Cardiovascular effects in the rat of ketanserin, a novel 5-hydroxytryptamine receptor blocking agent

Following intravenous administration of ketanserin (0.3-10 mg kg-1) to conscious or anaesthetized normotensive and spontaneously hypertensive rats there were dose-dependent blood pressure reductions but no compensatory tachycardia. Intracerebroventricular administration of ketanserin (25-500 microgram) had inconsistent and largely insignificant cardiovascular effects. In a dose range where it produces hypotension ketanserin antagonized the pressor responses to adrenaline and noradrenaline as well as to 5-hydroxytryptamine in monoamine depleted and spinalized rats. It is suggested that the hypotensive action of ketanserin in the rat does not involve a central mechanism but a peripheral alpha-adrenolytic action is implicated.     

SOME CARDIOVASCULAR EFFECTS OF MONOAMINE OXIDASE INHIBITORS IN UNANAESTHETIZED RATS

The effects of four monoamine oxidase (MAO) inhibitors on the blood pressure of conscious normotensive and DOC-salt hypertensive rats were measured. Harmaline (20 mg/kg p.o.), pargyline (100 mg/kg p.o.) and tranylcypromine (10 mg/kg p.o.) all lowered blood pressure significantly in both normotensive and hypertensive rats whereas methylaplysinopsin (10 mg/kg p.o.) had no effect on blood pressure. The effects of these MAO inhibitors on blood pressure responses to serotonin, tyramine and beta-phenylethylamine were determined in conscious normotensive rats. Pargyline and tranylcypromine shifted the dose-response curves for tyramine and beta-phenylethylamine, but not serotonin, to the left, indicating inhibition of type B MAO. Harmaline and methylaplysinopsin shifted the dose-response curves for tyramine and serotonin but not beta-phenylethylamine, to the left, indicating inhibition of type A MAO. Since the four antagonists tested inhibited at least one form of MAO, and yet not all of these MAO inhibitors lowered blood pressure, we suggest that our results are consistent with the view that the hypotensive action of MAO inhibitors is not necessarily related to inhibition of MAO.     

Haemodynamic effects of dicentrine, a novel alpha 1-adrenoceptor antagonist: comparison with prazosin in spontaneously hypertensive and normotensive Wistar-Kyoto rats.

1. The haemodynamic effects of dicentrine, an aporphine derivative isolated from the plant Lindera megaphylla, were investigated and compared with prazosin in rats. 2. In anaesthetized normotensive Wistar-Kyoto (WKY) rats, i.v. administration of dicentrine (0.1, 0.5, 1.0 mg kg-1) and prazosin (0.01, 0.05, 0.1 mg kg-1) induced a dose-related reduction of mean arterial pressure (MAP) which reached a maximal effect 5-10 min after injection and persisted for 2 h. 3. In anaesthetized WKY rats, a higher dose of dicentrine (1.0 mg kg-1, i.v.) did not cause any significant changes in heart rate (HR), cardiac output (CO) and stroke volume (SV) but markedly increased tail blood flow. In contrast, a higher dose of prazosin (0.1 mg kg-1, i.v.) produced a decrease in HR which paralleled the time course of the hypotensive response. 4. The hypotensive activity of dicentrine was completely abolished by alpha-adrenoceptor blockade. Both dicentrine and prazosin significantly attenuated pressor responses to noradrenaline but failed, even at maximal hypotensive doses, to impair the pressor effects of angiotensin II or vasopressin. These observations suggest that dicentrine appears to exert its hypotensive action through alpha 1-adrenoceptor blockade. 5. In conscious normotensive and spontaneously hypertensive (SH) rats, dicentrine (0.5-2.0 mg kg-1, i.v.) and prazosin (0.05-0.2 mg kg-1, i.v.) also evoked dose-related decreases in MAP which were of greater magnitude in SH rats. Oral administration of dicentrine (5 and 8 mg kg-1) to conscious SH rats caused a hypotensive effect which persisted for over 15 h.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of inhibitors of the L-arginine/nitric oxide pathway on endotoxin-induced loss of vascular responsiveness in anaesthetized rats.

