes and integrated responses of both HR and FBF were not different between sexes. 4. The increases in FBF following either 10 min FA ischaemia or 10 min FA exercise were similar in men and women in terms of peak blood flow, percentage change, rate of recovery and total blood flow response. 5. In conclusion, although women were less tolerant of orthostatic stress than men, the cardiovascular responses to this and the other stressors appeared essentially independent of sex.     

Cardiovascular effects of adenosine and the adenosine A1 Receptor antagonist NPC 205 are altered with age in guinea pigs

Responsiveness of the cardiovascular system to the effects of vasoactive agents can vary with age. The endogenous metabolite adenosine has negative chronotropic, inotropic, and hypotensive effects. The purpose of this study was to determine if the effects of exogenously administered adenosine and the adenosine A₁ receptor antagonist 1,3-di-n-propyl-8-(hydroxyphenyl) xanthine (NPC 205) vary with age. The effects of adenosine on mean arterial blood pressure (MABP), heart rate, and cardiac contractility (LV dP/dt) were investigated in two groups of guinea pigs: a young group (3–4 weeks) and an older group (72–75 weeks). In vivo, the older animals were shown to be significantly more sensitive to the negative inotropic, chronotropic, and hypotensive effects of adenosine, whereas the responses to R-N⁶-phenylisopropyladenosine (R-PIA), a metabolically stable analog of adenosine, were similar in both age groups. In vitro, right atria from young (3–4 weeks) and old (72–75 weeks) guinea pigs exhibited no age-related differences in the sensitivity to the negative chronotropic effects of adenosine or R-PIA. Younger animals were more sensitive to the positive inotropic effects of the adenosine A₁ receptor antagonist, NPC 205. In addition, basal heart rates were significantly lower in the older group of animals. It may therefore be concluded that there age-related effects of adenosine. Furthermore, comparison of the effects of adenosine to the effects of the stable analog R-PIA and the adenosine antagonist NPC 205 suggests that these differences may be due to changes in adenosine metabolism with age. © Wiley-Liss, Inc.     

Cardiovascular effects of the essential oil of Ocimum gratissimum leaves in rats: role of the autonomic nervous system

1. The cardiovascular effects of intravenous (i.v.) administration of the essential oil of Ocimum gratissimum (EOOG) were investigated in rats. In addition, the present study examined: (i) whether the autonomic nervous system is involved in the mediation of EOOG-induced changes in mean aortic pressure (MAP) and heart rate (HR); and (ii) whether these changes could be attributed, at least in part, to the actions of eugenol, the major constituent of EOOG. 2. In both pentobarbitone-anaesthetized and conscious rats, i.v. bolus injections of EOOG (1-20 mg/kg) elicited immediate and dose-dependent decreases in MAP and HR. These responses to EOOG were of the same order of magnitude irrespective of whether the animal was under general anaesthesia. 3. Pretreatment of anaesthetized rats with bilateral vagotomy did not significantly modify the EOOG-induced dose-dependent hypotension, whereas it significantly reduced the bradycardia at the highest dose used. 4. In conscious rats, i.v. injections of bolus doses (1-10 mg/kg) of eugenol also elicited immediate and dose-dependent decreases in MAP and HR. Intravenous pretreatment of conscious rats with either methylatropine (1 mg/kg) or hexamethonium (30 mg/kg) significantly reduced the EOOG-induced dose-dependent bradycardia without affecting the hypotension. 5. These data show, for the first time, that i.v. administration of EOOG to either anaesthetized or conscious rats induces an immediate and significant hypotension and bradycardia, which appear to be due, at least in part, to the actions of the major constituent of EOOG, eugenol. These cardiovascular effects appear to be mediated by different pathways because only EOOG-induced hypotension appears to be independent of the presence of an operational autonomic nervous system. This may suggest that the hypotensive activity of EOOG results from its vasodilatory effects directly upon vascular smooth muscle.     

下丘脑前核微量注射褪黑素及其受体拮抗剂对大鼠血压和心率的影响

目的：研究下丘脑前核微量注射褪黑素及其受体拮抗剂对正常血压和应激性高血压大鼠心血管活动的影响。方法：微量注射褪黑色及其受体拮抗剂至下丘脑前区前核,记录血压、平均动脉压和心率。结果：微量注射褪黑素可降低平均动脉压,其竞争性ML1受体拮抗剂luzindole可完全阻断褪黑素的降压反应,而其ML2受体拮抗剂prazosin不能阻断褪黑素的降压反应。结论：褪黑素为一种降压因子,其降压反应主要通过激活ML1受体,而不是ML2受体来介导的。下丘脑前核是褪黑素影响心血管活动的重要中枢闰。     

Plasma concentrations and haemodynamic effects of nitroglycerin during and after intravenous infusion in healthy volunteers

Summary The effects of nitroglycerin, infused intravenously at 3.4 and 7.5 µg/min over 30 min, on haemodynamic parameters were determined in the morning and the afternoon in a randomized, placebo-controlled study in 5 healthy volunteers. The mean steady-state concentrations of nitroglycerin reached in the plasma during the infusions of 3.4 and 7.5 µg/min were 0.35±0.06 ng/ml and 0.64±0.22 ng/ml, respectively. Wide inter-individual variation was noted. The nitroglycerin-induced increase in the orthostatic rise in heart rate and the change in digital-pulse-wave morphology roughly paralleled the plasma concentration, whereas the reduction in systolic blood pressure in the upright position was still evident 15 mins after the infusion, i.e. when nitroglycerin was no longer measurable in plasma. No significant diurnal variation in vascular sensitivity to the vasodilative action of nitroglycerin was demonstrable. The change in pulse-wave morphology resulting from the reduction in peripheral resistance (shift of the dicrotic wave in the descending limb towards the base-line) proved to be the most sensitive haemodynamic parameter.