Capsaicin-like effect of (6)-shogaol on substance P-containing primary afferents of rats: a possible mechanism of its analgesic action.

The effects of (6)-shogaol, a pungent component of dried ginger with a capsaicin-like chemical structure, on the release of immunoreactive substance P from the spinal dorsal horn were examined by in vitro superfusion of the dorsal-half slices of the spinal cord of the rat. (6)-Shogaol (30 microM to 1 mM) increased dose-dependently the release of immunoreactive substance P. The maximum effect of (6)-shogaol was observed at a concentration of 100 microM and less than a half of the effect of 10 microM capsaicin. The effect of (6)-shogaol (100 microM) was attenuated in slices from rats with dorsal rhizotomy and abolished by elimination of calcium ions from the perfusion medium. Pretreatment with (6)-shogaol in vitro inhibited the capsaicin-evoked release of immunoreactive substance P. On the other hand, systemic administration of (6)-shogaol (160 mg/kg) produced antinociception in rats, with a peak effect between 15 and 30 min and a smaller dose of 80 mg/kg was without effect. Treatment of rats with (6)-shogaol, at a dose of 160 mg/kg but not at 80 mg/kg, for 20 min significantly decreased release of immunoreactive substance P, evoked by capsaicin (10 microM), from the slices of cord. These data suggest that (6)-shogaol shares the sites of action with capsaicin, on the terminals of substance P-containing primary afferents, to release of the neuropeptide and inhibit the release of substance P, by subsequent stimulation of the primary afferents. The latter action of (6)-shogaol might be relevant to its analgesic effect.     

Role of capsaicin-sensitive sensory nerves in mediation of the cardiovascular effects of the essential oil of croton zehntneri leaves in anaesthetized rats

The essential oil of Croton zehntneri Pax et Hoffm. (EOCZ) contains anethole (42%) and estragole (46%), two isomers that share some chemical structural similarities with capsaicin. The present study investigated the cardiovascular effects of EOCZ and the role of capsaicin-sensitive sensory nerve fibres in the mediation of these effects in anaesthetized rats. 2. Intravenous bolus injection of EOCZ (1-20 mg/kg) elicited dose-dependent hypotension and bradycardia that were immediate and transient. Similar responses were also observed with anethole and estragole (both at 10 mg/kg). After cervical bivagotomy or perineural treatment of both cervical vagus nerves with capsaicin (250 mg/mL) to selectively block the conduction of sensory C-fibres, both cardiovascular responses to EOCZ (10 mg/kg) were abolished. 3. Like capsaicin, an epigastric retrograde intra-arterial injection of EOCZ (10 mg/kg, i.a.) into the femoral artery elicited a monophasic hypotensive response. This reflex response was blocked by either neonatal pretreatment with capsaicin (50 mg/kg, s.c.) or intrathecal injection of the substance P receptor antagonist RP 67580 (7.8 nmol, at the spinal level L5-L6), suggesting that it is mediated exclusively by substance P-containing primary afferent fibres. 4. The cardiovascular responses to EOCZ (10 mg/kg, i.v.) were also significantly reduced by the selective vallinoid TPRV1 receptor antagonist capsazepine (1 mg/kg, i.v.). 5. It is concluded that i.v. administration of EOCZ in anaesthetized rats elicits a capsaicin-like bradycardic and depressor reflex, which appears to be mediated by the activation of vallinoid TPRV1 receptors located on vagal sensory nerves. Like capsaicin, i.a. injection of EOCZ induces a spinally mediated sensory reflex.     