1. The effects on blood pressure and on pressor responses to noradrenaline (NA), of NG-monomethyl-L-arginine (L-NMMA) and NG-nitro-L-arginine methyl ester (L-NAME), inhibitors of the L-arginine/nitric oxide pathway, were investigated in anaesthetized rats receiving an infusion of bacterial endotoxin (E. coli lipopolysaccharide, LPS). 2. Infusion of LPS (10 mg kg-1 h-1) for 50 min had no effect on mean arterial blood pressure (MABP) but induced a reduction in responsiveness to noradrenaline (100 ng-1 micrograms kg-1). L-NMMA (30 mg kg-1), but not D-NMMA, caused an increase in MABP of approximately 30 mmHg and restored responses to NA. This effect was reversed by L- but not D-arginine (100 mg kg-1). 3. In LPS-treated rats, blood pressure responses to NA were only marginally increased by the cyclooxygenase inhibitor, indomethacin (5 mg kg-1). L-NAME (1 mg kg-1) caused a similar increase in MABP and restored pressor responses to NA both in the presence and absence of indomethacin. 4. Co-infusion of vasopressin (100 ng kg-1, for 10 min) with LPS (10 mg kg-1 h-1) in order to reproduce the hypertensive effect of L-NMMA and L-NAME increased pressor responsiveness to 100 and 300 ng kg-1 NA but not to 1 microgram kg-1 NA. 5. Infusion of sodium nitroprusside (30 micrograms kg-1 min-1) decreased responsiveness to NA even when the hypotension was corrected by co-infusion of vasopressin (50 ng kg-1 min-1).(ABSTRACT TRUNCATED AT 250 WORDS)     

In-vivo pharmacological studies of 2-N-carboxamidinonormianserin, a histamine and 5-hydroxytryptamine antagonist lacking central effects.

The in-vivo pharmacological properties have been examined of FCC5 (2-N-carboxamidino-1,2,-3, 4, 10, 14b-hexahydrodibenzo (c.f.) pyrazino (1, 2-alpha)azepine hydrochloride), a guanidino analogue of mianserin. FCC5 (30-100 micrograms kg-1, i.v.) caused long-lasting (> 1 h) attenuation of histamine- and 5-hydroxytryptamine (5-HT)-induced bronchoconstriction in the anaesthetized guinea-pig. FCC5 (< or = 1 mg kg-1, i.v.) had no effect on submaximal bronchoconstrictor responses caused by i.v. acetylcholine or the thromboxane A2-mimetic U46619 ((15S)-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5Z,13E-dienoic acid). The pressor effects of 5-HT in anaesthetized and pithed rats were inhibited by FCC5 (0.3-1.0 mg kg-1, i.v.). Higher doses of FCC5 (3 mg kg-1, i.v.) reduced bradycardia and depressor responses to 5-HT in anaesthetized rats. In anaesthetized cats and rats and also pithed rats, FCC5 (0.1-1.0 mg kg-1, i.v.) caused sympathomimetic effects as demonstrated by pressor responses and tachycardia. FCC5 (0.1-0.3 mg kg-1, i.v.) inhibited pressor responses to tyramine whereas those to noradrenaline and sympathetic nerve stimulation were potentiated. Oedema in the rat paw caused by intraplantar 5-HT was inhibited by FCC5 (ID50 0.76 mg kg-1, i.p.; and 2.7 mg kg-1, p.o.). In decerebrate rats which had been spinalized at T6-8, fenfluramine-induced facilitation of the flexor reflex of the anterior tibialis muscle was inhibited by mianserin (ID50 0.36 mg kg-1, i.p.) but not by FCC5 (< or = 3 mg kg-1, i.p.).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of reserpine on the pressor responses to angiotensin in the conscious cat

