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.     

The effect of cyclic AMP elevating agents on bradykinin- and carbachol-induced signal transduction in canine cultured tracheal smooth muscle cells.

1. The effects of the beta 2-adrenoceptor agonist, procaterol, on sympathetic neuroeffector transmission were studied in the pithed adrenal demedullated rat to determine if generation of angiotensin II was involved in its effect. Pressor responses were elicited by either electrical stimulation (20 V, 2 Hz) of the entire spinal sympathetic outflow or methoxamine (0.1 mg kg-1, i.v.). 2. Sodium nitroprusside (3 and 5 micrograms kg-1 min-1, i.v.) produced hypotension and the pressor responses to both sympathetic nerve stimulation and methoxamine were reduced. This indicates that decreasing blood pressure in pithed rats reduces pressor responses. Procaterol (10 and 30 ng kg-1 min-1, i.v.) also produced hypotension but did not alter pressor responses to sympathetic nerve stimulation. Nevertheless, procaterol (10 and 30 ng kg-1 min-1, i.v.) did reduce pressor responses to to methoxamine. Together these results suggest that procaterol may have enhanced sympathetic neurotransmitter release. This was confirmed in another series of experiments where procaterol (30 ng kg-1 min-1, i.v.) increased plasma noradrenaline levels during sympathetic nerve stimulation. 3. Captopril (5 mg kg-1, i.v.) produced hypotension and as expected reduced pressor responses to sympathetic nerve stimulation. When the hypotensive effect of captopril was abolished by concomitant vasopressin infusion (1.5-4.5 i mu kg-1 min-1, i.v.), pressor responses to sympathetic nerve stimulation were restored to pre-captopril levels. (ABSTRACT TRUNCATED AT 250 WORDS)     

Participation of angiotensin II in pressor response and norepinephrine release to spinal nerve stimulation in pithed rats

Experiments were carried out to examine whether endogenous angiotensin II (A-II) is involved in the regulation of release of norepinephrine (NE) elicited by the stimulation of spinal sympathetic nerves in pithed rats. It was assessed in terms of the alterations in concentrations of arterial blood plasma A-II and NE elicited by nerve stimulation (5 Hz, 50 V, 1 msec for 45 s) in pithed rats under vehicle or captopril (3 mg/kg, i.v.) treatment. Comparative study with pentobarbital anesthetized rats showed that pithing rats have the characteristics of lower basal blood pressure and lower NE level, whereas they have higher basal A-II level. In pithed rats treated with vehicle, pressor response to nerve stimulation was accompanied by increases in both A-II and NE level. In rats treated with captopril, the nerve stimulation caused about 40% lower increases in pressor response and NE level than those observed in rats treated with vehicle. These results suggest that the sympathetic nerve-induced NE release is facilitated by endogenous A-II in pithed rats, and that captopril exerts its inhibitory effect on the pressor response to nerve stimulation through the suppression of this interaction.     

Apparent vascular to cardiac sympatholytic selectivity of omega-conotoxin GVIA in the pithed rat

The effects of omega-conotoxin GVIA (omega-CTX), a blocker of N-type voltage-operated calcium channels (VOCCs), were investigated in the pithed rat, omega-CTX (1.6 and 3.2 micrograms/kg i.v.) did not alter resting diastolic pressure or heart rate nor the pressor and chronotropic responses to noradrenaline injections (0.1-10 micrograms/kg). In contrast, the pressor responses to electrical stimulation of the whole spinal cord (0.2-6.4 Hz) were dose dependently reduced by omega-CTX whereas the concomitant tachycardia was less affected. When selective stimulation of the cardiac sympathetic outflow was applied, the resulting chronotropic response was more sensitive to omega-CTX. This result is discussed in the light of the possible interference of adrenal catecholamine release during whole spinal cord stimulation which is not sensitive to omega-CTX. These results provide in vivo evidence that omega-CTX is able to reduce sympathetic neurotransmission to the vasculature and the heart, presumably by blocking N-type VOCCs on pre- and post-ganglionic nerve terminals.     

