Inhibition of noradrenaline release from the sympathetic nerves of the human saphenous vein by presynaptic histamine H3 receptors

Summary The human saphenous vein was used to examine whether presynaptic histamine receptors can modulate noradrenaline release and, if so, to determine their pharmacological characteristics. Strips of this blood vessel were incubated with [³H]noradrenaline and subsequently superfused with physiological salt solution containing desipramine and corticosterone. Electrically (2 Hz) evoked ³H overflow was inhibited by histamine and the H₃ receptor agonist R-(–)--methylhistamine. Histamine-induced inhibition of electrically evoked tritium overflow was not affected by ₂-adrenoceptor blockade by rauwolscine. S-(+)--methylhistamine (up to 10 mol/l) as well as the histamine H₁ and H₂ receptor agonists 2-(2-thiazolyl)ethylamine (up to 3 mol/l) and dimaprit (up to 30 mol/l), respectively, were ineffective. The selective histamine H₃ receptor antagonist thioperamide abolished the inhibitory effect of histamine. The histamine H₂ and H₁ receptor antagonists ranitidine and pheniramine, respectively, did not affect the histamine-induced inhibition of evoked tritium overflow. The present results are compatible with the suggestion that the sympathetic nerves of the human saphenous vein are endowed with inhibitory presynaptic histamine receptors of the H₃ class. Send offprint requests to M. Gothert at the above address     

Different activation of vascular mitogen-activated protein kinases in spontaneously and DOCA-salt hypertensive rats

Regulation mechanisms of the activity of vascular mitogen-activated protein (MAP) kinases, enzymes believed to be involved in the pathway for cell proliferation, may be altered in hypertension. To examine whether vascular MAP kinase activation mechanisms are altered in hypertension, we measured the activity of MAP kinases in rat aorta strips from spontaneously hypertensive rats (SHR) and from deoxycorticosterone acetate (DOCA)-salt hypertensive rats, and examined whether vascular angiotensin and endothelin systems are responsible for the alteration of MAP kinase activation in these hypertensive models. Endothelium-denuded aorta strips were incubated at 37 degrees C in medium. MAP kinase activity after incubation was increased in rat aorta strips. The MAP kinase activation was greater in 9- and 15-week-old SHR aorta strips than in age-matched Wistar Kyoto rats (WKY) aorta strips. Similarly, MAP kinase activation was enhanced in aorta strips from DOCA-salt hypertensive rats. In aorta strips from these kinds of rats, the angiotensin receptor antagonist, losartan, and the endothelin receptor antagonist, cyclo (D-alpha-aspartyl-L-prolyl-D-valyl-L-leucyl-D-tryptophyl) (BQ123), inhibited the MAP kinase activation. The losartan-induced, but not BQ123-induced, inhibition of MAP kinase activation was enhanced in 15-week-old SHR aorta strips, whereas the BQ123-induced, but not losartan-induced, inhibition of MAP kinase activation was enhanced in DOCA-salt hypertensive rat aorta strips. Angiotensin II-induced MAP kinase activation was enhanced in 15-week-old SHR aorta strips, whereas it was depressed in DOCA-salt hypertensive rat aorta strips. These results indicate that MAP kinase activation function is enhanced in aorta strips from both kinds of hypertensive rats. It appears that the enhancement of MAP kinase activation results partly from enhanced vascular angiotensin system in SHR and from enhanced vascular endothelin system in DOCA-salt hypertensive rats.     

Involvement of the sympathetic nervous system in the reversal of critical haemorrhagic hypotension by endogenous central histamine in rats