Possible mechanisms underlying the hypertensive response to clonidine in freely moving, normotensive rats

Possible mechanisms underlying the hypertensive response to intracerebroventricular (i.c.v.) or intravenous (i.v.) injection of clonidine were investigated in freely moving, normotensive rats. In conscious rats, clonidine (2-20 micrograms) injected i.c.v. caused a dose-dependent and long-lasting pressor response associated with bradycardia. A similarly long-lasting pressor response was induced following an initial rapid rise in mean blood pressure after i.v. bolus injections of clonidine (5-50 micrograms/kg). In pentobarbital-anesthetized rats, the prolonged pressor responses to i.v. and i.c.v. injected clonidine at high doses were significantly smaller than those in conscious rats. Low doses of clonidine caused only depressor responses which developed gradually. No significant changes in concentrations of plasma norepinephrine and epinephrine were found during the pressor period after i.c.v. injection of clonidine (20 micrograms). Systemic (2 mg/kg, i.v.) or central (100 micrograms, i.c.v.) pretreatment with phentolamine abolished only the prolonged pressor response to both i.c.v. (20 micrograms) and i.v. (50 micrograms/kg) injected clonidine. The prolonged pressor response to clonidine (20 micrograms, i.c.v.) was enhanced by pretreatment with hexamethonium (25 mg/kg, i.v.), methylatropine (1 mg/kg, i.v.) or atropine (1 mg/kg, i.v.) and it was not affected by pretreatment with saralasin (300 micrograms/kg and 25 micrograms/kg/min, i.v.), d(CH2)5Tyr(Me)-arginine-vasopressin, a vasopressin antagonist (50 micrograms/kg, i.v.) or naloxone (1 mg/kg, i.v.). Neither adrenalectomy nor adrenal demedullation had an effect on the pressor response to clonidine (20 micrograms, i.c.v.). In adrenalectomized rats, systemic pretreatment with hexamethonium (25 mg/kg, i.v.) caused a potentiation of the pressor response to clonidine (20 micrograms, i.c.v.). These results suggest that clonidine induces the pressor response through activation of central alpha-adrenoceptors, probably the alpha 2 subtype, without an increase in sympatho-adrenomedullary activity. It is speculated that the response may be mediated by vasoactive humoral substance(s).     

Further evidence for a central hypotensive action of α-methyldopa in both the rat and cat

1. alpha-Methyldopa (300 mg/kg i.p.) produced a fall in blood pressure in conscious genetic hypertensive rats. Pretreatment with intraventricular 6-hydroxydopamine prevented this hypotensive effect of alpha-methyldopa, whilst intravenous 6-hydroxydopamine reduced but did not prevent the hypotension.2. The hypotensive effect of alpha-methyldopa was prevented or reversed by intraventricular injection of phentolamine (200 mug/rat).3. Pressor responses obtained by stimulation of the entire sympathetic outflow in the Gillespie & Muir preparation, were unaffected by pretreatment with alpha-methyldopa (300 mg/kg i.p.).4. Vasoconstrictor responses to periarterial nerve stimulation of the isolated renal artery preparation of the rat were markedly reduced by pretreatment with alpha-methyldopa. Furthermore, alpha-methylnoradrenaline was found to have one-eighth the vasoconstrictor potency of noradrenaline in this particular artery preparation.5. Pressor responses obtained by stimulation of the posterior hypothalamus or midbrain reticular formation in the rat anaesthetized with urethane were markedly reduced by pretreatment with alpha-methyldopa. FLA-63, a selective dopamine-beta-hydroxylase inhibitor, prevented the reduction of the pressor responses to hypothalamic stimulation produced by alpha-methyldopa.6. Stimulation of the posterior hypothalamus in the anaesthetized cat caused both an increase in sympathetic nerve activity and a rise in blood pressure. These responses were markedly reduced 3-4 h after the injection of alpha-methyldopa (100 mg/kg i.v.).7. These results strongly suggest that the central actions of alpha-methyldopa are important for its hypotensive effect, although a possible peripheral effect cannot be excluded.     

The role of nitric oxide and platelet-activating factor in the inhibition by endotoxin of pentagastrin-stimulated gastric acid secretion.

