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).     

Depressed isoprenaline vascular response in endotoxic rats

The injection of a sublethal dose of E. coli endotoxin (0127 B8) to intact rats (2 mg/kg i.v.) or adrenalectomized rats (0.01 mg/kg i.v.) depressed hypotensive responses to isoprenaline (0.2, 0.4, 0.8 μg/kg i.v.) for at least 4 h following endotoxin injection. These findings evidence an early (under 1 h after administration) and long-lasting (over 4 h) depression of the vascular response to isoprenaline in endotoxic rats. This depression was not related to catecholamine adrenal discharge or to the hypotensive and lethal effects of endotoxin.     

Beta 2-adrenoceptors mediate adrenaline's facilitation of neurogenic vasoconstriction

Acute bilateral adrenal demedullation significantly reduced pressor responses in pithed spontaneously hypertensive rats. The subsequent infusion of adrenaline (50 ng/min i.v.) significantly enhanced neurogenic pressor responses without affecting those induced by noradrenaline. The adrenaline-induced enhancement of neurogenic pressor responses was unaffected by pretreatment with the beta 1-selective adrenoceptor antagonist atenolol (0.3 mg/kg i.v.), but was completely abolished by pretreatment with the beta 2-selective antagonist ICI 118551 (0.01 mg/kg i.v.). Pressor responses to noradrenaline remained unaltered.     

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.     

Pharmakologische Wirkungen von N,N-Di-isopropyl-N′-isoamyl-N′-diäthylaminoäthylharnstoff,einem Blocker des Nebennierenmarks

Zusammenfassung Untersuchungen über die Wirkungen des P-286 an verschiedenen Testobjekten haben zu folgenden Ergebnissen geführt:P-286 blockiert spezifisch das Nebennierenmark, und zwar in einer Dosierung (2,5–5,0 mg/kg), die auf vegetative Ganglien wirkungslos ist. Die Substanz schwächt die durch Splanchnicusreiz, Carotissinusentlastung, Asphyxie, zentralen Vagusreiz, DMPP und MBPO hervorgerufenen Blutdrucksteigerungen ab und hemmt die durch chemische oder nervöse Reize ausgelöste Freisetzung von Brenzcatechinaminen aus der Nebenniere.Auf das obere Halsganglion, die paravertebralen Ganglien und die parasympathischen Ganglien des N. pelvicus, der Chorda tympani und des Vagus übt P-286 in diesem Dosierungsbereich keine blockierende Wirkung aus; höhere Dosen hemmen vorübergehend die Übertragung in den parasympathischen Ganglien. Die durch DMPP und MBPO verursachten Hypertensionen beruhen vorwiegend auf einer Ausschüttung von Nebennierenmarkhormonen; nach Entfernung beider Nebennieren sind diese Blutdruckwirkungen fast aufgehoben. Die Kombination P-286 und Bretylium führt zu einer Ausschaltung des gesamten sympathoadrenalen Systems.P-286 ist weder adreno- noch sympathicolytisch wirksam, wirkt schwach parasympathicolytisch und setzt die Amplitude und die Frequenz des Vorhofpräparates herab; ferner weist es eine papaverinähnliche spasmolytische Wirkung auf.

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Summary Investigations carried out on the pharmacology of P-286 (N,N-diisopropyl-N-isoamyl-N-diethylaminoethylurea hydrochloride) led to the following conclusions:P-286 exerts a specific blocking action on the adrenal medulla of the dog in a dose range (2,5–5,0 mg/kg) in which it has no paralysing action at ganglionic sites. P-286 reduces the pressor responses to splanchnic nerve stimulation, carotid occlusion, asphyxia, stimulation of the central end of the vagus nerve or injection of DMPP and MBPO; it inhibits the adrenomedullary secretion of catecholamines caused by nerve stimulation or DMPP.In the referred dose range P-286 exerts no ganglioplegic action on sympathetic (superior cervical and paravertebral ganglia) and para-sympathetic ganglia (vagus nerve, pelvic nerve, chorda tympani); higher doses have a transient blocking action on para-sympathetic ganglia. The pressor responses to so called ganglionic stimulants like DMPP and MBPO are essentially mediated through release of adrenal catecholamines. The combined administration of P-286 and bretylium leads to the suppression of the reactivity of the adreno-sympathetic system.P-286 is devoid of adrenolytic or sympatholytic actions, exerts a slight para-sympatholytic action and depresses heart rate and contractile force; it has a papaverine-like antispasmodic action.