An increase in endogenous central histamine concentration after inhibition of histamine N-methyltransferase (HNMT) activity reverses critical hypotension and improves the survival of rats in haemorrhagic shock. The purpose of the study was to examine the involvement of the sympathetic nervous system in this endogenous central histamine-induced resuscitation.Experiments were carried out in ethylurethane-anaesthetised male Wistar rats subjected to haemorrhagic hypotension (mean arterial pressure MAP 20–25 mmHg), which led to the death of all control animals within 30 min. The HNMT inhibitor metoprine (20 µg; i.c.v.) administered 5 min after establishing the critical hypotension increased the endogenous histamine concentration, measured 20 min after treatment, in the hypothalamus (534.33±67.52 vs. 423.98±54.17 ng/g wet tissue; P<0.05) and medulla oblongata (53.12±9.78 vs. 39.58±11.16 ng/g wet tissue; P<0.05). These responses were accompanied by plasma levels of noradrenaline and adrenaline 2.7 and 1.7 times higher respectively than in the control group (P<0.01). Metoprine evoked dose-dependent (5, 10, 20 µg; i.c.v.) rises in MAP and heart rate (HR) that were significantly higher than those in normotensive animals, and resulted in a 100% survival rate at 2 h after treatment (20 µg; i.c.v.). The resuscitative effect was associated with rises in renal, hindquarters and mesenteric blood flows. The nicotinic cholinoceptor antagonist hexamethonium (3 mg/kg; i.v.) attenuated the MAP and HR changes, whereas the muscarinic cholinoceptor blocker methylatropine (2 mg/kg; i.v.) attenuated only the pressor effect. Metoprine-induced MAP and regional haemodynamic effects were also reduced by ₁- and ₂-adrenoceptor antagonists prazosin (0.5 mg/kg; i.v.) and yohimbine (1 mg/kg; i.v.), while the -adrenoceptor blocker propranolol (1 mg/kg; i.v.) diminished only HR changes. Ganglionic transmission inhibitors and adrenoceptor antagonists did not influence the survival rate at 2 h in the metoprine-treated groups. Bilateral adrenal demedullation diminished the pressor effect of metoprine, however, without influence on HR and survival at 2 h after treatment.In conclusion, the study demonstrates the activation of the sympathetic nervous system elicited by endogenous central histamine in haemorrhage-shocked rats and confirms its involvement in histamine-induced resuscitation.     

Effects of histamine H3 receptor ligands in experimental models of anxiety and depression

Histamine H₃ receptor ligands have been proposed to be of potential therapeutic interest for the treatment of different central nervous system disorders; however, the psychopharmacological properties of these drugs have not been studied extensively. In this work, we investigated the possible involvement of histamine H₃ receptor function in experimental models of anxiety (elevated plus-maze) and depression (forced swimming test). Male Sprague-Dawley rats were treated IP with the histamine H₃ receptor agonist R-α-methylhistamine (10 mg/kg) or the histamine H₃ receptor antagonist thioperamide (0.2, 2 and 10 mg/kg) and 30 min afterwards the time spent in the open arms of an elevated plus-maze was registered for 5 min. The immobility time of male OF1 mice in the forced swimming test was recorded for 6 min, 1 h after the IP administration of R-α-methylhistamine (10 and 20 mg/kg), thioperamide (0.2, 2, 10 and 20 mg/kg) or another histamine H₃ receptor antagonist, clobenpropit (5 mg/kg). The locomotor activity of mice was checked in parallel by means of an activity meter. Both saline controls and active drug controls were used in all the paradigms. Neither thioperamide nor R-α-methylhistamine significantly changed animal behaviour in the elevated plus-maze. R-α-methylhistamine and the higher dose of thioperamide assayed (20 mg/kg) were also inactive in the forced swimming test. By contrast, thioperamide (0.2–10 mg/kg) dose-dependently decreased immobility, the effect being significant at 10 mg/kg (33% reduction of immobility); clobenpropit produced an effect qualitatively similar (24% reduction of immobility). None of these histamine H₃ receptor antagonists affected locomotor activity. These preliminary results suggest that the histamine H₃ receptor blockade could be devoid of anxiolytic potential but have antidepressant effects. Besides, the stimulation of these receptors does not seem to be followed by changes in the behavioural parameters studied. Received: 1 July 1998/Final version: 8 September 1998     

Identification of endothelial H1, vascular H2 and cardiac presynaptic H3 receptors in the pithed rat