ATTENUATION BY CAPTOPRIL OF PRESSOR RESPONSES TO PERIPHERAL SYMPATHETIC NERVE STIMULATION IN RATS IS ABOLISHED AFTER BILATERAL NEPHRECTOMY AND DURING MINERALOCORTICOID HYPERTENSION

Intravenous administration of captopril (0.1-0.3 mg/kg) to normotensive pithed rats, with or without unilateral nephrectomy, was followed by a sustained fall in arterial blood pressure. Concomitantly pressor responses to electrical stimulation of the spinal sympathetic outflow (T11-L3), ganglion stimulation with McNeil-A-343 (4-(m-chlorophenylcarbamoyloxy)-2-butynyl-trimethylammonium chloride) or intravenous injection of noradrenaline were reduced. Attenuation by captopril (1 mg/kg) of pressor responses to McNeil-A-343 persisted after intravenous propranolol (1 mg/kg). Tachycardia caused by electrical stimulation of the spinal sympathetic nerves (C7-T2) was unchanged after 3.0 mg/kg captopril. After procedures reducing the activity of the renin angiotensin system, bilateral nephrectomy or induction of mineralocorticoid hypertension by unilateral nephrectomy and administration of desoxycorticosterone acetate, pressor responses to McNeil-A-343 or noradrenaline were unchanged after 1 mg/kg captopril. It is concluded that in the pithed rat, basal arterial blood pressure and the height of pressor responses to either postganglionic sympathetic nerve activation or intravenous noradrenaline depend on converting enzyme activity maintaining circulating angiotensin II levels.     

PRESYNAPTIC DOPAMINE RECEPTORS MEDIATE THE INHIBITORY ACTION OF DOPAMINE AGONISTS ON STIMULATION-EVOKED PRESSOR RESPONSES IN THE RAT

1 The effects of the dopamine agonists TL-99, M-7 (N, N-dimethyl analogues of aminotetralins) and N, N-din propyldopamine (NNPD) on stimulation-evoked pressor responses and tachycardia in pithed Sprague-Dawley rats were investigated when pressor responses to the compounds per se had subsided. Various antagonists were used to characterise the effects of the dopamine agonists. 2 M-7 (3 μg/kg i.v.) and NNPD (1 mg/kg i.v.), but not TL-99 (1–30 μg/kg i.v.), inhibited pressor responses evoked by low frequency electrical stimulation of the spinal cord in the pithed rat. 3 M-7 (3 μg/kg i.v.), but neither NNPD (1 mg/kg i.v.) nor TL-99 (1–30 μg/kg), inhibited tachycardia evoked by low frequency electrical stimulation of the spinal cord in the pithed rat. 4 The inhibition of stimulation-evoked pressor responses by M-7 and NNPD was prevented by pimozide, metoclopramide and sulpiride but not by yohimbine, atropine, cimetidine or propranolol. 5 The inhibition of stimulation-evoked tachycardia by M-7 was prevented by yohimbine (and to a certain extent by sulpiride) but not pimozide, metoclopramide, atropine or cimetidine. 6 Pressor responses elicited by TL-99, M-7 and NNPD were selectively antagonised by yohimbine, but not by prazosin, indicating that these responses were mediated by stimulation of vascular postsynaptic α₂-adrenoreceptors. 7 This study demonstrates that, in the rat, presynaptic dopamine receptors exist on sympathetic pre- or postganglionic nerve endings to blood vessels, but not on sympathetic pre- or postganglionic nerve endings to the heart, where inhibition by M-7 of stimulation-evoked tachycardia is mediated by stimulation of presynaptic α₂-adrenoreceptors.     