Administration of E. coli endotoxin (1 mg/kg i.v.) abolished the acid secretory response induced by a bolus injection of pentagastrin (100 micrograms/kg i.v.) in the continuously perfused stomach of the anaesthetized rat. Endotoxin administration did not modify mean systemic arterial blood pressure. Pretreatment with NG-nitro-L-arginine methyl ester (L-NAME; 5-20 mg/kg i.v.), but not dexamethasone (5 mg/kg s.c. twice) or indomethacin (5 mg/kg i.m.), substantially restored the secretory responses to pentagastrin. The actions of L-NAME were reversed by the prior administration of L-arginine (100 mg/kg i.v.), but not by its enantiomer D-arginine (100 mg/kg i.v.). L-NAME (10 mg/kg i.v.) increased blood pressure but this does not seem to be the mechanism by which endotoxin-induced acid inhibition was prevented, since similar systemic pressor responses induced by noradrenaline (15 micrograms/kg per min i.v.) had no such effect. The platelet-activating factor (PAF) receptor antagonist, WEB 2086 (2 mg/kg), induced a partial reversal of the inhibition by endotoxin of acid responses to pentagastrin. In endotoxin-treated rats, the combined administration of L-NAME (10 mg/kg) and WEB 2086 (2 mg/kg) completely restored the degree of H+ output induced by pentagastrin to levels similar to those of control, vehicle-treated animals. These findings suggest that endotoxin-induced acute inhibition of acid responses to pentagastrin involves NO synthesis and the release of PAF.     

Beneficial attenuating effect of L-threo-3,4-dihydroxyphenylserine on postural hypotension in anesthetized rats

The effects of L-threo-DOPS (L-threo-3,4-dihydroxyphenylserine), a non-physiologic precursor amino acid of the natural form of norepinephrine, on postural hypotension were assessed in anesthetized rats. Rats were pretreated with DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine), a norepinephrine-decreasing agent acting on central and peripheral tissues, or hexamethonium, a ganglion-blocking agent. Postural hypotension was induced by 60 degrees head-up tilt for 4 min. L-Threo-DOPS (1-10 mg/kg, i.v.) produced an increase in basal blood pressure and attenuation of the postural hypotension, which persisted in a dose-related manner in rats pretreated with DSP-4 (50 mg/kg, i.p. 24 h prior to the tilt-experiment). Hexamethonium (5 mg/kg, i.v.)-induced postural hypotension was also attenuated dose-dependently by i.p. (3-30 mg/kg)- or p.o. (30 and 100 mg/kg)-administered L-threo-DOPS, associated with an increase in basal blood pressure. Neither attenuation of postural hypotension nor increase in basal blood pressure was observed after L-threo-DOPS (30 mg/kg i.p.) in rats pre-injected with carbidopa (20 mg/kg i.v.), a peripheral aromatic L-amino acid decarboxylase inhibitor, under the hexamethonium pretreatment. The effects of L-threo-DOPS administered by cumulative i.v. infusion (12.5-50 micrograms/kg/min) on the pressor responses to either spinal sympathetic nerve stimulation (1-10 Hz) or i.v. bolus-injected tyramine were also examined. L-Threo-DOPS dose-relatedly potentiated the pressor response to nerve stimulation in rats either untreated or pretreated with DSP-4 and the pressor response to tyramine in rats pretreated with DSP-4.(ABSTRACT TRUNCATED AT 250 WORDS)     

STUDIES ON THE SPECIFICITY OF THE INHIBITORY ACTION OF N,N-DIISOPROPYL-N''-ISOAMYL-N''-DIETHYLAMINOETHYLUREA (P-286) ON ADRENAL CATECHOLAMINE RELEASE IN THE ANAESTHETIZED RAT