Summary In pithed and vagotomized rats the effects of the H₃ receptor agonist R-(–)--methylhistamine, the H₁ receptor agonist 2-(2-thiazolyl)ethylamine and the H₂ receptor agonist dimaprit on basal diastolic blood pressure, basal heart rate and the electrically induced rise in heart rate were examined.Basal diastolic blood pressure was not altered by low, but increased by high doses of R-(–)--methylhistamine; the latter effect was not affected by selective H₁, H₂ or H₃ receptor antagonists and by prazosin, but was attenuated by rauwolscine. Rauwolscine also unmasked a vasodepressor response to R-(–)--methylhistamine not affected by the H₃ receptor antagonist thioperamide, but counteracted by the H₁ receptor antagonist dimetindene or the H₂ receptor antagonist ranitidine. The vasodepressor responses to 2-(2-thiazolyl)ethylamine and dimaprit were antagonized by dimetindene and ranitidine, respectively. The vasodepressor response to 2-(2-thiazolyl)ethylamine was not altered by indomethacin, but reduced by an inhibitor of endothelial nitric oxide synthase, N-nitro-L-arginine methyl ester (which, by itself, markedly increased blood pressure). Both drug tools did not alter the effect of dimaprit. Basal heart rate was not affected by 2-(2-thiazolyl)ethylamine (examined after administration of propranolol), dimaprit and R-(–)--methylhistamine. The electrically induced increase in heart rate (studied in animals which had received rauwolscine) was decreased by R-(–)--methylhistamine but not affected by 2-(2-thiazolyl)ethylamine and dimaprit. The effect of R-(–)--methylhistamine was abolished by thioperamide. R-(–)--methylhistamine did not influence the increase in heart rate produced by isoprenaline.In conclusion, the pithed rat offers the opportunity to study cardiac presynaptic H₃ receptors, endothelial H₁ receptors and vascular H₂ receptors in the same experimental model. Cardiac presynaptic H₁ and H₂ receptors as well as postsynaptic H₃ receptors in the heart and in the resistance vessels were not found. R-(–)--methylhistamine is a weak agonist at ₂, H₁ and H₂ receptors.Correspondence to E. Schlicker at the above address     

Anti-hypertensive effect of the dongchunghacho,isaria sinclairii,in the spontaneously hypertensive rats

The present study examined the effect of the methanol extract of Isaria sinclairii, a kind of Donchunghacho (Tochukaso), on blood pressure in spontaneously hypertensive rats (SHR). Blood pressure and heart rate were measured after treatment with the methanol extract of I. sinclairii by the indirect tail-cuff method and the direct in vivo model. Starting at 12 weeks of age, male SHR were treated with the extracts for 2 or 4 weeks. We found that, when compared to untreated control SHR, oral treatment with I. sinclairii methanol extract (30 mg/kg/day) remarkably decreased systolic blood pressure from 200 to 112 mmHg and decreased diastolic blood pressure from 114 to 88 mmHg. Furthermore, efficacy of methanol extract of I. sinclairii was superior to captopril (30 mg/kg/mL, positive control), an angiotensin-converting enzyme inhibitor, with a lowering effect that dropped systolic blood pressure from 201 to 130 mmHg and diastolic blood pressure from 102 to 92 mmHg. However, in normal Wistar Kyoto rats, I. sinclairii methanol extract did not significantly change the normal blood pressure, suggesting that this type of Dongchunghacho has a selective effect against hypertension. Therefore, methanol extract of I. sinclairii may be used as an anti-hypertensive food/agent. Furthermore, this extract also has multiple actions such as No production in endothelial cells, inhibiting thrombin-induced blood coagulation by thrombin and mildly decreasing in prostaglandin E2 levels in cultured macrophage cells, all of which might contribute to protection against atherogenesis and thrombus formation. HPLC and MS analysis of methanol extract of I. sinclairii revealed the presence of adenosine.     