RESISTANCE OF SYMPATHETIC CARDIAC NERVE FUNCTION IN THE PITHED RAT TO PREJUNCTIONAL EFFECTS OF ANGIOTENSIN II

1. The spinal sympathetic outflow (C7-T2) of pithed male Wistar rats was electrically stimulated (30-50 V, 0.5 ms, 0.1-1.0 Hz) and heart rate and arterial blood pressure were recorded. D-Tubocurarine (1 mg/kg) and atropine (1 mg/kg) were administered intravenously (i.v.) to reduce voluntary and parasympathetic nerve activity. 2. Angiotensin II (0.39-3.4 micrograms/kg per min) was infused at a rate which caused a sustained rise in diastolic blood pressure of at least 25 mmHg but which did not alter basal heart rate. 3. Chronotropic responses to sympathetic nerve stimulation were not affected by infusion of angiotensin II, and were also unaltered by pretreatment of rats with indomethacin (5 mg/kg, i.v.) 10 min prior to commencement of stimulation. 4. These results suggest that positive chronotropic responses to cardiac sympathetic nerve stimulation in pithed rats are not affected by increased angiotensin II levels. Indomethacin had no effect, which indicates that cyclo-oxygenase products were not involved in modulation of chronotropic responses to cardiac sympathetic nerve stimulation.     

D-myo-inositol-1,2,6-trisphosphate is a selective antagonist of neuropeptide Y-induced pressor responses in the pithed rat.

The antagonistic effects of a new inositol phosphate derivative, D-myoinositol-1,2,6-trisphosphate (PP56), on pressor responses to preganglionic sympathetic nerve stimulation and exogenously administered phenylephrine or neuropeptide Y (NPY) were investigated in vivo in the pithed rat. In this model an intravenous (i.v.) bolus administration of PP56 (1-50 mg/kg) dose dependently inhibited the increase in mean arterial blood pressure (MAP) induced by a continuous infusion of NPY (2 micrograms/kg per min for 10 min). PP56 in a dose of 5 mg/kg i.v. bolus reduced the entire NPY dose-response curve (0.4-8 microgram/kg per min 10 min infusion) without any shift to the right indicating a non-competitive interaction. Furthermore, PP56 (10-50 mg/kg i.v.) was found to inhibit the pressor response to preganglionic sympathetic nerve stimulation and i.v. bolus injection of the alpha 1-adrenoceptor agonist, phenylephrine. The dose-response curves for increasing doses of phenylephrine and incremental preganglionic sympathetic nerve stimulation were not significantly altered by a lower dose of PP56 (5 mg/kg i.v. bolus). We conclude that PP56, representing a new class of synthetic drugs, can antagonize the actions of exogenous and endogenous NPY in vivo, an action which is specific for NPY within a limited dose range.     

Inhibitory effect of KT3-671, a non-peptide angiotensin subtype 1 receptor antagonist, on sympathetic neurotransmission in isolated rabbit aorta.

Effect of KT3-671 on the sympathetic neurotransmission in isolated rabbit aorta was studied and compared with those of losartan and its active metabolite, EXP3174. Angiotensin (Ang) II (30 n m) produced approximately 1.7-fold increase in the transmural nerve stimulation (TNS)-evoked tritium overflow in the aorta preloaded with [(3)H]noradrenaline. KT3-671 (1 microm) by itself did not alter the TNS-evoked tritium overflow but it (0.1-1 microm) concentration-dependently inhibited the enhancing effect of Ang II on the TNS-evoked tritium overflow. Both losartan (1 and 3 microm) and EXP3174 (0.03-0.3 microm) also inhibited the Ang II effect. KT3-671 was approximately 8.6 and 0.3 times more potent than losartan and EXP3174, respectively, in inhibiting the Ang II response. This is consistent with the previous results showing the relative potency of the three antagonists to block AT(1)receptors. None of Ang II, KT3-671, losartan and EXP3174 affected significantly the spontaneous tritium outflow. These results suggest that KT3-671 as well as losartan and EXP3174 may inhibit vascular sympathetic neurotransmission by blocking presynaptic Ang II subtype 1 receptors, which appears to contribute partly to its antihypertensive action. 2000 Academic Press@p$hr Copyright 2000 Academic Press.     