1. The ability of P-286 (N,N-diisopropyl-N'-isoamyl-N'-diethylaminoethylurea) to reduce selectively the release of catecholamines from the adrenal medulla has been studied in urethane-anaesthetized rats. 2. Pressor responses to acetylcholine (Ach) and the nicotinic receptor-agonist 1,4-dimethylphenylpiperazine (DMPP) in rats treated with atropine, (+/-)-propranolol and guanethidine were used as the index of adrenal catecholamine release. 3. The injection of P-286 (1-10 mg/kg, i.v.) elicited a dose-dependent bradycardia which was associated with hypotension. P-286 reduced pressor responses to Ach and DMPP in a dose-dependent manner with an IC50 of 2.5 mg/kg and, following near complete blockade, pressor responses to DMPP returned to 50% of control after 90 min. 4. In non-atropinized rats, P-286 (30 mg/kg, i.v.) was without effect on the bradycardic responses elicited by stimulation of the right vagus nerve at frequencies of 5-40 Hz while pressor responses to DMPP in bilaterally adrenalectomized, non-guanethidine treated rats were reduced by approximately 50% after P-286 (10 mg/kg, i.v.). 5. The latter effect of P-286 on responses to DMPP in adrenalectomized rats cannot be attributed to ganglionic blockade since in rats with intact adrenals P-286 (10 mg/kg, i.v.) also reduced pressor responses to i.v. adrenaline and i.v. angiotensin II by approximately 50%. Thus the reduction in response to DMPP in adrenalectomized rats and to the non-nicotinic agonists may be a reflection of an action on the mechanism of contraction of vascular smooth muscle; that is, at a post-receptor event. 6. The results of the study show that P-286 selectively reduces adrenal catecholamine release at doses which do not affect autonomic ganglia. Its usefulness as a tool in cardiovascular research, however, may be limited by an action of vascular smooth muscle.     

Pharmacological analysis of the mode of action of mandelamidine with sustained antihypertensive effect. (II). Mechanism of transient hypotensive action of mandelamidine]

The mode of a transient hypotensive action of dl-Mandelamidine (MA) was studied in both anesthetized and unanesthetized animals. In the blood pressure of unanesthetized rats, a transient hypotensive action of MA (1 approximately 30 mg/kg i.v.) like papaverine (1 approximately 10 mg/kg i.v.) was much less predominant than in rats anesthetized with urethane (1.5 g/kg s.c.). The transient hypotensive action of MA (10 mg/kg i.v.) in rats anesthetized with urethane (1.5 g/kg s.c.) was not reduced when MA was injected continuously. Moreover C6 (5 mg/kg i.v.), propranolol (1 mg/kg i.v.), diphenhydramine (10 mg/kg i.v.) and atropine (2 mg/kg i.v.) did not block this transient hypotensive action. MA blocked the pressor action of epinephrine (3 mug/kg i.v.) in three minutes, but then potentiated it. MA (10 mug/kg i.a. approximately 1 mg/kg i.a.) caused a temporary vasodilation on the perfused leg artery and vertebral artery in dogs anesthetized with sodium pentobarbital (30 mg/kg i.v.). In the perfused leg artery, atropine (2 mg/kg i.v.) and propranolol (1 mg/kg i.v.) did not block the vasodilation of MA, and MA showed no marked blocking effect of the vasoconstriction of norepinephrine (0.2 mug/kg i.a.). In the dog heart-lung preparation and the guinea-pig heart, MA showed inhibiting effects. On the contraction of the cat nictitating membrane elicited by the stimulation of the postganglionic cervical sympathetic nerve, the blocking action of MA (1 mug/kg i.a. approximately 1 mg/kg i.a.) was much less predominant than that of phentolamine (10 mug/kg i.a.). In the rabbit descending aorta, MA (3 X 10(-4) g/ml) antagonized non-competitively the contraction elicited by norepinephrine. These findings suggest that a transient hypotensive action of MA depends upon the inhibiting effects on the cardiovascular system, and the adrenergic alpha-blocking effect of MA may be very weak.     

Quipazine-induced hypertension in anaesthetized cats is mediated by central and peripheral 5-HT2 receptors: role of the ventrolateral pressor area.

