Cardiovascular responses to intravenous administration of human hemokinin-1 and its truncated form hemokinin-1(4-11) in anesthetized rats

Human hemokinin-1 and its carboxy-terminal fragment human hemokinin-1(4-11) have been recently identified as the members of the tachykinin family. The peripheral cardiovascular effects of these two tachykinin peptides were investigated in anesthetized rats. Lower doses of human hemokinin-1 (0.1-3 nmol/kg) injected intravenously (i.v.) induced depressor response, whereas higher doses (10 and 30 nmol/kg) caused biphasic (depressor and pressor) responses. The depressor response is primarily due to the action on endothelial tachykinin NK(1) receptor to release endothelium-derived relaxing factor (NO) and vagal reflex was absent in this modulation. The pressor response is mediated through the activation of tachykinin NK(1) receptor to release catecholamines from sympathetic ganglia and adrenal medulla. Moreover, human hemokinin-1 injected i.v. produced a dose-dependent tachycardia response along with blood pressure responses and the activation of sympathetic ganglia and adrenal medulla are involved in the tachycardia response. Human hemokinin-1(4-11) only lowered mean arterial pressure dose-dependently (0.1-30 nmol/kg) and the mechanisms involved in the depressor response are similar to that of human hemokinin-1. Additionally, human hemokinin-1(4-11) could also produce tachycardia response dose-dependently and the mechanisms involved in the tachycardia response are similar to that of human hemokinin-1 except that bilateral adrenalectomy could not affect the tachycardia markedly, indicating that the tachycardia induced by human hemokinin-1(4-11) is primarily due to the stimulation of sympathetic ganglia. In a word, to a certain extent, human hemokinin-1(4-11) is the active fragment of human hemokinin-1, however, the differences between human hemokinin-1 and hemokinin-1(4-11) involved in the effects of cardiovascular system suggest that the divergent amino acid residues at the N-terminus of human hemokinin-1 produced different activation properties for tachykinin NK(1) receptor.     

Cardiovascular responses to central and peripheral prostaglandins in the anesthetized rat

The prostaglandins E₂ and F_2α were injected into the lateral cerebral ventricles (i.v.t.) or into the jugular vein (i.v.) of rats anesthetized with urethane. All injections were 10 μg of the prostaglandin (PG) in a volume of 10 μl delivered over 30 s (i.v.t.) or over 10 s (i.v.). Blood pressure and heart rate were recorded before and after four consecutive injections of PGE₂ or PGF_2α given i.v.t. or i.v. 45 min apart. The first i.v.t. injection of E₂ and of F_2α elevated blood pressure and heart rate. After 45 min, the blood pressure in both groups had returned to baseline but the heart rate remained markedly elevated. The second, third and fourth i.v.t. injection of PGE₂ produced a decrease in blood pressure that returned to control levels after 5 min, but had no further effect on heart rate. The second, third and fourth i.v.t. injections of PGF_2α had no effect on blood pressure or on heart rate. All four i.v. injections of PGE₂ produced a consistent biphasic depressor then pressor effect on blood pressure and elevated heart rate. Both parameters had returned to control values by the time of the next injection. The four i.v. injections of PGF_2α produced identical rapid depressor responses within 30 s and blood pressure was back to control levels within 1 min. PGF_2α given i.v. had no effect on heart rate. From these results, it appears that the cardiovascular effects of central and peripheral PGs are different, that tolerance (tachyphylaxis) develops to the central pressor effects of PGE₂ and PGF_2α but that the particular central effect of PGE₂ depends on the recent exposure of the brain to PGE₂. The cardiovascular effects of centrally administered PG are probably mediated via CNS neural mechanisms.     