Contribution by bradykinin to the natriuretic response to the angiotensin converting enzyme inhibitor ramiprilat in spontaneously hypertensive rats

Summary It is well documented that angiotensin converting enzyme inhibitors decrease blood pressure, which is associated with natriuresis in humans and certain animal models of hypertension. However, it is not clear whether these beneficial effects are due solely to blockade of angiotensin-II production and/or also involves any contribution by kinins. The present study was performed in Inactin^® (5-ethyl-5-(1-methylpropyl)-2-thio-barbiturate sodium)-anesthetized spontaneously hypertensive rats aged 10–13 wks to examine the relative influence of the angiotensin receptor antagonist losartan (2-n-butyl-4-chloro-5-hydroxymethyl-1- [(2-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl] imidazole potassium salt) and the bradykinin receptor 2 antagonist HOE 140 (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8] bradykinin) on renal and hemodynamic responses to the angiotensin converting enzyme inhibitor ramiprilat. We found that ramiprilat (1 mg/kg, i.v.) caused sustained reduction in mean blood pressure, marked increases in urine output and urinary sodium excretion without alteration in glomerular filtration rate. In a separate group of animals, it was found that losartan (1 mg/kg, i. v.) decreased blood pressure to a similar degree as ramiprilat and the magnitude of blood pressure fall seen following the combined administration of ramiprilat and losartan was similar to that caused by either compound alone. However, the increase in urinary sodium excretion seen following losartan administration was significantly smaller than that following ramiprilat or ramiprilat plus losartan. It was also found that HOE 140 (50 g/kg, i.v.), which did not significantly affect both hemodynamic and renal parameters when administered alone, significantly attenuated the natriuretic and diuretic, but not the antihypertensive effect of ramiprilat. These results indicate that inhibition of angiotensin II formation accounts for the major portion of antihypertensive, diuretic and natriuretic effects of ramiprilat and that the accumulation of kinins contributes significantly to renal but not the acute antihypertensive effects of ramiprilat. Correspondence to: M. F. Lokhandwala at the above address     

Influence of chronic naloxone treatment on development of hypertension in the spontaneously hypertensive rat

Summary Chronic administration of naloxone by means of miniosmotic pumps retarded the development of hypertension in young spontaneously hypertensive rats (SHRs) in a dose-related manner. Abrupt termination of naloxone treatment resulted in acceleration in the rate of the blood pressure increase, while increasing the naloxone concentration further slowed the development of hypertension in SHRs. The heart rates of SHRs undergoing chronic naloxone treatment were generally lower than those of control SHRs. Naloxone had no influence upon the mean systeolic blood pressures or heart rates of normotensive Wistar-Kyoto control rats. These findings indicate that chronic naloxone treatment can alter the development of hypertension in the SHR.     

Inhibitory dopamine receptors on sympathetic neurons innervating the cardiovascular system of the pithed rat

Summary Additional experimental evidence was obtained for an inhibitory function of prejunctional ₂-adrenoceptors and/or dopamine receptors located on noradrenergic neurons innervating the heart and resistance vessels of the pithed normotensive rat. Mixed ₂-adrenoceptor receptor agonists, differing in selectivity towards either receptor type, i.e. N,N-di-n-propyldopamine (DPDA), 2-N, N-di-n-propylamino-6, 7-dihydroxy-1,2,3,4-tetrahydronaphthalene (DP-6,7-ADTN), B-HT 920 and B-HT 933 (azepexole) were used.In pithed normotensive rats, DPDA (30 and 100 g/kg/min) dose-dependently inhibited the electrical stimulation-induced increase in diastolic pressure, but did not significantly affect the stimulation-evoked increase in heart rate. The inhibition exerted by DPDA was blocked by haloperidol and sulpiride (0.3 mg/kg of each), but not by yohimbine (1 mg/kg), indicating the involvement of dopamine receptors. In this respect, sulpiride and haloperidol were found approximately equipotent.DP-6,7-ADTN (10 and 30 g/kg/min) impaired both tachycardic and vasoconstrictor responses in a dose-dependent manner. Sulpiride (0.3 mg/kg) only partially restored the DP-6,7-ADTN-depressed stimulation-evoked increase in diastolic pressure, whereas yohimbine (1 mg/kg) alone was without effect. The combination of both antagonists completely prevented the inhibition caused by DP-6,7-ADTN. On the other hand, yohimbine (1 mg/kg), but not sulpiride (0.3 mg/kg), selectively antagonized the DP-6,7-ADTN-induced inhibition of stimulation-evoked tachycardia.B-HT 920 (1, 3 and 10 g/kg/min) very effectively reduced the increase in diastolic pressure and heart rate caused by electrical stimulation. Inhibitory dopamine as well as ₂-adrenoceptors participated in the vascular effects of B-HT 920, whereas ₂-adrenoceptors were only involved in the cardioinhibitory response to this agonist.B-HT 933 (0.6 and 1 mg/kg/min) dose-dependently reduced the stimulation-evoked increase in arterial pressure through selective stimulation of inhibitory ₂-adrenoceptors, dopamine receptors not taking a part.The results confirm and extend the observations that in addition to ₂-adrenoceptors inhibitory dopamine receptors are located on the sympathetic neurons connected with the arterial vasculature of the pithed normotensive rat. The sympathetic nerves innervating the rat heart do not contain inhibitory dopamine receptors; their activity only can be modulated by ₂-adrenoceptor stimulation. In the pithed normotensive rat, activation of prejunctionally located ₂-adrenoceptors more effectively inhibits the sympathetic activity directed to the heart than that to the resistance vessels.     