Quipazine (0.5 mg/kg i.v.) produced a sustained pressor response and an increase in splanchnic nerve activity in intact as well as in baroreceptor-denervated cats without causing a significant change in heart rate. These effects were prevented by the 5-HT2 receptor antagonists, ritanserin (0.5 mg/kg i.v.) or BW 501 C (0.5 mg/kg i.v.). Quipazine induced an hypertensive response and an increase in splanchnic discharge in cats pretreated with prazosin (0.1 mg/kg) or hexamethonium (10 mg/kg i.v.). Bilateral application of quipazine (25 micrograms/side) to the ventrolateral pressor area produced a rapid increase in mean blood pressure and in splanchnic discharge. Pretreatment with prazosin (0.1 mg/kg i.v.) abolished the hypertension but not the sympatho-excitatory effects of quipazine. Local application of the 5-HT2 receptor antagonists, LY53857 (10 micrograms/side) or cyproheptadine (10 micrograms/side), had no effects on blood pressure and splanchnic nerve activity but prevented or reversed the actions of locally applied quipazine. LY 53857 (10 micrograms/side) antagonized the sympatho-excitatory effects of systemically administered quipazine. These results indicate that the cardiovascular changes induced by quipazine in anaesthetized cats are mediated by central 5-HT2 receptors located in the ventrolateral pressor area and by peripheral vascular 5-HT2 receptors.     

ATTENUATION OF PRESSOR RESPONSES TO SYMPATHETIC STIMULI IN THE RAT BY ENALAPRIL

Intravenous administration to pithed Wistar rats of the angiotensin converting enzyme inhibitor enalapril (0.1-1.0 mg/kg) lowered the diastolic blood pressure and reduced pressor responses occurring during electrical stimulation (1-30 Hz) of the spinal sympathetic outflow. These doses of enalapril given intravenously also attenuated pressor responses to intravenous injection of the muscarinic ganglion stimulant McNeil-A-343 (50, 100, 150 micrograms/kg) and noradrenaline (0.1-5.0 micrograms/kg). Enalapril (1.0 mg/kg, i.v.) reduced pressor responses to the nicotinic ganglion stimulant 1,1-dimethyl-4-phenyl-piperazinium (300 micrograms/kg, i.v.). These results confirmed that the actions of enalapril resemble those of captopril in the pithed rat, by causing reductions in both blood pressure and pressor responses to sympathetic stimuli.     

Central autonomic effects of prostaglandin F2α on the cardiovascular system of the dog

1. Prostaglandin F(2alpha) infused into the vertebral artery of the anaesthetized greyhound in doses which had no effect when given intravenously ((8-64 ng/kg)/min) caused an increase in blood pressure and heart rate.2. This response was not significantly altered by beta-adrenoceptor blockade with propranolol (10 mg i.v.) or by cervical cord section at C(4-6).3. The tachycardia was abolished and the pressor response greatly reduced by vagotomy or atropine (250 mug/kg i.v.).4. The pressor response which remained after vagotomy was abolished by subsequent sympathetic blockade with bethanidine (2-3 mg/kg i.v.) or bretylium (10 mg/kg i.v.).5. In contrast to the effects of propranolol or cervical cord section bethanidine (4-5 mg/kg i.v.) or bretylium (10 mg/kg i.v.) significantly reduced blood pressure and heart rate responses to intravertebral prostaglandin F(2alpha). This result suggests that bethanidine and bretylium have some central actions.6. It is concluded that the cardiovascular effects of intravertebral infusions of prostaglandin F(2alpha) are mediated by the autonomic nervous system and that the preferential pathway is withdrawal of vagal tone to the heart.     

The central pressor actions of a novel tachykinin peptide, gamma-preprotachykinin-(72-92)-peptide amide.

Intracerebroventricular (i.c.v.) injections of a novel tachykinin peptide, gamma-preprotachykinin-(72-92)-peptide amide (neuropeptide gamma, NP gamma), caused dose-dependent increases in blood pressure. The NP gamma-induced pressor responses (1 microgram i.c.v.) were blocked by peripheral administration of pentolinium (10 mg/kg i.v.) and phentolamine (10 mg/kg i.v.), but were not inhibited by a vasopressin antagonist. These results suggest that central NP gamma increases the blood pressure via sympathetic nerve activity.     

Inhibition of angiotensin converting enzyme by SQ 14,225 in conscious rabbits.