Vasopressor and heart rate responses to systemic administration of bombesin in anesthetized rats

The aim of the present study was to investigate the effects of aortic depressor nerve (ADN) transection, supranodosal vagi denervation (NG vagi cut) and adrenergic receptor blocker treatment on the cardiovascular responses evoked by systemic injection of bombesin. The cardiovascular effects were studied in spontaneously breathing rats that were (i) bilaterally, midcervically vagotomized (MC vagi cut) and subjected to section of the aortic depressor nerves, (ii) midcervically vagotomized and subsequently vagotomized at the supranodosal level or (iii) midcervically vagotomized before and after pharmacological blockade of α- or β-adrenergic receptors with phentolamine and propranolol, respectively. An intravenous bolus of bombesin (10 μg/kg) in midcervically vagotomized and ADN denervated animals increased mean arterial blood pressure (MAP) and heart rate (HR). An approximate 20% increase in blood pressure occurred immediately following bombesin injection and lasted for 2-3 min. Augmentation of the heart rate occurred 30-60 s after the bombesin challenge and persisted for more than 10 min. After section of the supranodosal vagi, bombesin failed to induce an increase in heart rate. Blockade of α-adrenergic receptors with an intravenous dose of phentolamine significantly reduced post-bombesin hypertension. These results indicate that bombesin-evoked increases in blood pressure do not require aortic depressor nerves and supranodosal vagi and are presumably mediated by the activation of peripheral α-adrenergic receptors. Bombesin-induced tachycardia was dependent on an intact supranodose pathway and was amplified by activation of β-adrenoceptors.     

P2X1 receptor-mediated pressor responses in the anesthetized mouse

P2X₁ receptors and adrenoceptors are mainly responsible for vasoconstriction in a variety of blood vessels. However, previous studies have shown that α,β-methylene adenosine 5′-triphosphate (α,β-MeATP), a stable analogue of ATP, can induce both pressor and depressor responses in laboratory animals. In this study, the effects of increasing intravenous doses of α,β-MeATP and noradrenaline (NA) (0–30 nmol/kg) administered at 20 min intervals on systolic (SBP), diastolic (DBP) and mean (MBP) blood pressure in groups of anesthetized mice (n=6) were compared. Both α,β-MeATP and NA caused transient, dose-dependent increases in SBP, DBP and MBP but the effect of α,β-MeATP was more rapid and significantly larger at doses of 10 and 30 nmol/kg (P<0.01). At the dose of 30 nmol/kg, α,β-MeATP increased SBP, DBP and MBP by 65.8±7.0, 65.7±5.0 and 65.7±5.5 mmHg, respectively, compared to increases of 36.8±4.6, 33.3±4.9 and 34.5±4.7 mmHg, respectively, produced by NA. These results indicate P2X₁ receptors play an important role in BP regulation although purinergic vasoconstriction alone may not explain the more potent pressor response to α,β-MeATP in the anesthetized mouse.     

Higher potency of RP 67580, in the mouse and the rat compared with other nonpeptide and peptide tachykinin NK1 antagonists.

1. This study was undertaken to compare the potency and selectivity of the nonpeptide (RP 67580, (+/-)-CP-96,345 and its chloro-derivative [(+/-)-cis-3-(2-chlorobenzylamino)-2-benzhydrylquinuclidine] (CP-C1)) and peptide (GR 71,251 and spantide) neurokinin1 (NK1) antagonists in mouse and rat preparations. 2. Among the NK1 antagonists tested, RP 67580 was the most potent in inhibiting the specific binding of [125I]-Bolton Hunter substance P ([125I]-BHSP) to crude synaptosomes from the rat brain (Ki: 2.9 nM). (+/-)-CP-96,345 was about ten fold less potent (Ki: 31 nM) than RP 67580 while other compounds exhibited even less affinity. 3. All NK1 antagonists inhibit competitively the activation of phospholipase C by [Pro9]substance P ([Pro9]SP) in cultured cortical astrocytes from the newborn mouse, a preparation rich in NK1 receptors but devoid of NK2 and NK3 receptors. pA2 values for the most potent compounds, RP 67580 and (+/-)-CP-96,345, were 8.28 and 7.08 respectively. When used alone, all antagonists showed some agonist activity at 10(-5) M, except spantide which was already effective at 10(-6) M. 4. An excellent correlation was found between the potency of the NK1 antagonists in blocking the stimulation by [Pro9]SP of phosphoinositide breakdown in cortical astrocytes and in inhibiting [125I]-BHSP specific binding to rat brain synaptosomes. 5. As shown on single cells by use of the Indo-1 microfluorometric method, RP 67580 (10(-7) M) prevented reversibly the elevation of cytosolic calcium concentration induced by [Pro9]SP (10(-8) M) in cultured cortical astrocytes. 6. Several experiments indicated that the antagonists were highly selective for NK1 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanisms of relaxing response induced by rat/mouse hemokinin-1 in porcine coronary arteries: roles of potassium ion and nitric oxide