Effects of impromidine- and arpromidine-derived guanidines on recombinant human and guinea pig histamine H1 and H2 receptors

Imidazolylpropylguanidines derived from impromidine and arpromidine are more potent and efficacious agonists at the guinea pig histamine H2 receptor (gpH2R) than at the human H2R (hH2R) in the GTPase assay. Additionally, such guanidines are histamine H1 receptor (H1R) antagonists with preference for the human relative to the guinea pig receptor. The purpose of this study was to examine structure-activity relationships of guanidines at human and guinea pig H1R and H2R species isoforms expressed in Sf9 insect cells. Three impromidine analogues and six arpromidine analogues exhibited agonistic activity at H2R and antagonistic activity at H1R as assessed in the steady-state GTPase assay. Species selectivity of derivatives was similar as compared with the parent compounds. None of the structural modifications examined (different aromatic ring systems and different ring substituents) was superior in terms of H2R potency and efficacy relative to impromidine and arpromidine, respectively. These data point to substantial structural constraints at the agonist binding site of H2R. Guanidines exhibited distinct structure-activity relationships for H1R antagonism in a radioligand competition binding assay and the GTPase assay and for H1R inverse agonism. Our data indicate that it is difficult to obtain guanidine-type agonists with high potency and high efficacy for hH2R, but those compounds may be useful tools for exploring the antagonist binding site and constitutive activity of H1R.     

Brain histamine H3 receptors in rats with portacaval anastomosis: in vitro and in vivo studies

The long-term effects of portacaval anastomosis (PCA) on histamine H₃ receptors in rat brain were studied by in vitro and in vivo methods. The overflow of histamine from the anterior hypothalamus and from cortex after long-term PCA was determined by in vivo microdialysis. The binding properties of [³H]-R-α-methylhistamine in membranes from cortex, cerebellum, and rest of brain (ROB) were examined with saturation binding experiments. The regional distribution of [³H]-R-α-methylhistamine binding sites in the brain of sham- and PCA-operated rats was assessed also with autoradiography. The tissue levels of histamine were significantly elevated in cortex and ROB of PCA-operated rats. In addition, the spontaneous and K⁺-evoked overflow of histamine from anterior hypothalamus, and the thioperamide-induced overflow from both anterior hypothalamus and cortex were increased after chronic PCA. In spite of the significantly elevated tissue concentrations and the moderate increase in histamine release, the binding properties of [³H]-R-α-methylhistamine to cortical membranes were not significantly changed. However, the autoradiography study did reveal a decrease in [³H]-R-α-methylhistamine binding density, particularly in striatum and cortex, where H₃ receptors are located mainly at non-histaminergic neurons. In conclusion, we suggest that there is a region-selective increase in the histaminergic activity in chronic PCA, which leads to the down-regulation of somadendritic and pre-synaptic H₃ receptors located at non-histaminergic neurons. At the same time, the autoreceptor mediated control of histamine neuronal activity via pre-synaptic H₃ receptors located at histaminergic neurons is preserved after long-term PCA. Received: 11 May 1998 / Accepted: 10 August 1998     

Activation of histamine H3 receptors in human nasal mucosa inhibits sympathetic vasoconstriction