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Mit 8 Textabbildungen     

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.     

Effects of intracerebroventricular injected choline on cardiovascular functions and sympathoadrenal activity.

Intracerebroventricular (i.c.v.) injection of choline (50-150 micrograms) increased blood pressure (SP) and decreased heart rate (HR) in freely moving rats. Intracerebroventricular pretreatment of rats with mecamylamine (50 micrograms) blocked the reduction in HR and reduced the increase in SP induced by i.c.v. choline (150 micrograms). Central muscarinic blockade with atropine (10 micrograms, i.c.v.) reduced the pressor response to i.c.v. choline (150 micrograms) by about 70%, without influencing the decrease in HR. The decrease in HR induced by i.c.v. choline was prevented by intraarterial (i.a.) treatment of atropine methylnitrate (2 mg/kg). Intracerebroventricular choline (150 micrograms) produced a fivefold increase in catecholamine concentrations in adrenal venous plasma. Bilateral adrenalectomy reduced, but did not block, choline's effect on SP. Intracerebroventricular choline (150 micrograms) showed an ability to increase and restore SP in rats subjected to spinal cord transection or pretreatment with hexamethonium (15 mg/kg, i.a.) or with phentolamine (10 mg/kg, i.a.). Intracerebroventricular choline (150 micrograms) increased plasma vasopressin (VP) levels from 2.2 +/- 0.4 to 25.6 +/- 2.5 pg/ml. Pretreatment of rats with a VP antagonist reduced the pressor response to i.c.v. choline. It is concluded that (a) the reduction in HR results from a central nicotinic receptor-mediated increase in vagal tone, (b) the increase in SP appears to be due to activation of both nicotinic and muscarinic central cholinergic receptors, and that (c) the central activation of the adrenal medulla and the increase in plasma levels of VP are involved in the pressor response to i.c.v. choline.     

SHORT COMMUNICATION: EFFECTS OF NIFEDIPINE AND BAY-K-8644 ON THE RELEASE OF CATECHOLAMINES FROM THE DOG ADRENAL GLAND IN RESPONSE TO SPLANCHNIC NERVE STIMULATION

1. The effects of nifedipine and Bay-K-8644 on the release of adrenal catecholamines were examined in anaesthetized dogs. 2. Splanchnic nerve stimulation (SNS) at 1 and 3 Hz produced frequency-dependent increases in adrenaline (ADR) and noradrenaline (NA) output determined from adrenal venous blood. 3. Neither nifedipine (10 and 30 μg/kg, i.v.) nor Bay-K-8644 (10 and 30 μg/kg, i.v.) modified the SNS-induced increases in catecholamine output. Basal catecholamine output tended to be increased and decreased by nifedipine and Bay-K-8644, respectively. 4. Nifedipine produced significant decreases in arterial pressure and renal blood flow rate. Bay-K-8644 produced a significant increase in arterial pressure associated with a decrease in renal blood flow rate. 5. These results suggest that dihydropyridine-sensitive calcium channels do not play a major role in adrenal catecholamine release evoked by SNS.     

