Differential cardiovascular effects of central clonidine and B-HT 920 in conscious rats

The effect of intracerebroventricular (i.c.v.) injection of the alpha 2-adrenoceptor agonists clonidine and B-HT 920 on mean arterial pressure (MAP), heart rate (HR), and plasma concentrations of noradrenaline and adrenaline was examined in conscious unrestrained rats. The injection of 1.0 microgram clonidine significantly decreased MAP and slightly decreased HR. Plasma noradrenaline and adrenaline levels were slightly but not significantly decreased after the injection of 1 microgram clonidine. In contrast, the injection of 0.1-10.0 micrograms B-HT 920 increased MAP and decreased HR. Plasma noradrenaline and adrenaline levels were slightly increased after the injection of the 1- and 10-micrograms doses. The i.c.v. injection of the alpha 2-antagonist rauwolscine slightly but not significantly increased MAP and plasma noradrenaline and adrenaline levels. The responses to i.c.v. injection of clonidine and B-HT 920 were not changed by prior administration of rauwolscine. Neither the pressor response to B-HT 920 nor the depressor response to clonidine was abolished by rauwolscine, suggesting that neither response was mediated by alpha 2-adrenoceptors.     

Characteristics of the central adrenergic mechanisms regulating arterial pressure in rats with hereditary arterial hypertension

Adrenergic mechanisms of blood pressure regulation were studied in a newly developed strain of rats with inherited stress-provoked arterial hypertension, spontaneously hypertensive rats (SHR) and normotensive Wistar rats. A number of adrenergic agonists (noradrenaline, adrenaline, phenylephrine, clonidine, naphazoline, isoproterenol, dobutamine, Alupent) were infused into the lateral brain ventricle under nembutal anesthesia and the reaction of the peripheral blood pressure was measured. It was shown that blood pressure reactions were similar in rats with inherited stress-provoked arterial hypertension and in SHR but significantly differed from those of normotensive Wistar rats. The data obtained suggest that the development of inherited hypertension was accompanied by changes in alpha 1 to alpha 2 adrenoreceptor ratio in pressor and depressor brain regions. A decrease in the depressor effect after stimulation of beta 1 and beta 2 receptors has been also observed.     

Effects of prostacyclin on cardiovascular reflexes from the ventricular epicardium of the dog: Comparision with the effects of prostaglandin E2

Application of bradykinin to the exposed ventricular surface of the dog's heart produced reflex pressor effects and tachycardia, whereas application of nicotine evoked reflex hypotensin and bradycardia. Prostacyclin (PGI₂) or prostaglandin E₂ (PGE₂), when applied epicardially, had no effects by themselves but potentiated the reflex pressor changes to bradykinin; the depressor responses to nicotine were not changed. The potentiating effect of PGI₂ was prompt but short-lived, whereas that of PGE₂ was slow in onset but prolonged. The results suggest that PGI₂, which is present in the pericardial fluid, may contribute to signalling of pain and reflex circulatory changes when kinin formation occurs during myocardial ischaemia or pericardial inflammation.     

Depressor reactions to sural nerve stimulation in intact unanesthetized cats]

Changes in the arterial pressure, in the heart and respiratory rate evoked by the gastrocnemuis nerve stimulation were studied on conscious cats before and during intravenous injection of noradrenaline. Stimulation of the gastrocnemius nerve increased the arterial pressure, the heart and respiratory rates. The same stimulation of the nerve during hypertension caused by noradrenaline injection led to the fall of arterial pressure and tachycardia. The depressor response failed to change under the effect of the beta-adrenoreceptor block and disappeared after the m-cholinoreceptor block with methylatropine. The depressor response was absent in the unanesthetized decerebrated cats. It is supposed that the depressor response of the arterial pressure depended on the strong cholinergic vasodilatation, reflexively evoked by stimulation of the motor nerve in the intact cats.     