Rat and mouse hemokinin-1(r/m hemokinin-1) is a recently described member of the tachykinin family whose cardiovascular functions are not fully understood. In this study, we investigated the mechanisms of the relaxing response induced by r/m hemokinin-1 in isolated porcine coronary arteries by using a specific antagonist of tachykinin NK(1) receptor (SR140333), a nitric oxide synthase inhibitor N(omega)-nitro-L-arginine (L-NNA), and 1H-[1,2,4] Oxadiazolo [4,3-a] quinoxalin-1-one (ODQ), a blocker of cGMP production. r/m Hemokinin-1 (10(-12)-10(-6 )M) evoked a marked endothelium-dependent vasodilatation (E(max)=121.12+/-10.6% and 91.79+/-2.39% in 10(-6) M PGF(2)alpha and 30 mM KCl precontracted arterial rings, respectively) of coronary arteries mediated by activation of endothelial tachykinin NK(1) receptors. Two components contributed to this r/m hemokinin-1-elicited vasodilatation, the first of which was endothelium-derived hyperpolarizing factor (EDHF), which played a major role. This EDHF was identified as a potassium current through certain kinds of potassium channels on the endothelial cell membrane of porcine coronary arteries. Specific antagonists of Ca(2+)-activated K(+) channels (dequalinium and clotrimazole) did not have an inhibitory effect on the r/m hemokinin-1-induced vasodilatation, whereas they did on the substance P-induced vasodilatation. When potassium ion efflux was impaired by a high K(+) concentration (30 mM) or removal of K(+) from the surroundings, NO synthesis was triggered by r/m hemokinin-1 to produce an equivalent EDHF (K(+))-independent vasorelaxation as a compensatory mechanism.     

Difference in pressor responses to NG-monomethyl-L-arginine between conscious and anesthetized rats

NG-Monomethyl-L-arginine (L-NMMA; 0.1-10 mg/kg, i.v.), a selective inhibitor of nitric oxide (NO) synthesis derived from L-arginine, elicited a greater increase in blood pressure in urethane/alpha-chloralose- and pentobarbital-anesthetized rats than in conscious Wistar rats. The pressor response to phenylephrine was almost equivalent in both conscious and anesthetized rats. These findings suggest that the experimental conditions (anesthetized or conscious) modify the spontaneously released NO's contribution to blood pressure regulation in vivo.     

Cardiovascular responses to sympathetic nerve stimulation in morphine-treated rats

The effects of morphine on the responses of blood pressure and pulse rate to stimulation of sympathetic nerves or to intravenous administration of noradrenaline were studied in female rats which had been treated with either an increasing concentration of morphine sulphate in their drinking fluid (5% sucrose solution), or an acute intraperitoneal injection of morphine. Sympathetic nerve excitation was effected by electrical stimulation of the thoracic segments of the spinal cord in pithed rats. Both sympathetic nerve stimulation and noradrenaline produced dose-dependent changes in blood pressure and pulse rate in naive rats and in the sucrose-drinking controls. Animals which had been chronically treated with morphine in their drinking fluid for 21 days showed significantly less intense responses to sympathetic nerve stimulation. However, these decreased responses were not observed in rats given acute treatment with morphine. Chronic treatment with morphine did not significantly influence the changes in blood pressure or pulse rate induced by noradrenaline. These findings suggest that chronic treatment with morphine lessens the cardiovascular responses to stimulation of peripheral sympathetic nerves in rats. The mechanism is not clear, but it seems unlikely to be due to changes in the sensitivity, or perhaps the number, of adrenoceptors.     