1. Blood pressure recordings have been made in conscious cats in an attempt to reveal a possible indirect component to the angiotensin pressor response.2. Reserpine (50 to 250 mug/kg per day) caused a maximal reduction of about 50% in the pressor response to angiotensin whilst virtually abolishing the responses to tyramine and McN-A-343. Responses to noradrenaline were only slightly and transiently reduced.3. Syrosingopine (0.5 mg/kg) and reserpine (250 mug/kg) reduced the responses to angiotensin, McN-A-343 and tyramine to much the same extent, but tetrabenazine only reduced the responses to all these agents in a dose (25 mg/kg) which probably had effects on the catecholamine stores of smooth muscle.4. The reduction in the responses to angiotensin, tyramine and McN-A-343 by reserpine was partly reversed by tranylcypromine. Noradrenaline and (+/-)-dopa infusions were ineffective by themselves, but increased the effects of tranylcypromine in restoring the responses to angiotensin, tyramine and McN-A-343 after reserpine.5. Infusion of alpha-methyldopa markedly increased the responses to angiotensin, tyramine and McN-A-343 after these had been reduced by reserpine.6. The results suggest that the pressor response to angiotensin in the conscious cat is partly mediated by release of noradrenaline from peripheral neuronal stores.     

Studies on the anti-vasoconstrictor activity of BRL 34915 in spontaneously hypertensive rats; a comparison with nifedipine.

1. The blood pressure lowering and anti-vasoconstrictor effects of BRL 34915 and nifedipine were compared in female spontaneously hypertensive rats (SHR). 2. In conscious SHR, intravenous injection of BRL 34915 (0.1, 0.3 mg kg-1) produced rapid, dose-related falls in mean arterial pressure of greater than 3 h duration. Nifedipine, at the same intravenous dose levels, also evoked rapid anti-hypertensive effects, though these responses were of lesser magnitude and duration than those observed for BRL 34915. 3. In anaesthetized, ganglion-blocked SHR, BRL 34915 (0.1, 0.3 mg kg-1 i.v.) dose-dependently antagonized the pressor responses to incremental intravenous infusions of noradrenaline (3.8-28.5 ng min-1) or phenylephrine (120-907 ng min-1) but did not inhibit pressor responses to incremental infusions of methoxamine (0.47-3.63 micrograms min-1), angiotensin II (7.0-52.9 ng min-1) or vasopressin (0.27-2.0 mu min-1). 4. In anaesthetized, ganglion-blocked SHR, nifedipine (0.1, 0.3 mgkg-1 i.v.) antagonized the pressor responses to each of the infused vasoconstrictor agents, being most effective against responses to noradrenaline or angiotensin II. 5. In pithed SHR, both BRL 34915 and nifedipine (each at 0.3 mg kg-1 i.v.) reduced the basal blood pressure level and produced marked inhibition of frequency-dependent pressor responses evoked by electrical stimulation of the spinal cord sympathetic outflow (0.25-4.0 Hz). Restoration of the basal diastolic blood pressure to within the control range, using a continuous intravenous infusion of vasopressin (0.98 mu min-1), prevented the inhibitory effect of BRL 34915. In the case of nifedipine, however, even raising the basal blood pressure to a level exceeding that recorded in control rats (with vasopressin, 2.0 mu min-1), did not reverse the inhibitory effect of the drug on frequency-dependent pressor responses. 6. It is concluded that the anti-hypertensive properties of BRL 34915 in SHR are probably unrelated to an anti-vasoconstrictor action. In contrast, it is suggested that the broadly-based anti-vasoconstrictor properties of nifedipine may contribute substantially to the anti-hypertensive properties of this drug.     

Effect of urethane on hydralazine-induced tachycardia in rats.

1. In conscious normotensive rats, hydralazine (5-10 mg kg-1 p.o.) produced a dose-related fall in systolic blood pressure, accompanied by a pronounced increase in heart rate. 2. The tachycardia induced by hydralazine (10 mg kg-1 p.o.) in conscious normotensive rats was strongly inhibited after anaesthesia with urethane (1.26 g kg-1 i.p.). 3. In anaesthetized normotensive rats, hydralazine (1 mg kg-1 i.v.) caused a fall in mean blood pressure, accompanied by irregular effects on the heart rate that consisted in a combination of initial tachycardia followed by bradycardia. 4. In pithed rats, hydralazine (1 mg kg-1 i.v.) did not affect mean arterial blood pressure but produced a significant decrease in heart rate. 5. In rat isolated atria, hydralazine (2 mM) produced a positive inotropic/negative chronotropic effect. 6. These results suggest that urethane inhibits the cardiovascular reflex that causes the tachycardia induced by hydralazine in conscious normotensive rats. For this reason, in anaesthetized normotensive rats appear the direct effect of the drug on the heart.     