Blood pressure responses of conscious rats to intravenous administration of enkephalin derivatives (D-ala methionine and leucine enkephalinamide, and methionine and leucine enkephalinamide)

The present study was designed to determine the blood pressure (BP) responses of conscious rats given intravenous (IV) injections of enkephalin derivatives (D-ala²-methionine enkephalinamide, DAMEA; D-ala²-leucine enkephalinamide, DALEA; methionine enkephalinamide, MEA; leucine enkephalinamide, LEA) and the receptor mechanisms mediating the resultant change in BP. IV injection of 1.6–16.0 nmoles of DAMEA or DALEA caused a transient but potent decrease in mean arterial pressure (MAP) and mean heart rate (MHR). LEA and MEA (16.0 nmoles) given IV produced slight pressor responses, which were not associated with concomitant tachycardia whereas 48 nmoles of MEA elicited a hypotensive effect accompanied by a fall in MHR. Pretreatment studies whereby various receptor antagonists (naloxone, diprenorphine, phentolamine, D-L-propranolol or atropine) were given IV 5 min before subsequent IV administration of DAMEA, DALEA, MEA or LEA (16 nmoles) showed that naloxone, diprenorphine and atropine blocked the depressor and bradycardic effects of DALEA and DAMEA. Naloxone and phentolamine suppressed the pressor reponse of both MEA and LEA (16.0 nmoles) while diprenorphine blocked the rise in MAP to only MEA. The results show that DAMEA and DALEA mediate their depressor actions in conscious rats via a negative chronotropic effect through an interaction of muscarinic cholinergic receptors on the myocardium. It is suggested that the pressor response of MEA and LEA may be produced via an -receptor mediated effect on the peripheral vasculature to cause vasoconstriction.     

Cardiogenic reflexes after immune injury of the heart

Afferent and efferent spike activity from the parasympathetic (vagus) and sympathetic cardiac nerves were recorded simultaneously with ECG, and indices of heart function were measured in acute experiments on anesthetized dogs, which allowed us to study the modifications of cardio-cardiac reflex influences after a local immune heart injury. After an injury nidus has been formed in the heart, cardiogenic depressor reflexes evoked by an intracoronary application of veratrine or bradykinin were considerably suppressed or even abolished, and afferent spike activity in the vagus cardiac nerves noticeably decreased. At the same time, both the facilitation of activity in sympathetic afferent fibers and pressor reflex effects were preserved after the heart injury. Different localization of vagus and sympathetic afferent structures in the heart and their specialized sensitivity to the biologically active substances are suggested as the factors determining the pattern of cardiogenic reflex influences after a heart injury.Neirofiziologiya/Neurophysiology, Vol. 27, No. 1, pp. 18–25, January–February, 1995.     

Methylene blue selectively inhibits pulmonary vasodilator responses in cats

The effects of methylene blue on vascular tone and the responses to pressor and depressor substances were investigated in the constricted feline pulmonary vascular bed under conditions of controlled blood flow and constant left atrial pressure. When tone was elevated with U46619, intralobar injections of acetylcholine, bradykinin, nitroglycerin, isoproterenol, epinephrine, and 8-bromoguanosine-3',5'-cyclic monophosphate (8-bromo-cGMP) dilated the pulmonary vascular bed. Intralobar infusions of methylene blue elevated lobar arterial pressure without altering base-line left atrial or aortic pressure, heart rate, or cardiac output. When methylene blue was infused in concentrations that raised lobar arterial pressure to values similar to those attained during U46619 infusion, the pulmonary vasodilator responses to acetylcholine, bradykinin, and nitroglycerin were reduced significantly, whereas vasodilator responses to isoproterenol, epinephrine, and 8-bromo-cGMP were not altered. Moreover, the pressor responses to angiotensin II and BAY K 8644 during U46619 infusion and during methylene blue infusion were similar. The enhancing effects of methylene blue on vascular tone and inhibiting effects of this agent on responses to acetylcholine, bradykinin, and nitroglycerin were reversible. These responses returned to control value when tone was again increased with U46619, 30-45 min after the methylene blue infusion was terminated. The present data are consistent with the hypothesis that cGMP may play a role in the regulation of tone in the feline pulmonary vascular bed and in the mediation of vasodilator responses to the endothelium-dependent vasodilators, acetylcholine and bradykinin, and to nitrogen oxide-containing vasodilators such as nitroglycerin.     