Cardiovascular responses to adrenergic agonists in sinoaortic denervated rats

1. The cardiovascular effects of systemic alpha and beta adrenergic stimulation were studied in conscious sham-operated and sinoaortic denervated (SAD) rats, 7 days after the corresponding operation. 2. SAD does not modify the pressor response to phenylephrine (0.125-8 micrograms.kg-1, i.v.). The blood pressure increase was compensated for bradycardia in the sham-operated rats but not in the SAD. Only 8 micrograms.kg-1 of phenylephrine induced a slight fall of heart rate in the denervated animals. 3. The beta adrenergic agonist isoproterenol (7.8 ng.kg-1-2 micrograms.kg-1, i.v.) showed a greater hypotensive and a lesser tachycardic action in SAD than in sham-operated rats. However, these differences disappeared after autonomic ganglionic blockade (hexamethonium, 10 mg.kg-1, i.v.). 4. Our results suggest that after 7 days of SAD the pressor response to alpha adrenergic agonists may be unaltered and that the differences in the cardiovascular beta adrenergic response of SAD rats may be due to loss of the baroreflex mechanisms of cardiovascular compensation.     

Cardiovascular responses to cholinergic agonists in sinoaortic denervated rats

1. The cardiovascular effect of systemic nicotinic and muscarinic cholinergic stimulation were studied in conscious sham operated and sinoaortic denervated (SAD) rats, 7 days after the corresponding operation.2. The administration of the nicotinic ganglionic agent 1,1-dimethyl-4-phenylpiperazinium (DMPP, 50–100 μg·kg⁻¹, i.v.) induced a fall of heart rate that was significantly higher in SAD rats than in sham rats. DMPP induced in sham rats an increase of arterial pressure but in SAD animals a biphasic response: an initial hypotension followed by an increase of arterial pressure.3. Under muscarinic blockade, DMPP only showed a pressor and tachycardic action in both groups of rats without differences between them.4. The muscarinic agonist, carbachol (0.1–10 μg·kg⁻¹, i.v.) showed the same hypotensive and bradycardic action in both groups of rats.5. Our results suggest that after 7 days of SAD, differences in the response to DMPP between sham and denervated animals could be due to the loss of baroreflex mechanisms. The increased bradycardic effect of DMPP in SAD rats could be mediated by a supersensitivity of parasympathetic ganglionic nicotinic receptors, whilst the sympathetic ganglionic nicotinic receptors remained unaltered.On the other side, the cardiovascular muscarinic responses to carbachol remain unaffected in SAD rats.     

Cardiovascular responses to morphiceptin in spontaneously hypertensive and normotensive rats

In the urethane anesthetized spontaneously hypertensive rats (SHR) intraventricular injections of morphiceptin produced dose-related increase in heart rate and blood pressure. In contrary, intraventricular administration of morphiceptin in Wistar rats induced a fall in blood pressure and heart rate. Yohimbine antagonized pressor responses to morphiceptin in SHR. Naloxone counteracted both the stimulatory effects of morphiceptin in SHR as well as hypotensive responses in Wistar rats. Bilateral vagotomy blocked depressant action of morphiceptin in normotensive but failed to alter the pressor effects in SHR rats. After systemic injections of morphiceptin a fall in heart rate and blood pressure was obtained in both strains.     