Hypotensive effects of diltiazem hydrochloride in the normotensive, spontaneously hypertensive and renal hypertensive rats (author's transl)

In conscious and anesthetized normotensive rats, intravenous administration of diltiazem (0.1--3 mg/kg) produced a dose-related decrease in blood pressure. Administration of diltiazem (1--50 mg/kg) into the duodenum of anesthetized rats also reduced the blood pressure in a dose related manner. In parallel with the change in blood pressure, the heart rate increased in conscious rats and decreased in anesthetized animals. Such an increase in the heart rate was suppressed by pretreatment with propranolol. Similarly, in conscious spontaneously hypertensive rats (SHR), diltiazem dose-dependently decreased the blood pressure and increased the heart rate after intravenous administration (0.03--1 mg/kg). Oral administration of diltiazem (100 mg/kg) also reduced the blood pressure of SHR. In addition, the progressive increase in blood pressure in young SHR was significantly suppressed by chronic oral administration of diltiazem (30 mg/kg). The blood pressure in conscious renal hypertensive rats was also decreased with diltiazem (50 mg/kg p.o.). On the other hand, it was demonstrated that the pressor responses to norepinephrine and angiotensin II in the anesthetized normotensive rats were non-competitively inhibited by intravenous administration of diltiazem at a dose which had no effect on the blood pressure.     

Tolmesoxide, a drug that lowers blood pressure by a direct relaxant effect on vascular smooth muscle.

1 The blood pressure of conscious, deoxycorticosterone acetate (DOCA) hypertensive and 1 kidney Goldblatt hypertensive rats and renal hypertensive and normotensive cats was reduced by tolmesoxide (4,5-dimethoxy-o-tolyl methyl sulphoxide). 2 Tachycardia accompanied the hypotension. In rats the increase in heart rate was abolished by concurrent administration of propranolol. Tachycardia did not occur in pithed rats. 3 Vascoconstriction induced by sympathetic stimulation, noradrenaline, tyramine, angiotensin or vasporessin was antagonized by tolmesoxide. 4 The antagonism of vasoconstrictor responses produced by tolmesoxide was unaffected by beta-adrenoceptor, muscarinic or histamine antagonists. 5 It is concluded that the lowering of pressure produced by tolmesoxide results from a defect relaxant effect on vascular smooth muscle.     

In vivo and in vitro activity of selective 5-hydroxytryptamine2 receptor antagonists

The abilities of ketanserin, ritanserin, R56413 and LY53857 to inhibit 5-hydroxytryptamine (5-HT) and noradrenaline-induced vasoconstrictor responses both in vitro and in vivo and to lower blood pressure in the rat, were compared. In the isolated perfused mesenteric artery preparation of the rat all of the compounds tested were found to be potent inhibitors of 5-HT-induced vasoconstrictor responses. Ritanserin was the most potent compound, producing more than 50% inhibition of a near maximal response to 5-HT at a concentration of 10(-11) M. All four compounds were found to be competitive antagonists of noradrenaline; ketanserin being the most potent with a pA2 value of 7.64 +/- 0.06. 5-HT-induced pressor responses in the pithed rat were inhibited by low doses (0.3-10 micrograms kg-1) of the four compounds. Ketanserin, at doses of 0.1-3.0 mg kg-1, resulted in rightward shifts of the control dose-response curve to noradrenaline in the pithed rat. None of the other compounds had any significant effect on the noradrenaline-induced pressor responses. Ketanserin (0.1-1 mg kg-1) produced a dose-dependent decrease in the mean arterial blood pressure of anaesthetized rats. The maximum decrease in blood pressure observed following a dose of 1 mg kg-1 ketanserin was 73.7 +/- 4.7 mmHg. The other compounds at doses of 1.0-3.0 mg kg-1 produced a decrease in blood pressure of a lesser magnitude than that following ketanserin. In addition, this effect did not appear to be dose-dependent. It is suggested that the acute hypotensive effect of ketanserin results predominantly from alpha 1-adrenoceptor blockade.(ABSTRACT TRUNCATED AT 250 WORDS)     

Studies on the hypotensive action of alpha-methyldopamine.