MECHANISMS OF CAPTOPRIL-INDUCED POTENTIATION OF THE DEPRESSOR RESPONSES TO ARACHIDONIC ACID IN RATS

The mechanisms underlying potentiation by captopril of the depressor responses to arachidonic acid were studied in chloralose-anaesthetized rats. Captopril, in a dose (0.5 mg/kg, i.v.) which inhibited the pressor responses to angiotensin I (0.03-1 microgram/kg, i.v.), enhanced the depressor responses to bradykinin (3-300 micrograms/kg, i.v.) and potentiated the hypotensive action of arachidonic acid (3 mg/kg, intravenously). This phenomenon was observed not only when captopril and arachidonic acid were administered intravenously, but also when these compounds were injected directly into the aortic arch. The enhancement of arachidonic acid-induced hypotension by captopril was not significantly affected by pretreatment with a low dose of aprotinin (3 mg/kg, i.v.), but was abolished by bilateral nephrectomy or by pretreatment with a higher dose of aprotinin (6 mg/kg, i.v.). It is suggested that captopril augments the depressor responses to arachidonic acid by inhibiting angiotensin converting enzyme. This results in accumulation of bradykinin which in turn increases release of vasodilator prostaglandins, originating most probably, from the kidneys. The possibility that blockade of angiotensin II formation by captopril may leave the vasodilator action of prostaglandin unopposed cannot be excluded.     

THE EFFECTS OF SYMPATHOLYTIC DRUGS ON THE CARDIOVASCULAR RESPONSE TO TILTING IN ANAESTHETIZED CATS

1. Using cats anaesthetized with chloralose and urethane, comparison was made of the abilities of several antihypertensive and sympatholytic drugs to lower systemic blood pressure, and to depress the compensatory cardiovascular responses to bilateral carotid occlusion and to 45° head-up tilting. Similar comparisons were also made of the effects of these drugs on the perfusion pressure of the vascularly isolated autoperfused hindquarters, and the response of this to carotid occlusion and tilting. The effects of bilateral vagotomy and haemorrhage on these responses were also studied. 2. It was found that hypotensive doses of both bretylium and guanethidine (3.0mg/kg, i.v.) markedly depressed the ability of cats to restore their systemic blood pressure and to constrict their hindquarters vasculature during tilting. Both drugs depressed the carotid occlusion reflex in the systemic, but not in the hindquarters, circulation. Neither propranolol, 2.0mg/kg, i.v., nor bilaterial vagotomy had any effect on these parameters and haemorrhage sufficient to cause marked hypotension was without effect on the systemic responses to carotid occlusion or tilting. 3.Clonidine (1.0, 5.0 and 25/μg/kg, i.v.), xylazine (62.5, 125 and 250μg/kg, i.v.) and reserpine (0.5 and 2.0mg/kg, i.v.) all caused considerable hypotension but had no effect on the response to tilting of the systemic circulation, apart from somewhat prolonging recovering time. The highest dose of clonidine moderately depressed the hindquarters perfusion pressure, and the response of this to tilting. 4. Clonidine (5.0 and 25μg/kg, i.v.) and xylazine (125 and 250/μg/kg, i.v.) depressed the systemic pressor responses elicited by the ganglion stimulants DMPP and McN-A-343. This may indicate that the ability of clonidine to prolong the pressure recovery during tilt may be due to impaired peripheral sympathetic transmission. 5. It is concluded that drugs which significantly reduce the compensatory pressure responses to tilting in anaesthetized cats may also cause postural disturbances in man, whilst drugs which merely prolong the period required for pressure compensation seem much less likely to cause serious clinical impairment of orthostatic reflexes. It appears that the cardiovascular response to bilateral carotid occlusion may not provide a good index of the integrity of orthostatic reflexes.     

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.     

Facilitatory role of the renin-angiotensin system in controlling adrenal catecholamine release in hemorrhaged dogs.