Effects of systemic treatment with irbesartan and losartan on central responses to angiotensin II in conscious, normotensive rats

Angiotensin AT1 receptor antagonists represent a novel class of cardiovascular drugs. In conscious, normotensive rats, irbesartan ((2-n-butyl-3-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl) methyl]-1,3-diaza-spiro[4,4]non) and losartan ((2 n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl -4-yl) methyl] imidazol), two specific, high- affinity angiotensin AT1 receptor antagonists administered intravenously (i.v.) at doses of 0.3, 1, 3 and 10 mg/kg body weight, or orally (p.o.) at doses of 1, 3, 10 and 30 mg/kg body weight, antagonized the pressor responses to i.v. angiotensin II (50 ng/kg body weight) in a dose-related manner and with similar potency. In the following sets of experiments, we tested the hypothesis that these angiotensin AT1 receptor antagonists, when applied systemically, can inhibit the effects of angiotensin AT1 receptor stimulation in the brain. Irbesartan and losartan were administered i.v. or p.o. at doses of 3, 10, 30 and 100 mg/kg body weight. The responses to 100 ng angiotensin II injected into the lateral brain ventricle (i.c.v.), namely blood pressure increase, vasopressin release into the circulation and drinking, were recorded for up to 3 h. While both angiotensin AT1 receptor antagonists dose-dependently attenuated the pressor responses to central angiotensin AT1 receptor stimulation to a similar degree (maximal inhibition, irbesartan: 62% i.v., 39% p.o.; losartan: 62% i.v., 46% p.o.; respectively), irbesartan was more effective with respect to the inhibition of vasopressin release (76% i.v., 65% p.o.) and drinking (63% i.v., 79% p.o.) than losartan (58% i.v., 33% p.o and 22% i.v., 56% p.o., respectively). We conclude that systemically administered angiotensin AT1 receptor antagonists have access to central angiotensin receptors. The degree of central angiotensin AT1 receptor blockade following peripheral application may vary between different representatives of this class of drugs.     

(+)-Nantenine isolated from Nandina domestica Thunb. inhibits adrenergic pressor responses in pithed rats

The effects of (+)-nantenine on various pressor responses, recently reported exerting competitive antagonistic activity at the alpha1-adrenoceptor/5-hydroxytryptamine (5-HT)2A receptor, were examined in vivo. (+)-Nantenine (0.03-3 mg/kg) caused a dose-dependent inhibition of the pressor response to phenylephrine (alpha1-adrenoceptor agonist) or 5-HT (5-HT receptor agonist) in both anesthetized and pithed rats. The pressor response to UK 14304 (5-Bromo-N-[2-imidazolin-2-yl]-6-quinoxalinamine) (an alpha2-adrenoceptor agonist) was inhibited by (+)-nantenine (0.003-3 mg/kg) in pithed rats in a dose-dependent manner without affecting the angiotensin II-induced pressor response in anesthetized rats. The pressor response to sympathetic nerve stimulation was also inhibited by (+)-nantenine (0.3-3 mg/kg) in a dose-dependent manner. (+)-Nantenine (3 mg/kg) facilitated the norepinephrine release induced by sympathetic nerve stimulation in pithed rats. In the guinea pig vas deferens, the initial component of contractions induced by electrical field stimulation was enhanced by (+)-nantenine (1-30 microM) in a concentration-dependent manner, while the later component was inhibited by it. These data suggest that (+)-nantenine has antagonistic activities on alpha1-adrenoceptors, alpha2-adrenoceptors and 5-HT2A receptors in pithed rats.     

Antihypertensive action of a non-sulfhydryl angiotensin converting enzyme inhibitor (CV-3317) in various hypertensive models

The antihypertensive action of N-[N-[(S)-1-ethoxycarbonyl-3-phenyl-propyl]-L-alanyl]-N-(indan-2-yl) glycine hydrochloride (CV-3317), a nonsulfhydryl compound characterized as an angiotensin converting enzyme inhibitor in our previous work, was examined in hypertensive animal models. In 2-kidney, 1 clip hypertensive rats and dogs, CV-3317 (3 and/or 10 mg/kg, p.o.) produced a sustained antihypertensive action of about 15 to 25 mmHg. Daily oral administrations of CV-3317 (1 to 10 mg/kg/day) to spontaneously hypertensive rats (SHR) for 5 weeks produced a sustained antihypertensive action of 20 to 40 mmHg. When CV-3317 (3 mg/kg) was combined with hydrochlorothiazide (10 mg/kg), its antihypertensive action was intensified in potency and duration. CV-3317 (30 mg/kg) induced a slight hypotension (5 to 10 mmHg) in normotensive rats, but had no effect on the blood pressure of 1-kidney, 1 clip hypertensive rats and on that of a low renin type of DOCA/salt hypertensive rat. The antihypertensive activity of CV-3317 was more potent than that of captopril. In pithed SHR, the pressor response induced by an electrical stimulation of the preganglionic sympathetic nerve, but not the pressor response to norepinephrine, was attenuated by both agents (0.3 mg/kg, i.v.). Both agents may exert their antihypertensive action not only primarily by inhibiting the renin-angiotensin system, but also by inhibiting norepinephrine release from the sympathetic nerve terminals indirectly by reducing the formation of vascular angiotensin II.     