The peripheral histamine H3 receptor is a presynaptic heterologous receptor located on postganglionic sympathetic nerve fibers innervating sympathetic effector systems such as blood vessels and the heart. An extensive body of evidence shows that activation of the histamine H3 receptor attenuates sympathetic tone by presynaptic inhibition of noradrenaline release. It is proposed that this sympathoinhibitory action, in vivo, leads to reduced vasoconstriction, thereby eliciting a vasodilatory effect. In humans, the peripheral histamine H3 receptor has also been shown to exert a sympathoinhibitory function on specific peripheral autonomic effector systems. For example, human saphenous vein and heart possess functional presynaptic histamine H3 receptors on the sympathetic nerve terminals that upon activation decrease the sympathetic tone to these respective organs. The present studies were conducted to define the role of histamine H3 receptors on neurogenic sympathetic vasoconstrictor responses in human nasal turbinate mucosa. Contractility studies were conducted to evaluate the effect of histamine H3 receptor activation on sympathetic vasoconstriction in surgically isolated human nasal turbinate mucosa. We found that the histamine H3 receptor agonist, (R)-alpha-methylhistamine (30 and 300 nM), inhibited electrical field stimulation-induced (neurogenic) sympathetic vasoconstriction in a concentration-dependent fashion. Pretreatment with the selective histamine H3 receptor antagonist, clobenpropit (100 nM), blocked the sympathoinhibitory effect of (R)-alpha-methylhistamine on the neurogenic sympathetic vasoconstriction. In addition, analysis of Taqman mRNA expression studies showed a specific, high level of distribution of the histamine H3 receptor localized in the human nasal mucosa.Taken together, these studies indicate that histamine H3 receptors modulate vascular contractile responses in human nasal mucosa most likely by inhibiting noradrenaline release from sympathetic nerve terminals in nasal mucosa. It is further suggested that histamine H3 receptors may play a role in the regulation of vascular tone and nasal patency in histamine-dependent allergic nasal congestive disease.     

Cardiovascular effects of endothelin 1 in pithed spontaneously hypertensive rats: evaluation of its mechanism(s) of action

Summary The present experiments were carried out to investigate the cardiovascular effects of endothelin 1 (ET) in pithed spontaneously hypertensive (SH) rats and to evaluate its mechanism of action. The results show that ET (0.1 – 3 nmol/kg i.v.) is a powerful vasoconstrictor agent in the pithed rat. However, at a dose of 3 nmol/kg i.v. all the pithed animals died following a gradual decrease in mean arterial blood pressure and pulse pressure and changes in the form of the electrocardiogram (ECG). The predominant feature of the change in the ECG was a progressive decrease in the amplitude of the T wave resulting in a depression of the curve representing repolarization. Investigations in isolated perfused SH rat hearts showed that ET powerfully reduces coronary flow concentration-dependently (IC₅₀ 2.1 ±0.3 nM) an effect associated with sinus bradycardia and a decrease in coronary pressure amplitude. No overt ECG changes were seen. Control experiments with mechanical flow restriction suggest that bradycardia is a consequence of reduced coronary flow and that the ECG changes observed in vivo can be explained on the basis of coronary insufficiency and resulting myocardial hypoxia. Vasoconstrictor responses to angiotensin II (0.4 g/kg i.v.), phenylephrine (8 g/kg i.v.) and ET (0.5 nmol/kg i.v.) were antagonised by around 70% by isradipine (0.03 mg/kg i.a.). The results suggest that endothelin-induced vasoconstriction may involve receptor operated channel activation and opening of voltage sensitive Ca²⁺ channels.Send offprint requests to A. K. Mir at the above address     

Opiate antagonists reverse the centrally mediated antihypertensive action of propranolol in spontaneously hypertensive rats

In anesthetized spontaneously hypertensive rats naltrexone, 2 mg/kg i.p., inhibited the hypotension and bradycardia caused by intracisternal injection of (±)-propranolol. Naltrexone and naloxone also reversed the antihypertensive effect of chronic oral treatment with propranolol (60 mg/kg per day from age 4–14 weeks) in unanesthetized spontaneously hypertensive rats, whereas in untreated littermates the opiate antagonists had insignificant effects on blood pressure and heart rate.     