1. Intraventricular alpha-methyldopamine (50-200 mug) produced a dose-related fall in blood pressure in conscious spontaneously hypertensive rats. Pretreatment with intraventricular 6-hydroxydopamine prevented this hypotensive effect of alpha-methyldopamine. 2. The hypotensive effect of alpha-methyldopamine was prevented by intraventricular injection of phentolamine or desmethylimipramine, but not by intraperitoneal injection of haloperidol. 3. Pretreatment with U-14,624, a selective central dopamine-beta-hydroxylase inhibitor, prevented the hypotensive effect of alpha-methyldopamine. 4. Alpha-methyldopamine was considerably less potent than noradrenaline as a pressor agent in the pithed rat, but noradrenaline and alpha-methylnoradrenaline were found to be equipotent. 5. Alpha-methyldopamine (1-5 mg i.c.v.) reduced pressor responses elicited by electrical stimulation of the midbrain reticular formation in cats anaesthetized with chloralose. 6. It is concluded that the hypotensive action of alpha-methyldopamine in conscious animals involves intact central alpha-adrenergic neurones and a central adrenergic uptake mechanism for the formation of alpha-methylnoradrenaline.     

Interactions between angiotensin II, sympathetic nerve-mediated pressor response and cyclo-oxygenase products in the pithed rat.

1. The influence of angiotensin II (AII) on resting blood pressure and on sympathetic nerve-mediated pressor responses in the pithed rat was investigated either by inhibiting the renin-angiotensin system or by infusing AII. 2. Plasma AII levels in the pithed rat were approximately 20 fold higher than in normotensive rats. 3. Infusion of a subpressor dose of AII (50 ng kg-1 min-1) had no effect on sympathetic nerve mediated pressor responses but a pressor dose of AII, (200 ng kg-1 min-1) facilitated nerve-mediated pressor responses. 4. The angiotensin converting enzyme inhibitor, teprotide, and the AII-receptor antagonist, saralasin, lowered the diastolic blood pressure and attenuated sympathetic nerve-mediated pressor responses. There was no difference in the effects of teprotide at 1 mg kg-1 and 10 mg kg-1. Infusion of sodium nitroprusside at concentrations producing a fall in diastolic blood pressure of similar magnitude to that produced by teprotide and saralasin significantly attenuated nerve-mediated pressor responses. 5. After teprotide, AII 50 mg kg-1 min-1 increased diastolic blood pressure. The inhibitory effect of teprotide on nerve-mediated pressor responses was antagonized by this infusion of AII only if the rats were pretreated with the cyclo-oxygenase inhibitor, flurbiprofen. 6. It is concluded that AII is a major determinant of vascular tone in the pithed rat and that inhibition of the renin-angiotensin system attenuates sympathetic nerve-mediated pressor responses at least in part through the fall in blood pressure per se. The demonstration of this is complicated by an excessive release of vasodilator prostaglandins possibly due to the infused AII.(ABSTRACT TRUNCATED AT 250 WORDS)     

Further investigations into the mechanism of the antihypertensive activity of the angiotensin AT1 receptor antagonist, GR138950.