Neuropeptide tyrosine (NPY)-induced potentiation of the pressor activity of catecholamines in conscious rats

IV bolus administration of 2.5-50 micrograms NPY (0.6-12.5 nmol) to conscious rats produced a dose- and time-dependent increase in systolic and diastolic blood pressure. Following priming with 2.5 micrograms NPY, or larger doses, the subsequent administrations of noradrenaline produced pressor responses that were potentiated both in magnitude and duration. The NPY-induced potentiation of the pressor response to noradrenaline was dose-dependent and extended to the pressor action of adrenaline and angiotensin II but not to the hypotensions produced by bradykinin or isoproterenol. The potentiation was not related to the fact that multiple doses of catecholamines were repeated. Reserpine did not substantially modify the NPY-induced potentiation of the pressor activity of the catecholamines. Chemical sympathectomy following 6-hydroxydopamine caused a marked supersensitivity to the catecholamines and NPY but obliterated the NPY-induced potentiation of the pressor effect of adrenaline. Nifedipine reduced the pressor action of the catecholamines and NPY but did not attenuate the NPY-induced potentiation of the pressor action of catecholamines. It is concluded that the acute pressor effect of NPY and of the potentiation of the catecholamine pressor effects involve different mechanisms.     

Effect of indomethacin-induced inhibition of arachidonic acid metabolism on the development of cardiogenic reflexes

In acute experiments on anesthetized cats, afferent spike activity from the parasympathetic (vagal) and sympathetic cardiac nerves, ECG, and cardiodynamic indices were recorded. The effects of indomethacin-induced blockade of cyclo-oxygenase pathway in metabolism of arachidonic acid on the development of cardiogenic reflex responses after intracoronary injections of veratrine, bradykinin, or prostacyclin were tested. It was found that after indomethacin injection depressor cardiogenic vagal reflexes, evoked by veratrine or bradykinin administrations, became significantly suppressed or practically disappeared. This was accompanied by a drop in the frequency of afferent vagal activity in the cardiac nerves. This effect could be observed throughout the entire period of influence of indomethacin (about 2 h after its injection). Veratrine or bradykinin, being injected simultaneously with prostacyclin, provided faster partial recovery of depressor responses (at 1 h) and promoted some activation of vagal cardiac nerves, despite the effect of indomethacin. Injection of indomethacin did not change the pattern of sympathetic afferent activity. It is suggested that the main derivative of cyclo-oxygenase pathway of arachidonic acid metabolism, prostacyclin, is able to modulate vagal nervous activity at the level of afferent structures in the heart. Prostacyclin may appear a humoral component of cardiogenic depressor reflexes of a vagal nature.Neirofiziologiya/Neurophysiology, Vol. 28, No. 1, pp. 53–61, January–February, 1996.     

Cardiac and vascular actions of sarafotoxin S6b and endothelin-1

Snake venom-derived sarafotoxin S6B (SRT) and porcine endothelium-derived endothelin-1 (ET) have striking structural similarities. In conscious, freely-moving rats, ET (0.67 nmol/kg) produced a transient tachycardia and fall in arterial blood pressure which was followed by a long-lasting increase in arterial pressure, bradycardia, decrease in cardiac output (CO) and marked increase in total peripheral resistance. In contrast, SRT (0.67 nmol/kg) produced only the sustained cardiovascular responses. The sustained cardiovascular effects of SRT or ET were similarly attenuated by nifedipine. SRT and ET (30 nM) produced vasoconstriction in the isolated perfused mesenteric vascular bed without initial vasodilation. SRT and ET had potent positive inotropic and negative chronotropic effects on isolated perfused hearts and induced toxic reactions including coronary vasospasm, arrhythmias, A-V block and ventricular fibrillation. In addition to SRT lacking the initial depressor response in vivo, several differences in the activities of the peptides were also observed. ET produced greater and longer-lasting actions than SRT in producing pressor and vasoconstrictor responses in all 3 preparations, and in its ability to induce toxic effects on the heart.     