Chronic inhibition of farnesyl pyrophosphate synthase attenuates cardiac hypertrophy and fibrosis in spontaneously hypertensive rats

Farnesyl pyrophosphate synthase (FPPS), an essential enzyme in the mevalonate pathway, was reported to be upregulated in young spontaneously hypertensive rats (SHR) when compared with Wistar-Kyoto (WKY) rats, and this was accompanied by development of left ventricular hypertrophy. Five-week-old rats were daily gavaged with vehicle or an FPPS inhibitor (alendronate, 1 or 10 mg/kg) and blood pressures was monitored by the tail-cuff method every other week. Twelve weeks of alendronate treatment attenuated the left ventricular weight to body weight ratio (LVW/BW), hydroxyproline content, collagen deposition in the interstitia, and gene expression of atrial natriuretic peptide, B-type natriuretic peptide, and procollagen type I/III in the SHR left ventricle, all of which were significantly higher in SHRs than in WKY rats. Furthermore, long-term treatment with an FPPS inhibitor significantly reduced RhoA activation, ERK phosphorylation, and TGF-β1 expression in the SHR left ventricle, all of which were upregulated more in SHRs than in WKY rats. In conclusion, chronic treatment with an FPPS inhibitor attenuates the development of cardiac hypertrophy and fibrosis, and the suppression of ERK1/2 phosphorylation and TGF-β1 expression with inhibition of RhoA activation may be an important mechanism.     

Central mediation of the antihypertensive effect of pargyline in spontaneously hypertensive rats.

The monoamine oxidase (MAO) inhibitor pargyline induced a moderate (about 20 mm Hg) but persistent (48 h) decrease of systolic blood pressure in unanesthetized adult spontaneously hypertensive rats (SHR) but not in normotensive rats. The fall of blood pressure correlated with the blockade of norepinephrine (NE) deamination by brain homogenates. After an intracerebroventricular (icv) injection of 6-hydroxydopamine, which lowered brain NE content by about 70%, pargyline was unable to diminish arterial pressure. Blockade of central alpha-adrenoceptors by treatment with phentolamine (100 microgram icv) could either prevent or reverse the fall of blood pressure in SHR induced by pargylline. Moreover, a low dose of pargyline injected directly into the brain lowered arterial pressure. We conclude that the hypotensive action of pargylline in SHR appears to be the consequence of NE accumulating at an inhibitory alpha-adrenoceptor in brain.     

Beneficial effects of the combination of amlodipine and losartan for lowering blood pressure in spontaneously hypertensive rats

A combination of antihypertensive agents can better control blood pressure and reduce the number and severity of side effects than a monotherapy. Since both CCBs (calcium channel blockers) and ARBs (angiotensin II receptor type-1 blockers) are current and effective antihypertensive drugs, this study assessed the synergistic antihypertensive effects as well as the optimal combination ratio of these two drugs. Amlodipine (3 mg/kg) or losartan (30 mg/kg) alone or a combination of each drug at a ratio 1:10 and 1:20 was administered orally to spontaneously hypertensive rats (SHR). A four-week treatment of either 3 mg/kg amlodipine or 30 mg/kg losartan alone decreased the systolic blood pressure (SBP). However, their combination significantly lowered the SBP from the 3^rd week, and there was a positive correlation between this reduction in blood pressure and the improvement in arterial endothelium-dependent relaxation. In addition, the combination therapy (1:20) decreased both the cardiac mass and left ventricular weight to a greater extent than with either amlodipine or losartan alone. The collagen content in the cardiac tissue was also significantly lower after the 4-week combination therapy (1:10). These results suggest that the combined use of amlodipine and losartan might be more effective in treating hypertension than a monotherapy.     