INHIBITION OF SYMPATHETIC NEUROTRANSMISSION BY THE OPIOID δ-RECEPTOR AGONIST DAMA IN THE PITHED RAT

1. The effects of [D-Ala2,Met5]enkephalinamide (DAMA), an analogue of [Met5]-enkephalin that acts selectively on opioid receptors of the delta-subtype, were studied on pressor responses elicited by sympathetic stimulation in pithed rats. 2. Intravenous injections of bolus doses of 0.1 mg/kg and 0.3 mg/kg of DAMA did not affect either the basal blood pressure or pressor responses to noradrenaline. 3. Pressor responses elicited either by electrical stimulation of the spinal sympathetic outflow or by stimulation of sympathetic ganglion cells with the muscarinic agonist McN-A-343 were reduced by DAMA. 4. Naloxone (1 mg/kg + 0.5 mg/kg per h) had no significant effect on the basal blood pressure or on pressor responses to spinal sympathetic stimulation, but antagonised the inhibitory effect of DAMA. 5. These results indicate that activation of opioid delta-receptors on sympathetic vasomotor nerve terminals can inhibit noradrenergic neurotransmission.     

Selective inhibition of angiotensin pressor responses in the pithed rat by tetraethylthiuram disulphide (disulfiram) and sodium diethyldithiocarbamate (DDC)

1. Pressor responses to sympathetic outflow stimulation, noradrenaline and angiotensin have been recorded in pithed rats.2. Disulfiram (50 mg/kg) and sodium diethyldithiocarbamate (DDC) (5-100 mg/kg) both caused an initial increase in the pressor response to all three procedures followed by a selective inhibition of the angiotensin responses.3. Penicillamine (1-100 mg/kg) and ascorbic acid (1-500 mg/kg) increased the pressor responses to all three procedures without any subsequent blocking action.4. Reserpine (5 mg/kg daily for 3 days) abolished responses to sympathetic outflow stimulation but did not impair angiotensin or noradrenaline responses.5. In reserpinized rats, the initial enhancement of angiotensin responses after disulfiram and sodium diethyldithiocarbamate was absent or reduced and the onset of the subsequent block was accelerated.6. Possible mechanisms for the angiotensin-blocking action of disulfiram and sodium diethyldithiocarbamate are discussed.     

EFFECTS OF THE α2-ADRENOCEPTOR AGONIST UK14304 ON PRESSOR RESPONSES IN PITHED RATS

1. Intravenous infusions of UK14304 (0.3-10 micrograms/kg per min) in pithed rat produced dose-dependent pressor responses which were not affected by prazosin (10 micrograms/kg) but were reduced by yohimbine (0.3 mg/kg). 2. Pressor responses to noradrenaline (0.1 micrograms/kg), phenylephrine (1 micrograms/kg) and vasopressin (10 mU/kg) were enhanced during infusions of UK14304 (0.03-1 micrograms/kg per min). Likewise, pressor responses to spinal sympathetic stimulation were enhanced during infusions of low concentrations of UK14304 (0.03-0.3 microgram/kg per min) but were reduced during infusion of a higher concentration of UK14304 (10 micrograms/kg per min). 3. After administration of yohimbine (0.3 mg/kg) or the calcium channel blocking drug diltiazem (infused at 50 micrograms/kg per min), pressor responses to noradrenaline and UK14304 were reduced, and responses to noradrenaline during infusion of UK14304 were not enhanced. 4. Prazosin (10 micrograms/kg) revealed a secondary depressor component in the response to sympathetic stimulation which is due to beta-adrenoceptor activation, since it was abolished by ICI 118551 (0.3 mg/kg). In the presence of ICI 118551 plus prazosin, pressor responses to sympathetic stimulation were enhanced during infusions of UK14304. 5. The depressor response to nitroprusside and the depressor component of responses to sympathetic stimulation after prazosin were enhanced during infusions of UK14304 at concentrations that increased the blood pressure. 6. The findings show that alpha 2-adrenoceptor activation enhanced the pressor responses to sympathetic nerve stimulation, noradrenaline, phenylephrine and vasopressin in the pithed rat and beta-adrenoceptor activation produced depressor responses which increased with increasing blood pressure.     