Kallikrein as a modulator of serotoninergic and bradykininergic myotropic reactions in the small intestine

The effect of 0.01 U/ml of kallikrein on serotonin and bradykinin contractile action in the isolated intestinal segment has been described. The character of myotropic reactions was shown to change in accordance with the anatomical localization of the intestinal segment. Sensitivity to serotonin and bradykinin increases in duodenum segments and decreases in jejunum and ileum segments. Kallikrein is supposed to serve as a modulator of intestinal serotonin- and bradykininergic myotropic reactions.     

缓冲神经在电针抑制犬急性实验性高血压中的作用

在切除双侧窦神经与主动脉弓神经的慢性犬,血压很快回复至对照水平,但较易波动。在此种犬静脉匀速注射去甲肾上腺素造成高血压状态时,电针“足三里”不再有明显降压作用。在麻醉犬静脉勻速注射去甲肾上腺素时,肾交感冲动随血压上升而受到明显抑制,然后在16分钟内逐渐回升。血压上升时呼出气 CO_2百分比明显升高,伴随动脉血 CO_2分压升高而 O_2分压降低。在切除缓冲神经后再注射去甲肾上腺素时,肾交感冲动未见明显变化。在清醒犬静脉匀速注射去甲肾上腺素时,动脉血 O_2分压也有明显降低,而注射苯肾上腺素时,血 O_2分压很少改变。电针“足三里’对苯肾上腺素性高血压的降压作用不明显。且心得安可阻断电针对去甲肾上腺素性高血压的降压作用。此外,电针能抑制山梗菜碱所致的化学感受性升压反射,此种抑制作用可为静脉注射纳洛酮所阻断。结果表明,去甲肾上腺素除能收缩血管升高血压,增加压力感受性传入冲动外,还能刺激新陈代谢,改变血液气体成分而引起化学感受性升压反射。电针“足三里”主要因能抑制化学感受性反射而能降压,仅有压力感受性传入冲动的增多并不能使电针具有明显降压效应。     

Bradykinin induced a positive chronotropic effect via stimulation of T- and L-type calcium currents in heart cells

Using Fluo-3 calcium dye confocal microscopy and spontaneously contracting embryonic chick heart cells, bradykinin (10(-10) M) was found to induce positive chronotropic effects by increasing the frequency of the transient increase of cytosolic and nuclear free Ca2+. Pretreatment of the cells with either B1 or B2 receptor antagonists (R126 and R817, respectively) completely prevented bradykinin (BK) induced positive chronotropic effects on spontaneously contracting single heart cells. Using the whole-cell voltage clamp technique and ionic substitution to separate the different ionic current species, our results showed that BK (10(-6) M) had no effect on fast Na+ inward current and delayed outward potassium current. However, both L- and T-type Ca2+ currents were found to be increased by BK in a dose-dependent manner (10(-10)-10(-7) M). The effects of BK on T- and L-type Ca2+ currents were partially blocked by the B1 receptor antagonist [Leu8]des-Arg9-BK (R592) (10(-7) M) and completely reversed by the B2 receptor antagonist D-Arg[Hyp3,D-Phe7,Leu8]BK (R-588) (10(-7) M) or pretreatment with pertussis toxin (PTX). These results demonstrate that BK induced a positive chronotropic effect via stimulation of T- and L-type Ca2+ currents in heart cells mainly via stimulation of B2 receptor coupled to PTX-sensitive G-proteins. The increase of both types of Ca2+ current by BK in heart cells may explain the positive inotropic and chronotropic effects of this hormone.     