Cardiovascular responses to intraventricular adrenaline in spontaneous hypertensive rats.

The effects of intracerebroventricular (i.c.v.) injections of adrenaline on the blood pressure and heart rate of spontaneous hypertensive (SH) rats have been investigated. Adrenaline induced dose-related falls in blood pressure and heart rate in both conscious and urethane anaesthetised rats. In conscious rats, the hypotension and metoprolol, but were unaffected by pretreatment with phentolamine, piperoxan, fluphenazine or methysergide. However, in urethane-anaesthetised rats, the hypotension and bradycardia induced by i.c.v. adrenaline was not significantly affected by i.c.v. pretreatment with propranolol or oxprenolol, while metoprolol significantly antagonised only the bradycardia. Piperoxan, fluphenazine and methysergide were also without effect. Pretreatment with mecamylamine (i.p.) abolished the cardiovascular depressor effects of i.c.v. adrenaline in both conscious and urethane anaesthetised SH rats. It is concluded that the cardiovascular depressor effects of i.c.v. adrenaline are mediated by central adrenoceptors in SH rats and that, in conscious rats, these depressor effects may be mediated by central beta-adrenoceptors rather than alpha-adrenoceptors.     

Cardiovascular responses to milrinone in pertussis toxin-pretreated pithed rats.

The modulating effects of pertussis toxin on angiotensin II and B-HT 920-evoked hemodynamic changes were compared with those of milrinone to evaluate the possible role of guanine nucleotide regulatory proteins (G proteins) in the mechanism of action of milrinone. Both milrinone and pertussis toxin shifted the blood pressure dose-response curves of B-HT 920 to the right, but the responses to angiotensin II were decreased after milrinone pretreatment only. The increase in cardiac frequency evoked by milrinone and isobutylmethylxanthine (IBMX) was not sensitive to pertussis toxin. In contrast, the decrease in systolic blood pressure elicited by milrinone could be prevented by pertussis toxin pretreatment, suggesting the involvement of a regulatory protein. Milrinone and IBMX did not influence the effects of arecoline on blood pressure or heart rate in either normal or pertussis toxin-pretreated rats. It is concluded that milrinone may affect a G protein, but not the adenylate cyclase-associated inhibitory protein, Gi.     

Potassium diet as a determinant for the renal response to systemic potassium channel modulation in anesthetized rats

The role of potassium intake in the response of kidney function and plasma renin activity (PRA) to systemic application of U37883A (4-morpholinecarboximidine-N-1-adamantyl-N’-cyclohexyl-hydrochloride), a putative blocker of ATP-sensitive potassium channels (K_ATP), and P1075 (N-cyano-N’-(1,1-dimethylpropyl)-N’’-pyridylguanidine), an opener of K_ATP channels, was studied in the anesthetized rat. It was found that under normal potassium diet (0.7% K), U37883A (15 mg/kg, i.v.) increased urinary flow rate (UV) and sodium excretion (UNaV), decreased urinary potassium excretion (UKV), and significantly diminished heart rate (HR) without affecting mean arterial blood pressure (MAP) or glomerular filtration rate (GFR). P1075 (10 μg/kg, i.v.) lowered UV, UNaV and UKV, at least in part due to the fall in MAP and GFR.PRA was diminished by U37883A and increased by P1075.Variation in potassium diet (0.04 or 2% K) left the response in MAP, HR or GFR to both potassium channel modulators essentially unchanged. The reduction in renal excretion rates to P1075 also appeared unaffected, further supporting a predominant role of the change in MAP and GFR in this response. Variation in potassium diet, however, elicited the following alterations: (1) under both low and high potassium diet U37883A did no longer cause a significant natriuresis; (2) U37883A elicited a significant kaliuresis under high potassium diet, whereas potassium excretion remained essentially unchanged on very low levels under low potassium diet; (3) the increase in PRA to P1075 was blunted under low potassium diet. Additional experiments provided evidence that P1075 releases renin from freshly isolated juxtaglomerular cells of rats on normal but not on low potassium diet. In summary, systemic potassium channel modulation employing U37883A or P1075, respectively, exerts distinct effects on blood pressure and heart rate independent of potassium diet. In contrast, potassium diet appears to be a determinant for the concomitant reponses in plasma renin activity and renal sodium and potassium excretion. Received: 3 December 1997 / Accepted: 23 April 1998     