1. The angiotensin AT1 receptor antagonist, GR138950, produces a long-lasting antihypertensive effect in conscious renal artery ligated hypertensive (RALH) rats but this effect does not correlate temporally with its antagonist profile against angiotensin II (AII). In the present experiments we have compared the inhibitory profiles of GR138950 and enalapril, against angiotensin I (AI), with their respective antihypertensive activities. 2. GR138950 (1 mg kg-1, i.a.) and enalapril (3 mg kg-1, i.a.) reduced blood pressure in RALH rats to a similar degree. Maximum reductions in blood pressure occurred approximately 5-24 h and 3-5 h after administration, respectively. The antihypertensive effect of GR138950 lasted for 24-48 h. However, the effect of enalapril lasted for only 5-24 h. 3. In conscious normotensive rats, inhibition of AI-induced pressor responses was maximal 1 h after systemic administration of GR138950 and enalapril. Dose-response curves to AI were displaced to the right, in a parallel manner, 1406 and 102 fold by GR138950 (1 mg kg-1, i.a.) and enalapril (3 mg kg-1 i.a.), respectively. The inhibitory effect of enalapril lasted for < 24 h whereas that of GR138950 lasted for up to 48 h. 4. Contractile responses to AI were extensively inhibited in aortae removed from either RALH rats or normotensive rats, 1 and 5 h after administration of GR138950 (1 mg kg-1, i.a.). Responses were still significantly reduced 24 h after administration but had returned to control levels after 48 h. Enalapril pretreatment (3 mg kg-1, i.a.) did not inhibit contractile responses to AI in aortae isolated from normotensive rats at any time point. 5. These experiments confirm that GR138950 is an effective and long-lasting antihypertensive agent. GR138950 was a more potent and longer lasting antagonist against AI than has previously been found against AII, and the duration of its antihypertensive activity coincides better with its blockade of responses to AI. Blockade of the effects of AII generated locally within the vascular wall might play an important role in the antihypertensive profile of GR138950.     

Pharmacological properties of FPL 63547, a novel inhibitor of angiotensin-converting enzyme.

1. FPL 63547, in its active diacid form, was a potent inhibitor of rabbit lung angiotension converting enzyme (ACE) in vitro (IC50 0.51 nM). 2. In conscious normotensive dogs, FPL 63547 (10-300 micrograms kg-1 i.v.) produced prolonged, dose-related inhibition of plasma ACE activity and angiotensin I pressor responses, without affecting basal blood pressure, heart rate or pressor responses to angiotensin II. 3. In anaesthetized dogs, FPL 63547 diacid (3-300 micrograms kg-1 i.v. cumulatively) produced dose-related increases in cardiac output accompanied by falls in total peripheral resistance indicative of vasodilatation. Mild stimulation of cardiac rate and contractility was also observed. Enalapril diacid had a similar profile. 4. FPL 63547 was a highly effective antihypertensive agent after oral administration to spontaneously hypertensive rats (SHR) pretreated with a diuretic. It lowered systolic blood pressure (SBP) on acute administration over the range 3 X 10(-7)-10(-5) mol kg-1 p.o. (congruent to 0.13-4.5 mg kg-1 p.o.). FPL 63547 was more potent than other ACE inhibitors tested, threshold active doses for lisinopril, enalapril and captopril being 10(-6), 10(-6) and 3 X 10(-5) mol kg-1 p.o., respectively. The antihypertensive effects of FPL 63547, unlike those of enalapril and captopril, were of long duration. 5. The antihypertensive efficacy of FPL 63547 was also observed following chronic oral administration. A dose of 0.5 mg kg-1 day-1 once daily for 23 days produced a sustained reduction of SBP. By the end of the treatment period, SBP was significantly lowered both pre- and post-dose, i.e. effective 24 h control had been achieved.(ABSTRACT TRUNCATED AT 250 WORDS)     

Release of catecholamines in the locus coeruleus of freely moving and anaesthetized normotensive and spontaneously hypertensive rats: effects of cardiovascular changes and tail pinch

