Lionel Finch

Central hypertensive action of histamine in conscious normotensive cats

In conscious normotensive cats intraventricular (i.c.v.) administration of histamine (2.0-50.0 mug) induced dose-related rises in blood pressure, with no increase in heart rate. The hypertensive response elicited by a sub-maximal dose of histamine (10.0 mu i.c.v.) was significantly antagonised by central pretreatment with the H1-receptor antagonist mepyramine maleate (200 mug i.c.v.) but not by the H2-receptor antagonist metiamide hydrochloride (1.0 mg i.c.v.). Behavioural responses were obtained in response to to histamine (10.0 and 50.0 mug i.c.v.), which were not antagonised by these antihistamine pretreatments.

A comparison of the effects of 6‐hydroxy‐dopamine immunosympathectomy and reserpine on the cardiovascular reactivity in the rat

In the conscious rat, 6‐hydroxydopamine, or reserpine (5 mg/kg) pretreatment produced a marked fall in the mean systolic blood pressure whilst immunosympathectomized rats had resting blood pressures just below that of control animals. In pithed preparations, 6‐hydroxydopamine treatment or immunosympathectomy potentiated the pressor responses to injected noradrenaline; reserpine pretreatment did not potentiate the noradrenaline response to the same degree. Tyramine responses were abolished after 6‐hydroxydopamine or reserpine pretreatment but were unaffected by immunosympathectomy. Stimulation of the sympathetic outflow by the Gillespie & Muir (1967) preparation was abolished after 6‐hydroxydopamine and reserpine pretreatment, and reduced after immunosympathectomy. It is concluded that 6‐hydroxydopamine produces a destruction of the sympathetic nerve endings, abolishing the physiological uptake process and, therefore, producing supersensitivity to injected noradrenaline. Immunosympathectomy, although showing a marked reduction in sympathetic nerve supply leaves a functional uptake process. Reserpine (5 mg/kg), given 6 h previously, depletes endogenous catecholamines without significantly altering the sensitivity to injected noradrenaline, the uptake process remaining functional.

Changes in vascular reactivity in experimental hypertensive animals following treatment with indapamide

Indapamide at doses of 8–16 mg kg−1 day−1, orally, lowered arterial blood pressure (9–26 mm Hg) in conscious renal hypertensive cats during a two week treatment period. The antihypertensive effect was sustained for 5–7 h after dosing and was not accompanied by reflex tachycardia. Antihypertensive responses to injection of clonidine (20 μg, i.c.v.) were significantly enhanced one week after the completion of indapamide treatment but had returned to normal two weeks later. In DOCA/saline hypertensive rats, administration of indapamide 10 mg kg−1 day−1, orally, or hydrochlorothiazide, 5 mg kg−1 day−1, intraperitoneally, for 10 days produced similar falls in blood pressure (40–45 mm Hg) as measured by an indirect method. Pressor responses to intravenous noradrenaline or tyramine or electrical stimulation of the sympathetic outflow in the pithed rat preparation were much reduced by pretreatment with indapamide (10 mg kg−1, orally) for 10 days. However, cardiovascular reactivity was unaffected by hydrochlorothiazide pretreatment (5 mg kg−1 day−1, i.p.). Isolated perfused mesenteric artery***/preparations from indapamide‐treated rats showed no changes in reactivity to noradrenaline, 5‐hydroxytryptamine or adenosine‐5′‐triphosphate from those of control DOCA/saline hypertensive rats. Isolated portal veins from rats pretreated with indapamide showed contractile responses to noradrenaline similar to those of control animals although the frequency of spontaneous contractions was reduced in the former group. The results support a vascular site of action for indapamide and suggest a mode of action different from that of hydrochlorothiazide.

The α1- and α2-adrenoceptor involvement in the central cardiovascular action of clonidine in the conscious renal hypertensive cat

An attempt has been made to characterized the α-adrenoceptor subtype (α1 or α2) mediating the hypotensive and bradycardic action of clonidine in conscious renal hypertensive cats. The relatively selective α2-adrenoceptor agonists clonidine, UK-14,304, guanfacine and lofexidine caused significant hypotension and bradycardia when given intracerebroventricularly (i.c.v.). This suggests that α2-adrenoceptors can mediate hypotension and bradycardia. However, both α1- and α2-adrenoceptor antagonists, prazosin, UK-33,274, corynanthine, yohimbine, rauwolscine and RS21361 blocked the hypotensive effect of clonidine. These results suggest an α1-adrenoceptor may also mediate the central hypotensive action of clonidine, or possibly that the central α-adrenoceptors in which clonidine acts, may show pharmacological differences to peripheral α1- and α2-subtypes.

Does the adrenal medulla contribute to the maintenance of experimental hypertension

Abstract The development of renal and DOCA/NaCl hypertension in the rat was unaffected by demedullation. Chemical sympathectomy using 6-hydroxydopamine followed by demedullation also failed to prevent the development of these types of hypertension. In chronic renal and DOCA/NaCl hypertension 6-hydroxydopamine followed by demedullation produced a fall in blood pressure which returned to original levels after one week.