The cardiovascular pharmacology of SQ 14,225 (D-3-mercapto-2-methylpropanoyl-L-proline), a new orally effective inhibitor of angiotensin-coverting enzyme (ACE) was investigated in conscious normotensive rabbits. Intravenous administration of SQ 14,225 (3.1-310.0 microgram/kg) resulted in a dose related inhibition of the pressor responses to 310 ng/kg, i.v. of angiotensin I (AI) without diminishing the pressor responses to 100 ng/kg, i.v. of angiotensin II (AII). In fact, the responsiveness of the rabbits to AII was significantly enhanced by higher doses of SQ 14,225. This enhancement of the pressor effects of AII was found to be related to the inhibition of ACE and the resulting decrease in the levels of endogenous AII. In addition, SQ 14,225 (1.0 mg/kg, i.v.) markedly potentiated the magnitude and duration of the vasodepressor responses elicited by bradykinin (1.0 microgram/kg. i.v.). At a dose of 1.0 mg/kg. i.v., SQ 14,225 had no effect on the vasodepressor effects of intravenously administered isoproterenol (0.4 microgram/kg), acetylcholine (1.0 microgram/kg) or prostaglandin E2 (3.0 microgram/kg, i.v.). The pressor responses to norepinephrine (3.0 microgram/kg, i.v.) were similarly unaffected by SQ 14,225 (1.0 mg/kg, i.v.). In normal rabbits SW 14,225 (1.0 mg/kg, i.v.) caused a small but significant decrease in arterial pressure; it had no such effect in anephric rabbits. The observation of this study indicate that SQ, 14,225 is a specific inhibitor of ACE in conscious rabbits.     

Capsaicin-sensitive afferents in the rat urinary bladder activate a spinal sympathetic cardiovascular reflex

Summary In urethane-anesthetized rats with an intact spinal cord, application of capsaicin on the outer surface of the urinary bladder produced a transient bradycardia, hypotension and negative cardiac inotropism which were neither prevented by i. v. atropine (0.5 mg/kg) nor by cervical vagotomy. In acute spinal rats (C2-C3) application of capsaicin (0.2 and 2 pg in 25 pl) on the urinary bladder induced a transient hypertension, tachycardia and positive cardiac inotropism. A second application (30 min later) induced minor cardiovascular effects, expecially with the higher dose, indicating desensitization. All cardiovascular responses to topical capsaicin were abolished by systemic capsaicin desensitization (50 mg/kg s. c., 4 days before). The excitatory cardiovascular response to capsaicin in acute spinal rats was markedly reduced by bilateral section of pelvic but not hypogastric nerves. Further, it was abolished by pretreatment with hexamethonium (20 mg/kg i.v.) or reserpine (5 mg/kg i. p., 2 days before) and reduced, at various extent for the different components, by phentolamine (0.5 mg/kg i. v.) or propranolol (1 mg/kg). In rats with pelvic and hypogastric nerves intact, section of the cord at a level (T12-L1), just above the medullary segments which receive primary afferent input from the bladder (L6-S1), abolished the excitatory cardiovascular response to application of capsaicin on the bladder. In spinal rats (C2-C3) rapid distension of the urinary bladder with saline produced transient tachycardia, hypertension and positive cardiac inotropism similar to that evoked by capsaicin. These responses were not observed in rats systemically pretreated with capsaicin. These findings indicate that certain bladder afferents which are susceptible to capsaicin desensitization in adult rats activate a spinal reflex having excitatory influence on cardiovascular function. This response is apparently mediated by spinal centers located above the site of entry of bladder pelvic afferents into the cord and most likely involves excitation of preganglionic sympathetic neurons in the spinal cord.Send offprint requests to S. Giuliani at the above address     

Involvement of 5-hydroxytryptamine in the central control of respiration, blood pressure and heart rate in the anaesthetized rat.