奈比洛尔对自发性高血压大鼠循环和主动脉肾素-血管紧张素系统的影响

目的：探讨奈比洛尔（Nebivolol）对自发性高血压大鼠循环和主动脉肾素-血管紧张素系统（RAS）的影响。方法：18只自发性高血压大鼠（SHR）和6只同源正常血压大鼠Wistar-Kyoto（WKY）随机分为：（1）奈比洛尔组（n=6）：SHR给予奈比洛尔5mg·kg-1·d-1;（2）卡托普利组（n=6）：SHR给予卡托普利15mg·kg-1·d-1;（3）SHR对照组（n=6）;（4）WKY对照组（n=6）。奈比洛尔、卡托普利溶于蒸馏水中灌胃,对照组给予等体积蒸馏水灌胃。给药8周后测定血浆肾素活性（PRA）,血浆和主动脉血管紧张素Ⅱ（AngⅡ）、一氧化氮（NO）浓度,NO/AngⅡ和血管紧张素转化酶（ACE）活性。结果：与WKY比较,SHR血浆和主动脉NO含量降低,AngⅡ水平显著增加,NO/AngⅡ降低;主动脉ACE活性明显增加,而血浆ACE活性则降低;但PRA在两组间无显著性差异。奈比洛尔治疗对SHR血浆AngⅡ含量和ACE活性无影响,但可降低主动脉AngⅡ水平,抑制主动脉ACE活性,从而增加血浆及主动脉NO含量和NO/AngⅡ。结论：奈比洛尔抑制肾素-血管紧张素系统,可能是其降低血压的机制之一。     

Determination of muscarinic agonist potencies at M1 and M2 muscarinic receptors in a modified pithed rat preparation

Summary The agonistic potencies of (±)muscarine, (±)cis - 2 - methyl - 5 - [(dimethylamino)methyl] - 1,3 -oxathiolane methiodide (cis-oxathiolane) and its two enantiomers were determined at muscarinic M₁ and M₂ receptors in the pithed rat. In non-pretreated animals, i.v. administration of these agents produced bradycardic effects mediated by cardiac M₂ receptors followed by increases in heart rate mediated by M1 receptors in sympathetic ganglia. As these responses have been shown to partly overlap, “true” M₁ and M₂ potencies were determined after selective blockade of M₁ and M₂ receptors by pirenzepine and methoctramine, respectively. A similar rank order of agonist potencies was obtained at M₁ and M₂ receptors: (+)cis-oxathiolane > (±)cis-oxathiolane > (±)muscarine > (-)cis-oxathiolane. At both receptor subtypes, (+)cis-oxathiolane was considerably more potent (ca. 30-fold) than its corresponding (−) enantiomer indicating that the agonist binding sites of the two receptor subtypes may have similar stereochemical properties. While (±)muscarine showed similar potencies at M₁ and M₂ receptors, racemic cis-oxathiolane and its two enantiomers showed a slight selectivity (3–7 fold) for M₁ receptors indicating the potential usefulness of these compounds in the development of selective M₁ receptor agonists. Send offprint requests to F. Cantalamessa at the above address     

An opposing role for the adrenals in the hypotensive effects of propranolol in the spontaneously hypertensive rat.

d,l-Propranolol (1 and 5 mg/kg s.c.) did not cause a fall in blood pressure and induced only a limited decrease in heart rate in conscious spontaneously) hypertensive rats (SHR). In contrast, after bilateral adrenalectomy, d,l-propranolol induced a rapid and profound decrease in blood pressure and heart rate. Decreases in heart rate and blood pressure in the individual animals were not correlated. The effects were mainly caused by l-propranolol but an additional effect of d-propranolol cannot be excluded. The decrease in blood pressure was not observed after removal of the adrenal medulla. Heart rate decreased only slightly in these animals. After treatment of adrenalectomized SHR with corticosterone (1 mg/kg b.w./h) the decrease in blood pressure due to d,l-propranolol was completely abolished. The fall in heart rate was diminished. Central injection of d,l-propranolol into the lateral brain ventricle of adrenalectomized SHR caused cardiovascular changes which were less pronounced than those following peripheral injection of comparable doses. The inhibitory effects of d,l-propranolol also occurred in adrenalectomized normotensive Wistar Kyoto rats. However, no significant changes in blood pressure and only a limited fall in heart rate were observed in adrenalectomized normotensive and renal hypertensive Wistar rats. It is concluded that the presence of the adrenal cortex, but not of the adrenal medulla prevents acute hypotension and bradycardia after propranolol in the conscious SHR.