Mechanism of the cardiovascular response to systemic intravenous administration of leucine-enkephalin in the conscious dog

Leucine-enkephalin (Leu⁵-ENK) (35 μg/kg) increased heart rate and mean systemic arterial blood pressure following intravenous injection into chronically-instrumented, conscious dogs. Repeated injections at five-minute intervals were not associated with a diminished response. Naloxone (1 mg/kg) pre-treatment inhibited both heart rate and blood pressure increases. Prazosin (1 mg/kg) attenuated the increase in blood pressure but did not influence the heart rate response. Propranolol (1 mg/kg) attenuated the heart rate response but not the pressor response. Clonidine (30 μg/kg) attenuated the positive chronotropic effect of Leu⁵-ENK. Atropine (1 mg/kg) plus propranolol (1 mg/kg) blocked the heart rate response but the pressor effect was still present. The attenuation of the heart rate response by propranolol and the pressor response by prazosin suggests an adrenergic component to the enkephalin response; the reduction in the heart rate response by clonidine and atropine-propranolol indicates a role for cholinergic mechanisms in the chronotropic response. Hexamethonium (10 mg/kg) blocked the heart rate response and markedly inhibited the pressor response. Vagal interruption attenuated both heart rate and blood pressure responses. It is concluded that intravenous Leu⁵-ENK stimulates afferent pathways located in fibers which are contained in the vagosympathetic trunk to reflexly increase heart rate and blood pressure.     

The effects of pertussis toxin-treatment on integrated vasoactive response of vascular system in spontaneously hypertensive rats

We investigated the effect of pertussis toxin (PTX) on hypotensive response induced by acetylcholine (ACh) and bradykinin (BK) and on noradrenaline (NA)-induced pressor response in spontaneously hypertensive rats (SHR). Fifteen-week-old Wistar rats and age-matched SHR were used. Half of SHR received PTX (10 microg/kg/i.v.) and the experiments were performed 48 h later. After the anesthesia the right carotid artery was cannulated in order to record blood pressure (BP). The hypotensive response to ACh was enhanced in SHR compared to Wistar rats. After pretreatment of SHR with PTX the hypotensive response to ACh was reduced compared to untreated SHR and it was also diminished in comparison to Wistar rats. Similarly, the hypotensive response to BK was also decreased after PTX pretreatment. The pressor response to NA was increased in SHR compared to Wistar rats. NA-induced pressor response was considerably decreased after PTX pretreatment compared to untreated SHR. In conclusion, the enhancement of hypotensive and pressor responses in SHR was abolished after PTX pretreatment. Our results suggested that the activation of PTX-sensitive inhibitory G(i) proteins is involved in the regulation of integrated vasoactive responses in SHR and PTX pretreatment could be effectively used for modification of BP regulation in this type of experimental hypertension.     

Responses of the rat cardiovascular system to substance P,neurotensin and bombesin

The carotid arterial blood pressure and heart rate responses to intravenous injections of substance P, neurotensin and bombesin were compared in anaesthetized rats. In rats anaesthetized with urethane neurotensin produced only a fall in blood pressure but in rats anaesthetized with sodium thiobutabarbitone, the fall was preceded by a transient rise in blood pressure. The reason for the different responses to neurotensin with the two anaesthetics was not investigated. The hypotensive effect of neurotensin observed with both anaesthetics was abolished by mepyramine and therefore appeared to be mediated by action on H₁ receptors either of neurotensin directly or of histamine released. On the other hand, catecholamines might be implicated in the pressor response to neurotensin observed in rats anaesthetized with sodium thiobutabarbitone since it was reduced by phentolamine and hexamethonium. Low doses of substance P produced a depressor response which was not inhibited by the antagonists tested. At higher doses marked tachycardia occurred and the depressor response was less and was often followed by a pressor response. The tachycardia was abolished by propranolol but not by cervical cord section or by hexamethonium. Bombesin produced a pressor response which was unaffected by hexamethonium but was reversed to depressor by phentolamine. This depressor response to bombesin was abolished by propranolol. It was concluded that substance P produced a depressor response by action on its own specific receptors and tachycardia by catecholamine release whereas neurotensin and bombesin produced cardiovascular actions which were mediated entirely by amine release.     