5-Hydroxytryptamine (5-HT, 1 ng-25 μg) injected into the cerebral ventricles of urethananaesthetized rats produced a rise in blood pressure, a biphasic change in heart rate and a decrease in ventilation. Responses were largest after injections into the 3rd ventricle. Lateral ventricle injections produced smaller responses while 4th ventricle injections produced the least response. The cardiovascular responses were prevented or reduced by prior intraventricular injection of bromolysergic acid diethylamide. The pressor response was not blocked by hexamethonium (10 mg/kg i.v.) and was only partly reduced by pretreatment with either 6-hydroxydopamine (3 × 100 mg/kg i.v.) or atropine methonitrate (10 mg/kg i.v.). The pressor response was prevented by spinal transection at C1 or C3 but only slightly reduced by transection at C5 or C7. In animals curarized and artificially respired with air, the blood pressure response was reduced. It is conjectured that the rise in blood pressure may involve a direct effect of hypoxia or hypercapnia resulting from a decrease in respiratory activity which is in turn mediated by a direct action of 5-HT on structures lining the 3rd ventricles. There appears to be little or no involvement of the autonomic nervous system in the response. The fall in heart rate is mediated sympathetically.     

STUDIES ON THE MECHANISM OF ACTION OF THE HYPOTENSIVE EFFECT OF KETANSERIN

Ketanserin, 0.01-3.0 mg/kg i.v., was found to cause a dose-related fall in blood pressure in anaesthetized rats. However, these decreases were only significant after 1 and 3 mg/kg doses. Subsequent administration of prazosin, 0.2 mg/kg i.v., had no significant effect on blood pressure. In the presence of ketanserin 3 mg/kg, plus prazosin 0.2 mg/kg, adenosine caused a significant dose-dependent fall in blood pressure in anaesthetized rats. Methysergide, 1 mg/kg i.v., significantly attenuated the blood pressure responses to serotonin in anaesthetized rats whereas ketanserin (1 and 3 mg/kg) had no overall effect on serotonin responses. Ketanserin, 1 and 3 mg/kg i.v., was found to antagonize the pressor effects of phenylephrine and reverse the pressor effects of adrenaline in anaesthetized rats. Responses to angiotensin II were not significantly affected by ketanserin. These results suggest that ketanserin lowers blood pressure in anaesthetized rats by blockade of alpha-adrenoceptors.     

Prolonged effects of p-chlorophenylalanine on the blood pressure of conscious normotensive and DOCA/saline hypertensive rats.

1. In deoxycorticosterone acetate (DOCA) saline hypertensive rats a single dose of p-chlorophenylalanine methylester (PCPAME) (400 mg/kg i.p.) produced a significant fall in blood pressure (20-43 mmHg) which lasted for at least 8 days and was accompanied by a parallel depletion of brain stem 5-hydroxytryptamine (5-ht) but not of noradrenaline (NA). 2. In normotensive rats single doses of PCPAME (200 and 400 mg/kg i.p.) produced a significant hypotension (15-20 mmHg) after a latent period of 5 days. An initial pressor response (12 mmHg) was observed at the higher dose level only on day 3. 3. The hypotensive response to PCPAME (200 mg/kg i.p.) in normotensive rats was not modified by pretreatment with 5,6-dihydroxytryptamine (5,6-DHT; 50 mug i.c.v.) or 6-hydroxydopa (6-ohda; 3 X 250 mug intracerebroventricularly). 4. It is concluded that the hypotensive response to PCPAME in normotensive rats in independent of brain stem depletion of 5-HT and is probably not mediated by the formation of a false transmitter substance acting via central noradrenergic inhibitory pathways. The mechanism involved in the antihypertensive response to PCPAME in DOVA/saline hypertensive rats has yet to be defined.     