肾血管性高血压大鼠脑室注射γ-氨基丁酸的心血管效应(英文)

GABA(100和200μg,icv)在肾血管性高血压大鼠(RVHR)产生较伪手术鼠更强的降压作用,尤术后4 wk,GABA降压增强的大部分可被预先icv卡托普利所取消,而ip卡托普利作用较弱,GABA icv还明显改善RVHR已下降的压力感受性反射敏感性,提示RVHR脑内GABA抑制功能不足;外源性GABA降压效应增强可能与其抑制脑内血管紧张素系统有关。     

Cardiovascular responses in unrestrained WKY rats to inhaled ultrafine carbon particles

Based on epidemiologic observations, the issue of adverse health effects of inhaled ultrafine particles (UFP) is currently under intensive discussion. We therefore examined cardiovascular effects of UFP in a controlled animal exposure on young, healthy WKY rats. Short-term exposure (24 h) to carbon UFPs (38 nm, 180 microg m (-3)), generated by spark discharging, induced a mild but consistent increase in heart rate (18 bpm, 4.8%), which was associated with a significant decrease in heart-rate variability during particle inhalation. The timing and the transient character of these responses point to a particle induced alteration of cardiac autonomic balance, mediated by a pulmonary receptor activation. After 24 h of inhalation exposure, bronchoalveolar lavage revealed significant but low-grade pulmonary inflammation (clean air 1.9% vs. UFPs 6.9% polymorphonuclear cells) and on histopathology sporadic accumulation of particle-laden macrophages was found in the alveolar region. There was no evidence of an inflammation-mediated increase in blood coagulability, as UFP inhalation did not induce any significant changes in plasma fibrinogen or factor VIIa levels and there were no prothrombotic changes in the lung or the heart at both the protein and mRNA level. Histological analysis revealed no signs of cardiac inflammation or cardiomyopathy. This study therefore provides toxicological evidence for UFP-associated pulmonary and cardiac effects in healthy rats. Our findings suggest that the observed changes are mediated by an altered sympatho-vagal balance in response to UFP inhalation, but do not support the concept of an inflammation-mediated prothrombotic state by UFP.     

Cardiovascular responses to medullary microinjections of opiate agonists in urethane-anesthetized rats

Pressor (VLPA) and depressor (VLDA) areas of the ventrolateral medulla were identified by microinjections of L-glutamate in urethane-anesthetized rats. Cardiovascular effects of opiate agonists microinjected into the same sites were then studied. Agents used to stimulate mu, delta, sigma, kappa, and beta-endorphin (epsilon) receptors were morphiceptin, D-Ala2-D-Leu5-enkephalin, N-allyl-normetazocine, dynorphin, and beta-endorphin, respectively. Opiate receptor stimulation in VLPA decreased blood pressure (BP) and heart rate (HR), while in VLDA it increased BP and HR. Thus, it is the site of injection rather than the type of opiate receptor that determines cardiovascular responses. Naloxone, an opiate antagonist, reversed and prevented these responses. Abolition of cardiovascular responses by spinal transection at the C1 level indicated that the sympathetic nervous system mediated these responses. The following mechanism is proposed for these actions of opiates: Cell bodies in VLPA, but not in VLDA, project to the intermediolateral cell column of the spinal cord. Opiates inhibit VLPA and lower BP and HR by decreasing sympathetic outflow. Opiate-induced inhibition of VLDA, which has an inhibitory effect on VLPA, results in an increase in BP and HR.