Noradrenaline turnover has been found to be increased in the locus coeruleus of young spontaneously hypertensive rats (SHR). There is also evidence that the noradrenergic projection from the locus coeruleus to the posterior hypothalamus contributes to the development of genetic hypertension. To investigate whether the release of noradrenaline and dopamine in the locus coeruleus is modified in genetic hypertension, this brain region of adult SHR and normotensive Wistar-Kyoto (WKY) rats was superfused with artificial cerebrospinal fluid through a push-pull cannula. Dopamine and noradrenaline released in the superfusate were determined radioenzymatically. There was no difference in the basal release of noradrenaline and dopamine in the locus coeruleus of conscious, anaesthetized or diazepam-treated adult WKY rats and SHR. In conscious animals, a rise in blood pressure elicited by intravenous infusion of phenylephrine enhanced the release of noradrenaline and dopamine in both strains to the same extent. Intravenous infusion of sodium nitroprusside elicited a fall in blood pressure and also increased to the same degree the release of noradrenaline and dopamine in the locus coeruleus of normotensive and hypertensive conscious rats. In anaesthetized rats, baroreceptor activation by phenylephrine decreased the release of noradrenaline and dopamine, while sodium nitroprusside lowered blood pressure and enhanced the release rates of the two catecholamines. Treatment of conscious rats with diazepam (10 mg/kg, i.p., 120 min prior to starting collection of the superfusate) abolished the phenylephrine-evoked release of catecholamines observed in conscious animals. The sensory stimulus tail pinch led to a slight increase in blood pressure. In conscious animals, this aversive stimulus led to enhanced release of noradrenaline and dopamine that lasted longer in SHR than in WKY rats. The release of catecholamines evoked by tail pinch was abolished in rats treated with diazepam, as well as in anaesthetized animals. Our findings show that in adult rats, genetic hypertension does not modify the release of noradrenaline and dopamine in the locus coeruleus. Since in anaesthetized rats increases in blood pressure diminish, while decreases in blood pressure enhance, the release of noradrenaline and dopamine, it seems that both amines possess a counteracting, hypertensive function in the rat locus coeruleus. When baroreceptor activation by phenylephrine is carried out on conscious animals, stress predominates and the release of catecholamines is enhanced. This study demonstrates the importance of the noradrenergic system of the locus coeruleus in central cardiovascular control and in emotional, stress and pain-regulating processes.     

Study of the in vivo and in vitro cardiovascular effects of (+)-glaucine and N-carbethoxysecoglaucine in rats.

1. The cardiovascular and vasorelaxant effects of (+)-glaucine and of a semisynthetic derivative (N-carbethoxysecoglaucine) were studied in rats. 2. N-carbethoxysecoglaucine did not modify either systolic arterial pressure or heart rate values in conscious (25 mg kg-1, p.o.) and anaesthetized normotensive rats (5 mg kg-1, i.v.). Furthermore, this compound showed no activity in the experiments carried out on rat isolated aorta [contractility and 45Ca2+ influx assays (5 microM)] and did not modify the rate and force of contraction in rat isolated atria (5 microM). 3. In conscious normotensive rats, oral administration of (+)-glaucine (25 mg kg-1) did not modify either systolic arterial pressure or heart rate. 4. In anaesthetized normotensive rats, (+)-glaucine (5 mg kg-1, i.v.) produced a remarkable fall in mean arterial pressure (MAP) accompanied by a significant decrease in heart rate. In the same preparation, (+)-glaucine (5 mg kg-1, i.v.) did not modify the cardiovascular effects induced by noradrenaline (NA) (5 micrograms kg-1) and 5-hydroxytryptamine (5-HT) (300 micrograms kg-1) but markedly inhibited those induced by nicotine (200 micrograms kg-1). 5. In isolated intact aorta of rat, (+)-glaucine (0.15-5 microM) competitively inhibited the contractions induced by NA (with a pA2 value of 7.14) and non-competitively those induced by 5-HT (in normal Krebs solution) and Ca2+ (in depolarizing Ca(2+)-free high-K+ 50 mM solution), with depression of the maximal response and with pD2 values of 5.56 and 5.26, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Responses of mean arterial pressure to pressor agents and diuretics in renal hypertensive and salt hypertensive rats

1. The responses of the mean arterial pressure to (-)-noradrenaline, tyramine, angiotensin II-val(5)-amide, vasopressin and rat renin have been contrasted in renal hypertensive and in salt plus desoxycorticosterone hypertensive rats. The responses were measured in rats both unanaesthetized and rats anaesthetized with pentobarbitone.2. Responses of unanaesthetized, ganglion blocked renal hypertensive rats to noradrenaline, tyramine and vasopressin markedly exceeded, and to angiotensin II and renin were markedly smaller than, those of unanaesthetized ganglion blocked salt + DOC hypertensive animals. Responses to angiotensin and to renin were apparently enhanced in the latter animals.3. Hydrochlorothiazide and frusemide markedly reduced mean arterial pressure in salt + DOC hypertensive rats before and after ganglionic blockade.4. Neither diuretic caused significant reduction in the mean arterial pressures of unanaesthetized, renal hypertensive rats in the absence of ganglionic blockade: frusemide did so in anaesthetized and unanaesthetized rats after ganglionic blockade.5. Whereas the diuretics did not affect the responses of the renal hypertensive rats to pressor agents, frusemide and to a lesser extent hydrochlorothiazide tended to depress the responses to pressor agents in salt induced hypertension.6. Hydrochlorothiazide did not influence mean arterial pressure in unanaesthetized rats with neurogenic hypertension.     