Postsynaptic spinal α-adrenoceptors mediate effects of intrathecal clonidine

Abstract The cardiovascular effects of intrathecal administration of clonidine were examined after depletion of spinal cord noradrenaline or 5-hydroxytryptamine by pretreatment with 6-hydroxydopamine or 5,6-dihydroxytryptamine. Despite marked reduction in spinal noradrenaline or 5-hydroxytryptamine levels, resting blood pressure and heart rate were unchanged and the clonidine-induced hypotension and bradycardia were unimpaired. The results suggest that intrathecal clonidine acts via inhibitory spinal α-adrenoceptors located postsynaptically on the preganglionic nerve cell bodies.

A comparison of the cardiovascular effects of centrally administered clonidine and adrenaline in the anaesthetized rat.

Intracerebroventricular (i.c.v.) injections of clonidine and adrenaline‐induced hypotension and bradycardia in urethane anaesthetized spontaneous hypertensive rats. The hypotension induced by clonidine (3 μg i.c.v.) was antagonized by pretreatment with the α‐antagonists piperoxan, which also antagonized clonidine‐induced bradycardia, and yohimbine. The hypotension and bradycardia induced by adrenaline (10 μg i.c.v.) were unaffected by α‐antagonist pretreatment, while β‐antagonist pretreatment with (‐(‐propranolol or metoprolol was effective against adrenaline but not clonidine‐induced hypotension and bradycardia. Pretreatments with the histamine H2‐receptor antagonists metiamide and cimetidine antagonized clonidine but not adrenaline‐induced hypotension. These data indicate that different central mechanisms are involved in mediating the hypotension and bradycardia induced by centrally administered clonidine and adrenaline and do not, therefore, support the hypothesis that the hypotensive effects of clonidine (i.c.v.) are mediated by central adrenaline receptor activation in urethane‐anaesthetized spontaneous hypertensive rats.

Cardiovascular responses to intraventricular adrenaline in spontaneous hypertensive rats

The effects of intracerebroventricular (i.c.v.) injections of adrenaline on the blood pressure and heart rate of spontaneous hypertensive (SH) rats have been investigated. Adrenaline induced dose-related falls in blood pressure and heart rate in both conscious and urethane anaesthetised rats. In conscious rats, the hypotension and metoprolol, but were unaffected by pretreatment with phentolamine, piperoxan, fluphenazine or methysergide. However, in urethane-anaesthetised rats, the hypotension and bradycardia induced by i.c.v. adrenaline was not significantly affected by i.c.v. pretreatment with propranolol or oxprenolol, while metoprolol significantly antagonised only the bradycardia. Piperoxan, fluphenazine and methysergide were also without effect. Pretreatment with mecamylamine (i.p.) abolished the cardiovascular depressor effects of i.c.v. adrenaline in both conscious and urethane anaesthetised SH rats. It is concluded that the cardiovascular depressor effects of i.c.v. adrenaline are mediated by central adrenoceptors in SH rats and that, in conscious rats, these depressor effects may be mediated by central beta-adrenoceptors rather than alpha-adrenoceptors.

No evidence for central histamine-receptor involvement with the hypotensive effect of clonidine in cats

In conscious hypertensive cats, intraventricular (i.c.v.) administration of clonidine (25 mug), induced hypotension and bradycardia. Pretreatment with metiamide (2 mg i.c.v.) did not significantly antagonise either the hypotension or bradycardia induced by clonidine (25 mug), but induced marked behavioural changes. Central pretreatment with mepyramine (200 mug, i.c.v.) or procaine (600 mug i.c.v.), reduced the hypotension evoked by clonidine (25 mug), but no antagonism of the clonidine-induced bradycardia was apparent. Central phentolamine (200 mug, i.c.v.) or tolazoline (200 mug, i.c.v.) antagonised the hypotension and bradycardia evoked by i.c.v. clonidine.

STUDIES ON THE HYPOTENSIVE ACTION OF α‐METHYLDOPAMINE

1 Intraventricular α‐methyldopamine (50–200 μg) produced a dose‐related fall in blood pressure in conscious spontaneously hypertensive rats. Pretreatment with intraventricular 6‐hydroxydopamine prevented this hypotensive effect of α‐methyldopamine. 2 The hypotensive effect of α‐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‐β‐hydroxylase inhibitor, prevented the hypotensive effect of α‐methyldopamine. 4 α‐Methyldopamine was considerably less potent than noradrenaline as a pressor agent in the pithed rat, but noradrenaline and α‐methylnoradrenaline were found to be equipotent. 5 α‐Methyldopamine (1–5 mg i.c.v.) reduced pressor responses elicited by electrical stimulation of the mid brain reticular formation in cats anaesthetized with chloralose. 6 It is concluded that the hypotensive action of α‐methyldopamine in conscious animals involves intact central α‐adrenergic neurones and a central adrenergic uptake mechanism for the formation of α‐methylnoradrenaline.