Effects of the renin-angiotension system (RAS) on adrenal catecholamine release in response to hemorrhagic hypotension and splanchnic nerve stimulation (SNS) were studied in pentobarbital-anesthetized dogs. In hemorrhage experiments, mean blood pressure (MBP) was maintained at 50 mm Hg for 60 min by bleeding the arterial blood into a pressurized bottle. In the renal intact group (control), epinephrine (EPI) and norepinephrine (NE) output from the adrenal gland increased markedly during hemorrhagic hypotension: from 45 +/- 13 and 4.7 +/- 0.9 to 1,167 +/- 202 and 169 +/- 30 ng/min at 60 min after onset of hemorrhage, respectively. The increases in catecholamine output during hemorrhagic hypotension in the renal-intact group pretreated with captopril (1 mg/kg intravenously, i.v.) and in the renal-ligated group were significantly smaller than those in the control group. The increases in catecholamine output in the renal-ligated group infused with angiotensin II (AngII 10 ng/kg/min i.v.) were comparable to those in the control group. In SNS experiments, AngII infusion (10 ng/kg/min i.v.) enhanced increases in catecholamine output induced by 3 Hz SNS significantly. Captopril (1 mg/kg i.v.) did not affect the SNS-induced increases in catecholamine output. These results suggest that the renal RAS facilitates reflex release of adrenal catecholamines during hemorrhagic hypotension, at least in part, by acting directly on the release process of catecholamines from dog adrenal gland.     

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.     

Pharmacodynamic effects of a 2-piperazinotetralin (P-11)--combined alpha- and beta-adrenoceptor blocking drug with hypotensive action

The piperazinotetralin derivative P-11 at hypotensive doses of 0.25 to 1.00 mg/kg i.v. reduced the pressor effects of exogenous noradrenaline (10 micrograms/kg i.v.) in reserpine-pretreated rats, but was ineffective in nonreserpinized normotensive urethane-anesthetized rats. P-11 (0.25 to 1.00 mg/kg i.v.) decreased the positive chronotropic effects of isoprenaline (0.2 micrograms/kg i.v.), but potentiated the isoprenaline-induced hypotension in reserpine-pretreated rats. P-11 (10(-7) to 10(-5)M) did not modify the concentration-effect curves for isoprenaline in carbachol-contracted guinea-pig tracheal strips. The pD2 value of isoprenaline was 5.94 before and 6.35 after P-11. The combined alpha1-postsynaptic antagonist/beta1-blocking activity of this compound is discussed.     

FURTHER STUDIES ON THE EFFECTS OF ADRENAL STEROIDS IN THE ACTIVE TRANSPORT OF SEROTONIN INTO RAT PLATELETS

Male rats were treated with a fixed dose of aminoglutethimide (50 mg/kg s.c.) or with progressively increasing doses (50-100 mg/kg s.c.) for 3 days. Corticosterone levels were found to be decreased in the latter group. Platelet uptake of serotonin as well as the apparent Vmax were decreased, whereas the Km of uptake were increased when compared with that of the control group. Addition of ACTH (10 iu/dl) to control rat platelet and corticosterone (10-80 micrograms/dl) or triamcinolone (0.5-5.0 micrograms/dl) to adrenalectomized rat platelet suspension in vitro did not increase the serotonin uptake of the preparation. Administration of exogenous dexamethasone (0.05-0.2 mg/kg i.m.) or triamcinolone (0.05-5.0 mg/kg i.m.) to adrenalectomized rats, caused a dose related increase in active uptake of serotonin by the platelets. Deoxycorticosterone (0.1-1.0 mg/kg i.m.) did not have this effect. The time course of response to, and the maximum percentage increase in platelet serotonin uptake by, exogenous corticosteroids are related to their glucocorticoid potency. The possible role of glucocorticoids on platelet serotonin uptake process is discussed.     