Delta sleep-inducing peptide as a modulator of mediators acting on the heart

Experiments on 51 isolated rabbit hearts have documented, that delta sleep-inducing peptide (6 X 10(-6) M/l) has a modulating effect on the mediators influencing the heart. This peptide enhances negative chronotropic effect of acetylcholine (1 X 10(-6) M/l) and decreases positive chronotropic effect of noradrenaline (1 X 10(-6) M/l). Such effect may be one of mechanisms of changes in the extracardiac regulation on the heart influenced by this peptide.     

The acute effects of capsaicin on the cardiovascular system

Arterial blood pressure and heart rate were recorded from male Wistar rats anaesthetized with urethane. Intravenous injection of capsaicin, 1 microgram, produced a reproducible triphasic effect on blood pressure, comprising an initial fall in blood pressure and heart rate, followed by a transient and then a sustained pressor response. The depressor response and bradycardia were abolished by vagal section. The transient pressor response was altered in shape by hexamethonium. Slow intravenous infusion of capsaicin, 50 micrograms over 12 min, produced only a sustained pressor response accompanied by tachycardia, which was resistant to hexamethonium but abolished by morphine and pithing. Responses to both 1 microgram injection and 50 micrograms infusion of capsaicin were unaffected by the SP antagonist, spantide, but were abolished by capsaicin pretreatment of the rats. Capsaicin induces complex effects on the cardiovascular system, the nature of which varies with the dose and speed of administration.     

Biocybernetic studies on reflectory heart modification in the rabbit]

In rabbits the depressor nerves and cardiac vagal branches were stimulated. Their actions on heart rate, atrio-ventricular conduction time, myocardial action potential and mean central blood pressure were recorded. The frequency-effect characteristics of the chronotropic, dromotropic and electrotropic actions on the heart, resulting from afferent and efferent nerve stimulation, are compared. The participation of each of the depressor nerves in their total effects on heart rate and blood pressure is studied. Time courses of heart rate and blood pressure decrease by afferent and efferent nerve stimulation with sinusoidally modulated pulse rates are presented. The results are discussed with respect to the different dynamics of blood pressure and heart rate control. It is concluded that at least two mechanisms are involved in blood pressure control by the depressor nerves: 1. Decrease of vascular resistance by lowering the sympathetic tone. 2. Decrease of heart rate by enhancing the cardiac vagal activity. It is suggested that the parasympathetic control unit compensates rapid disturbances, whereas the slow-acting sympathetic vascular mechanism exerts a long-time pressure control of high efficiency.     

Role of kallikrein-kininogen system in insulin-stimulated glucose transport after muscle contractions.

Serum proteins [molecular weight (MW) > 10,000] are essential for increased insulin-stimulated glucose transport after in vitro muscle contractions. We investigated the role of the kallikrein-kininogen system, including bradykinin, which is derived from kallikrein (MW > 10,000)-catalyzed degradation of serum protein kininogen (MW > 10,000), on this contraction effect. In vitro electrical stimulation of rat epitrochlearis muscles was performed in 1) rat serum +/- kallikrein inhibitors; 2) human plasma (normal or kallikrein-deficient); 3) rat serum +/- bradykinin receptor-2 inhibitors; or 4) serum-free buffer +/- bradykinin. 3-O-methylglucose transport (3-MGT) was measured 3.5 h later. Serum +/- kallikrein inhibitors tended (P = 0.08) to diminish postcontraction insulin-stimulated 3-MGT. Contractions in normal plasma enhanced insulin-stimulated 3-MGT vs. controls, but contractions in kallikrein-deficient plasma did not. Supplementing rat serum with bradykinin receptor antagonist HOE-140 during contraction did not alter insulin-stimulated 3-MGT. Muscles stimulated to contract in serum-free buffer plus bradykinin did not have enhanced insulin-stimulated 3-MGT. Bradykinin was insufficient for postcontraction-enhanced insulin sensitivity. However, results with kallikrein inhibitors and kallikrein-deficient plasma suggest kallikrein plays a role in this improved insulin action.