On the cardiovascular action of dopamine in rats

Summary In rats anaesthetized with urethane the pressor effect of dopamine was not significantly altered by treatment with desipramine, which enhanced the action of noradrenaline on blood pressure and heart rate and abolished that of tyramine. Chemical sympathectomy with 6-hydroxydopamine in rats potentiated responses to noradrenaline and prevented the action of tyramine on blood pressure but did not significantly modify the pressor effects of dopamine. Furthermore, pretreatment with reserpine shifted the dose-response curves for dopamine and for tyramine on heart rate to the right. The dose-response curve for dopamine like that for noradrenaline on blood pressure was unaltered or shifted slightly to the left by reserpine. It is concluded that also in the rat an indirect, tyramine-like component contributes substantially to the cardiovascular action of dopamine.     

Pressor effects of the alpha 2-adrenoceptor agonist B-HT 933 in anaesthetized and haemorrhagic rats: comparison with the haemodynamic effects of amidephrine.

1. Blood pressure responses to single and multiple bolus doses of the alpha 2-adrenoceptor agonist B-HT 933 were analysed in intact anaesthetized rats which were either normotensive or hypotensive as a result of haemorrhage. Single bolus doses of B-HT 933 in normotensive rats induced a fall in blood pressure, whilst further doses induced dose-dependent pressor responses which were inhibited by the alpha 2-adrenoceptor antagonist yohimbine and unaffected by the alpha 1-adrenoceptor agonist prazosin. In the haemorrhagic, hypotensive animals, single bolus doses of B-HT 933 induced immediate dose-dependent pressor responses; the maximum pressor responses to the bolus of B-HT 933 and its ED50 values were the same in both the normotensive and hypotensive, haemorrhagic animals. 2. Cardiac output, its distribution and tissue blood flows were determined with tracer microspheres in intact anaesthetized normotensive and haemorrhagic, hypotensive rats during depressor (normotensive) and pressor (normotensive and hypotensive) responses to B-HT 933. Haemodynamics were also determined during pressor responses to the alpha 1-adrenoceptor agonist amidephrine. 3. In control normotensive rats, a single dose of B-HT 933 (1 mg kg-1) reduced blood pressure by reducing cardiac output (through a decrease in heart rate). It increased the fractional distribution of cardiac output to the spleen and stomach, reduced it to the heart and liver and reduced cardiac and hepatic blood flow. A further dose of B-HT 933 (1 mg kg-1 bolus followed by 100 micrograms min-1 infusion) increased blood pressure by increasing total peripheral resistance, which was accompanied by decreased proportions of cardiac output passing to the heart, liver and testes. There was also increased fractional distribution of cardiac output to the lungs, spleen, kidneys and stomach but blood flows through the liver and testes were reduced. Amidephrine (6 micrograms kg-1 bolus followed by 0.5 micrograms min-1 infusion) increased blood pressure by increasing cardiac output through an increased stroke volume. It increased cardiac output distribution to the kidneys and brain, increasing blood flow through the heart, lungs, brain, testes, epididimides, skin and large intestine. 4. Haemorrhage caused a fall in blood pressure which resulted from decreased total peripheral resistance and cardiac output (the latter due to decreases in both heart rate and stroke volume). It reduced the proportion of cardiac output distributed to the lungs, spleen, kidneys, testes and pancreas/mesentery and decreased blood flow through these organs as well as through the heart, liver, brain, epididimides, skin and the gastrointestinal tract.4