Peter E. Hicks

5HT-receptor antagonist properties of SCH 23390 in vascular smooth muscle and brain

The dopamine D1-receptor antagonist SCH 23390 was a potent competitive antagonist of 5HT-induced vasoconstriction in the isolated perfused rat tail artery preparation (pA2 8.17) but a very weak antagonist of phenylephrine-induced responses (pA2 5.94). In rat brain cerebral cortex, SCH 23390 inhibited 5-HT2-sensitive [3H]spiperone binding with an IC50 of 112 nM. Binding of [3H]5HT to 5HT1 receptors in the cortex was inhibited by SCH 23390 with an IC50 of 2.49 microM. SCH 23390 has significant affinity for 5HT receptors in addition to the reported selective dopamine D1-receptor antagonist properties.

Calcium channel receptor binding studies for diltiazem and its major metabolites: functional correlation to inhibition of portal vein myogenic activity.

Pharmacologically distinct but allosterically interacting calcium channel antagonist binding sites have recently been identified using radiolabeled dihydropyridine derivatives (e.g., [3H]nitrendipine) and the benzothiazepine [3H]diltiazem. Whereas the functional significance of the dihydropyridine calcium channel antagonist receptor is well documented, it remains to be established whether drug interactions with the recognition site for [3H]diltiazem within the slow calcium channel or the allosteric interaction of the diltiazem binding site with the dihydropyridine receptor are of physiological significance. In a study of structure-activity relationships, we therefore examined the effects of diltiazem and five of its analogs on the binding of [3H]diltiazem and [3H]nitrendipine to the rat cerebral cortex. In parallel, we studied the effects of these drugs on the spontaneous myogenic contractions of the rat portal vein, a functional test of calcium antagonism. The diltiazem analogs used in this study correspond to its major metabolites in humans, i.e., N-desmethyl-(MA, desacetyl-(M1), N-desmethyl, desacetyl-(M2), O-desmethyl, desacetyl (M4), N-desmethyl, O-desmethyl, desacetyl-diltiazem (M6). Unlabeled diltiazem inhibited [3H]diltiazem binding at 37 degrees C with a pIC50 [-log IC50 (M)] of 6.87. pIC50 values for M1, MA, M2, M4, and M6 were 6.72, 6.49, 6.03, 5.51, and 5.33, respectively. pIC50 values for these drugs on [3H]diltiazem binding were significantly correlated (p less than 0.01) with their pEC50 values for enhancement of [3H]nitrendipine binding to cerebral cortical membranes at 37 degrees C. Maximal enhancement of [3H]nitrendipine binding by diltiazem, M1, MA, M2, M4, and M6 was 73, 50, 9.7, 11, 12, and 52%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

Effect of acidosis on α1- and α2-adrenoceptor-mediated vasoconstrictor responses in isolated arteries

We have investigated the effect of reducing the pH (from 7.5 to 7.0 by addition of HCl) on vasoconstrictor responses to noradrenaline in cat middle cerebral artery (in which responses are mediated almost entirely by α2-adrenoceptors) and in rabbit pulmonary artery (in which responses are mediated by α1-adrenoceptors). In the cerebral artery, a reduction in pH caused a pronounced inhibition of the responses to noradrenaline, and the antagonistic effect of idazoxan (100 nM) was increased 10-fold. In contrast, in the pulmonary artery, a reduction in pH had no effect on the responses to noradrenaline and the antagonistic effect of prazosin (100 nM) was not altered. We conclude that acidosis selectively reduces the vasoconstriction mediated by α2-adrenoceptors in vitro.

Effects of ATP-dependent K+ channel modulators on an ischemia-reperfusion rabbit isolated heart model with programmed electrical stimulation

The effects of glibenclamide and BRL-38227 were studied in isolated rabbit hearts subjected to ischemia and programmed electrical stimulation. Coronary artery occlusion over 24 min decreased the ventricular effective refractory period in the ischemic zone. BRL-38227 (0.1 microM) showed significant coronary vasodilator effects, but failed to modify the ventricular effective refractory period under these conditions. A higher concentration (5 microM) of BRL-38227 potentiated the ischemia induced ventricular effective refractory period shortening effects. Glibenclamide (0.1 and 1 microM) delayed the onset of the ischemia-induced ventricular effective refractory period shortening. Glibenclamide (1 microM) inhibited the potentiated ventricular effective refractory period shortening effects of BRL-38227 (5 microM) during ischemia, but failed to antagonise the coronary vasodilator effects of BRL-38227 (5 microM). A higher incidence of ventricular fibrillation was inducible when an extra beat was applied in the ischemic zone through programmed electrical stimulation. The incidence of programmed electrical stimulation induced ventricular fibrillation was increased by BRL-38227 (5 microM) and antagonised by glibenclamide (1 microM). The results suggest that high concentrations of KATP-activators can accentuate ischemia-induced decreases in refractory period and increase the susceptibility of hearts to ventricular fibrillation when an extra beat is applied to the ischemic myocardium. These effects did not occur at lower coronary vasodilating concentrations of BRL-38227.

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.

Inhibitory effects of α,β-methylene ATP on nerve-mediated contractions of the nictitating membrane in reserpinised cats

Abstract Residual responses of the cat nictitating membrane to nerve stimulation were obtained after reserpine pretreatment (40% of controls), in spite of a pronounced reduction in noradrenaline content. The putative ATP-receptor desensitising agent α,β-methylene ATP (α,β-MATP), administered intraarterially through the lingual artery produced a contraction of the nictitating membrane and subsequently inhibited the residual responses evoked by sympathetic nerve stimulation in reserpinised cats. These doses of α,β-MATP did not modify the contractions evoked by exogenous noradrenaline (i.a.) but antagonized the contractions of the nictitating membrane elicited by β,γ-methylene ATP, which is an agonist at P2 receptors. These results are compatible with a co-transmitter role for ATP in the neurally mediated contractile responses of the nictitating membrane following depletion of endogenous noradrenaline stores by pretreatment with reserpine.

Vascular calcium overload produced by administration of vitamin D3 and nicotine in rats. Changes in tissue calcium levels, blood pressure, and pressor responses to electrical stimulation or norepinephrine in vivo.

Increased calcium content of cardiovascular tissues is a phenomenon common to natural aging and various pathological conditions such as hypertension and arteriosclerosis. We investigated an accelerated cardiovascular calcium overload model in young rats produced by treatment with a single dose of vitamin D3 (300,000 IU/kg, i.m.) followed by up to 4 days of twice daily doses of nicotine (25 mg/kg, p.o.). Large increases in the calcium content of the aorta, kidneys, and myocardium but not in the liver or brain were seen. The magnesium content of these tissues was not modified. On the day following the last nicotine injection, there was marked cardiovascular calcium overloading, the aortic calcium level increasing by up to nine times that of controls. The animals had lower body weights, however, and there was a significant degree of mortality (up to 42%). Signs of kidney failure were evident; the blood urea level, for instance, was doubled. If rats were allowed 13 or 180 days to recover, they showed normal growth and kidney function; aortic calcium overload was still pronounced: 16− and 7-fold increases, respectively. Cardiovascular function in recovery animals was characterized by a doubling of pulse pressure. Dose-response curves following noradrenergic stimulation were shifted to the right after 13 (but not after 180) days recovery. Arterial norepinephrine content doubled. The chronic effects of hypervitaminosis D plus nicotine may produce a useful model for the study of the physiological and/or pharmacological consequences of calcium overload.