Enkephalinase 'A' inhibition by thiorphan: central and peripheral cardiovascular effects

On the basis of the distribution of enkephalins within the central and peripheral nervous systems as well as on responses to their administration, it has been suggested that these peptides participate in the regulation of the circulation. The present series of experiments examined the effects of thiorphan, an inhibitor of enkephalinase A, on cardiovascular responses to intracerebroventricular (i.c.v.) administration of [D-Ala2,Met5]enkephalin (DAME) and its amide and on peripheral interactions with the sympathetic nervous system and vasoactive peptides. Thiorphan (30 micrograms i.c.v.) potentiated the pressor response to i.c.v. DAME and DAMEamide in conscious spontaneously hypertensive rats. Responses to i.c.v. angiotensin I (AI) were unaffected suggesting lack of inhibition of central angiotensin converting enzyme (ACE). Peripheral administration of relatively large doses of thiorphan (30 and 100 mg/kg s.c.) attenuated the pressor response to i.v. AI by 30-40% and enhanced the depressor effect of i.v. bradykinin in anesthetized normotensive rats indicating inhibition of peripheral ACE. Pressor and tachycardic responses to activation of spinal sympathetic outflow were not altered by thiorphan in pithed normotensive rats. Thiorphan itself did not affect baseline blood pressure or heart rate in any of these experiments. In conclusion, inhibition of central enkephalinase A by i.c.v. administration of thiorphan potentiates the pressor response to i.c.v. DAME. The compound inhibits peripheral ACE but has little direct cardiovascular activity in its own right.     

Milrinone inhibits sympathetic-mediated tachycardia by a postjunctional action independent of cyclic AMP.

In pithed rats with stimulated sympathetic outflow, the phosphodiesterase inhibitor milrinone (0.3 mg/kg, i.v.) decreased the peak tachycardiac response produced by both sympathetic nerve stimulation (15 s at 0.5-3 Hz) and norepinephrine administration (0.3-5 micrograms/kg, i.v.). However, another phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX, 0.5 mg/kg, i.v.) had no effect on the peak tachycardic response to sympathetic stimulation. Similarly, in isolated rat atria, milrinone (9 mumol/L) inhibited the tachycardia produced by norepinephrine, whereas IBMX (1 mumol/L) had no effect. The inhibitory effect of milrinone on sympathetic responses was not due to changes in norepinephrine release since milrinone (9 mumol/L) increased norepinephrine release in isolated rat atria incubated with [3H]norepinephrine. When the duration of the tachycardia (rather than the peak tachycardic response) produced by sympathetic nerve stimulation was measured, it was found to be prolonged by both milrinone and IBMX, suggesting that in this case cyclic AMP was involved. Furthermore, in contrast to its inhibitory effects on norepinephrine-induced tachycardia in rat atria, milrinone enhanced the tachycardia produced by the adenylate cyclase activator forskolin. These results suggest that milrinone has complex actions on sympathetic control of heart rate and that beta-adrenoceptor tachycardia occurs by mechanisms dependent on and independent of cyclic AMP.     

A facilitatory effect of anti-angiotensin drugs on vagal bradycardia in the pithed rat and guinea-pig.