Pharmacological alterations of vagally induced tachycardia in anesthetized dogs

Frequency-dependent tachycardia was obtained during vagal stimulation in anesnthetized, atropine-treated (1 mg/kg, i.v.) dogs. Vagally induced tachycardia was enhanced in both magnitude and duration by desipramine, whereas the magntide of tachycardia in response to cardioaccelerator nerve stimulation was not markedly enhanced. Vagal tachycardia was not inhibited by guanethidine (1 mg/kg, i.v.) but was markedly reduced after ganglion blockade by chlorisondamine (2 mg/kg, i.v.) or hexamethionium (10 mg/kg, i.v.). β-Receptor blockade by 1-oxprenolol (0.25 mg/kg, i.v.) totally blockade the response. Reserpine pretreatment decreased cardiac responses to sympathetic nerve stimulation to a greater degree than to vagal stimulation. From these results, it is suggested that the vagally induced tachycardia may be explained by acetylcholine (Ach)-mediated release of catecholamine from stores other than those susceptible to sympathetic nerve stimulation and these stores may reside in chromaffin tissue.     

KT3-671, an angiotensin AT1 receptor antagonist, attenuates vascular but not cardiac responses to sympathetic nerve stimulation in pithed rats

Effects of KT3-671 on vascular and cardiac sympathetic neurotransmission were investigated in pithed rats. The pressor response to spinal stimulation (5 Hz) of the pithed rat without the adrenals was approximately 75% of that with the adrenals. Guanethidine (8 mg/kg, i.v.) decreased by about 76% the pressor response to sympathetic stimulation in the pithed rat with intact adrenals and the guanethidine-resistant response was almost completely abolished by bilateral adrenalectomy. Therefore, the following experiments were done using the pithed rat without the adrenals. KT3-671 (1-10 mg/kg, i.v.) as well as losartan (1-10 mg/kg, i.v.) inhibited dose-dependently the pressor response to sympathetic stimulation. KT3-671 was approximately four times more potent than losartan in inhibiting the pressor response. The two angiotensin II subtype 1 receptor antagonists (10 mg/kg, i.v.) did not affect the pressor response to exogenously administered norepinephrine. Neither KT3-671 nor losartan influenced the tachycardia induced by spinal stimulation and isoprenaline. Intravenous infusion of angiotensin II (100 ng/kg/min) did not affect both pressor and tachycardic responses to sympathetic stimulation. In conclusion, KT3-671 as well as losartan inhibits vascular but not cardiac sympathetic neurotransmission of the pithed rats, which may contribute to its overall antihypertensive efficacy.     

Noradrenaline contracts rat retinal arterioles via stimulation of α(1A)- and α(1D)-adrenoceptors

The aim of this study was to characterize the α?-adrenoceptor subtype(s) involved in the noradrenaline-induced contraction of retinal arterioles in rats. In vivo ocular fundus images were captured with a digital camera equipped with a special objective lens. By measuring changes in diameter of retinal arterioles in the fundus images, retinal vascular response was assessed. The systemic blood pressure and heart rate in the animals were also continuously recorded. Following blockade of β?/β?-adrenoceptors with propranolol, noradrenaline (0.03-3 μg/kg/min, i.v.) decreased the diameter of retinal arterioles and increased the mean blood pressure in a dose-dependent manner. The highest dose (3 μg/kg/min, i.v.) of noradrenaline caused a small increase in heart rate. The α(1A)-adrenoceptor antagonist RS100329 (0.1 mg/kg, i.v.) and the α(1D)-adrenoceptor antagonist BMY 7378 (1 mg/kg, i.v.) significantly prevented noradrenaline-induced contraction of retinal arterioles and pressor responses whereas the α(1B)-adrenoceptor antagonist L-765314 (1 mg/kg, i.v.) did not. The α(1A)-adrenoceptor agonist, A 61603 (0.03-0.3 μg/kg/min, i.v.), also caused contractile responses of retinal arterioles and pressor responses. These responses were almost completely prevented by RS100329 (0.1 mg/kg, i.v.), but not by BMY 7378 (1 mg/kg, i.v.). These results suggest that the contractile effects of noradrenaline on retinal arterioles and peripheral resistance vessels are, at least in part, mediated by stimulation of α(1A)- and α(1D)-adrenoceptors. Furthermore, it is likely that the α?-adrenoceptor subtype(s) involved in rat vascular responses are similar in both retinal and peripheral circulation.