Adrenalectomy modifies the effect of intracerebral histamine on the cold-stimulated TSH secretion in male rats

Cold-stimulated TSH secretion remained normal after adrenalectomy in conscious male Sprague-Dawley rats, but the inhibitory effect of a small dose of histamine (1.0 micrograms/rat into the 3rd ventricle, i.c.v.) on the TSH secretion was abolished. Adrenaline (0.01-1.0 mg/kg s.c.) inhibited dose-dependently the cold-stimulated TSH secretion. However, although adrenalectomy causes a prominent decrease in releasable adrenaline, a larger dose of histamine (2.5 micrograms/rat i.c.v.) decreased the TSH secretion. The effect of histamine was not modified after pretreatment with either corticosterone or dexamethasone, irrespective of whether intact or adrenalectomized rats were studied. Corticosterone decreased and dexamethasone increased the cold-stimulated TSH secretion when given intraperitoneally. Chlorisondamine (10 mg/kg i.p.), a peripheral ganglionic blocking drug, suppressed the TSH cold-response in intact rats. Histamine (1.0 microgram/rat i.c.v.) had no additional inhibitory effect after chlorisondamine. The results suggest that the effect of intracerebral histamine on cold-stimulated TSH secretion is caused neither by stimulation of the hypothalamus-pituitary-adrenocortical axis nor by increased adrenomedullary catecholamine release. Further, the effect of intracerebral histamine is obviously not due to enhanced neurosympathetic activity. The effect of histamine is modified by adrenalectomy, but the adrenal glands are not essential for it.     

Intrinsic sympathomimetic activity of labetalol

In intact cats, cumulative doses (0.1-10 mg/kg i.v.) of labetalol produced dose-dependent decreases in heart rate and arterial blood pressure and dose-dependently reduced i.v. phenylephrine induced pressor responses. In spinal cats devoid of resting sympathetic tone, labetalol (1 mg/kg i.v.) produced a sustained elevation of heart rate and a transient fall in arterial blood pressure. In reserpine-pretreated, adrenalectomized cats, labetalol produced quantitatively the same effects as in spinal cats, indicating that the cardiovascular effects observed in cats with no resting sympathetic tone are due to a direct action of labetalol rather than via catecholamine release. The elevated heart rate due to labetalol in spinal cats was reduced by subsequent administration of the beta-adrenergic receptor antagonist, propranolol. Further, pretreatment with propranolol prevented the tachycardic and depressor effects of labetalol in spinal cats. In a separate group of spinal cats, labetalol administered in cumulative doses of up to 1 mg/kg i.v., produced graded increases in heart rate and also dose dependently reduced i.v. isoproterenol-induced tachycardic responses. Pindolol, a beta-adrenergic receptor antagonist with partial beta-agonist activity, produced similar effects in spinal cats at cumulative doses of 1-30 micrograms/kg. These results indicate that the alpha- and beta-adrenergic receptor antagonist, labetalol possesses partial beta-adrenergic receptor agonist activity. This intrinsic sympathomimetic action of labetalol appears to be more sustained on cardiac than on vascular beta-adrenergic receptors.     

Influence of the adrenal gland on the pressor effect and antagonistic potency of angiotensin II analogs.

In ganglion blocked vagotomized rats, several 1,8-substituted angiotensin II analogs (250 ng/kg/min, i.v.) antagonized the pressor effect of angiotensin II. Dose ratios measured at the ED20 levels were: [Sar1,Ile8]-28; [Gac1,Ile8]- 19;[MeAla1,Ile8i1- 16;[MeIle1,Ile8]- 10;[sar1,Ala8]- 9;[me2Gly1,Ile8]- 4. Elimination of aspajtic acid in position 1 of [Ile8]-angiotensin II significantly reduced the antagonistic potency of the analog. No antagonistic effect was observed with [Phe4,Ile8] and [Ala4,Ile8]-angiotensin II even when infused at 6 mug/kg/min. During infusion, a partial rise in blood pressure was observed with all the above 1,8-substituted angiotensin II analogs. Phentolamine (100 mug/rat) injected 30 min after the start of the analog infusion reduced and sometimes abolished the pressor effect. However, phenoxybenzamine )Pbz, 2 mg/kg) injected 30 min prior to the analog infusion diminished but did not completely abolish the initial pressor effect. In adrenalectomized rats, the pressor effect was reduced by approximately 50 percent and disappeared completely 15-30 min after start of the infusion. Under these conditions, dose ratios of [Sar1,Ile8]-,[MeAla1,Ile8]- and [Gac1,Ile8]-angiotensin II were significantly reduced. Noradrenaline, 83 ng/kg/min. increased the ED20 value of angiotensin II(ratio 1.79) in normal rats but did not do so in adrenalectomized rats. In these rats no regular correlation was found between the angiotensin II ED20 values and initial blood pressure. These data indicate that under the present experimental conditions, the low pressor effect observed with these angiotensin II antagonists appears to be due to both adrenal catecholamine release and a direct vasoconstrictor effect. Variations in antagonistic activity of angiotensin II analogs, apart from changes introduced in the molecule, may be the manifestation of a complex interaction between angiotensin II, its antagonists, and the sympathoadrenal system.     