1. In pithed rats, preganglionic vagal nerve stimulation (at 5 Hz) elicited a bradycardia. This bradycardia was potentiated by the angiotensin converting enzyme inhibitor, captopril (1 mg kg-1, i.v.) by about 40%. Subsequent angiotensin II infusion (0.03 micrograms kg-1 min-1) reversed this effect. A similar facilitatory effect was also seen with the angiotensin receptor antagonist, losartan (10 mg kg-1, i.v.). These results suggest a tonic inhibitory effect of endogenous angiotensin II on vagal transmission. 2. The effect of captopril in potentiating vagal bradycardia appears to be at the level of vagal neurones, since the bradycardia elicited by the muscarinic agonist, methacholine was unaffected. 3. After the pithed rats were nephrectomized, captopril had no effect on vagally-induced bradycardia, suggesting that the formation of the endogenous angiotensin II responsible for the effect was dependent on renin release from the kidney. 4. When the sympathetic nerves of the pithed rat were electrically stimulated there was a tachycardia, and this was unaffected by captopril. However, when the sympathetic and vagus nerves were activated concurrently, the resulting tachycardia was inhibited by captopril. 5. In pithed guinea-pigs, captopril also potentiated the bradycardia caused by vagal nerve stimulation. This appears to be a tissue-selective effect since the bronchoconstriction due to the vagal stimulation was not affected by captopril. 6. These results suggest that endogenous angiotensin II can have a tonic inhibitory effect on cardiac vagal transmission. Disruption of this mechanism by anti-angiotensin drugs may attenuate the reflex tachycardia associated with the fall in blood pressure in anti-hypertensive therapy.     

SELECTIVE STIMULATION OF VASCULAR POSTJUNCTIONAL α1-ADRENORECEPTORS BY (-)-AMIDEPHRINE IN RATS AND CATS

• 1 The vasopressor and chronotropic responses of (-)-amidephrine and the receptor types involved were studied in pithed rats of different strains and in pithed cats.
• 2 The increase in diastolic pressure of pithed rats after i.v. administration of (-)-amidephrine was not influenced by pretreatment with propranolol (1 mg/kg, i.v.), reserpine (2 times 5mg/kg in 48 h i.p.) or yohimbine (1 mg/kg, i.v.), but was strongly antagonized by prazosin (0.1 mg/kg, i.v.). In pithed cats, the pressor responses were antagonized by prazosin (1 mg/kg, i.v.) but much less so by yohimbine (1 mg/kg, i.v.).
• 3 (-)-Amidephrine elicited minor positive chronotropic responses in pithed rats and pithed cats. This tachycardia was not influenced by propranolol (1 mg/kg, i.v.) but was abolished by prazosin (0.1 – 1.0 mg/kg).
• 4 The results show that (-)-amidephrine acts as a selective agonist at vascular postjunctional α-adrenoreceptors in pithed rats and pithed cats. The positive chronotropic effects are attributable to stimulation of α-adrenoreceptors in the heart.

     

Chronic treatment of the spontaneously hypertensive rat with captopril attenuates responses to noradrenaline in vivo but not in vitro

Summary We have studied the attenuation by captopril of sympathetic neurotransmission in spontaneously hypertensive rats. Captopril (4 mg/kg for 15–17 days or 20 mg/kg for 4 days) was delivered i.v. by osmotic minipump. The higher dose lowered blood pressure, the lower dose did not. Both doses inhibited converting enzyme activity. In the pithed rat, both doses attenuated responses to exogenous noradrenaline and sympathetic nerve stimulation. In isolated tail arteries removed from captopril-treated rats, responses to sympathetic nerve stimulation and exogenous noradrenaline were the same as in controls. Perfusion of the tail artery of control rats with captopril, angiotensin I or angiotensin II had no effect on basal perfusion pressure or on vasoconstriction induced by exogenous noradrenaline or sympathetic nerve stimulation. Our results are consistent with the hypothesis that: 1. the attenuation of sympathetic neurotransmission by captopril depends upon the presence of an intact renin-angiotensin system, and 2. captopril has no direct postsynaptic effect in the isolated tail artery preparation. Send offprint requests to J. Atkinson at the above address