SENSITIVITY CHANGES OF THE PERFUSED HINDQUARTERS'' VASCULATURE IN RATS WITH ALLOXAN-INDUCED DIABETES MELLITUS

1. Arachidonic acid (AA, 0.125-1.0 mg/kg) injected via the aorta into the autoperfused hindquarters caused dose-dependent increases in perfusion pressure. This effect was reduced after intravenous administration of the thromboxane receptor antagonist AH23848 (5 mg/kg) or indomethacin (5 mg/kg). 2. Responses to AA (0.125-1.0 mg/kg) were reduced markedly in the Krebs-perfused hindquarters when compared with those occurring in the blood-perfused preparation. 3. Doses of guanethidine (1 mg/kg) and pentacynium (1 mg/kg) blocking pressor responses to intravenous administration of the ganglion stimulants McN-A-343 and DMPP, respectively, did not affect responses to AA. 4. Constrictor responses to AA (0.5-1.0 mg/kg) in blood-perfused hindquarters were increased in 14 day alloxan-diabetic rats but those to the thromboxane A2-mimetic U46619 (0.5-8.0 micrograms/kg, i.a.) were reduced when compared with non-diabetic controls. 5. In 14 day alloxan-diabetic rats vasoconstrictor responses to noradrenaline and methoxamine were potentiated but those to 5-hydroxytryptamine were reduced compared with non-diabetic animals. 6. It is concluded that AA causes constriction in the blood-perfused hindquarters by release of a product of cyclo-oxygenase acting on thromboxane A2-receptors. A constituent of blood, perhaps the platelet, appears necessary for this effect. Conversion of AA to the constrictor metabolite is augmented during experimentally induced diabetes.     

Evidence for muscarinic receptors in the adrenal medulla of the dog

1. The release of catecholamines from the adrenal medulla by the cholinergic drugs was monitored by the perfusion pressure rise in autoperfused and sympathetically denervated hindlimbs of the dog.2. Acetylcholine, dimethylphenylpiperazinium (DMPP) and methacholine, given in relatively small doses into the aorta proximal to the blood supply to the adrenal glands, caused a marked rise in perfusion pressure which was due to the release of catecholamines from the adrenal medulla.3. Atropine (1 mg/kg intravenously) blocked the pressor response to methacholine only. The ganglion-blocking agents (mecamylamine 4-5 mg/kg or hexamethonium 10 mg/kg) given subsequently blocked the pressor responses to the other two cholinergic drugs. The ganglion-blocking agents, when given before atropine, blocked the pressor action only of DMPP. These agents partly depressed, rather than potentiated, the pressor response to methacholine.4. The results suggest that muscarinic as well as nicotinic receptors are present in the adrenal medulla of the dog.5. Neither atropine nor ganglion-blocking drugs alone reduced the pressor response to acetylcholine. It is postulated that the blockade of one set of receptors makes more acetylcholine available for the other set of receptors and so inactivation of the former receptors are compensated by the increased release through the activation of the latter's.