Thomas C. Hamilton

Inhibition by glibenclamide of the vasorelaxant action of cromakalim in the rat.

1 In rat isolated thoracic aortic rings pre‐contracted with noradrenaline (10−6 m), cromakalim (3 × 10−7‐3 × 10−5 m) produced concentration‐related relaxation. This effect was progressively inhibited by increasing concentrations of the anti‐diabetic sulphonylurea drug, glibenclamide (10−6‐10−5 m). 2 In rat isolated portal veins, cromakalim (3 × 10−8‐10−6 m) produced concentration‐related inhibition of the spontaneous contractive activity and glibenclamide (3 × 10−7‐3 × 10−6 m) prevented this inhibitory action in a concentration‐dependent manner. 3 In both rat aortic rings and portal veins, cromakalim (10−5 m) stimulated 86Rb efflux. Prior exposure to glibenclamide (10−7‐10−6 m) produced a concentration‐related inhibition of this response. 4 In conscious rats, cromakalim, 0.075 mg kg−1 i.v., produced a rapid and sustained fall in arterial blood pressure which was not influenced by pretreatment (2 h) with a large oral dose of glibenclamide (100 mg kg−1). 5 In conscious rats, the hypotensive action of cromakalim, 0.075 mg kg−1 i.v., was abolished by pretreatment (30 min) with glibenclamide, 20 mg kg−1, given by the intravenous route. 6 The results suggest that the vasorelaxant and hypotensive actions of cromakalim involve a K+ channel which can be inhibited by glibenclamide, but which may be distinct from the ATP‐sensitive K+ channel of the pancreatic β‐cell.

Comparative effects of K+ channel blockade on the vasorelaxant activity of cromakalim, pinacidil and nicorandil

Three agents with K+ channel blocking activity, procaine, 4-aminopyridine (4-AP) and tetraethylammonium (TEA), were tested for inhibition of vasorelaxation and 86Rb+ efflux induced by cromakalim (BRL 34915), pinacidil and nicorandil in rabbit isolated mesenteric artery. The potency order for inhibition of vasorelaxation was procaine greater than 4-AP greater than TEA and for inhibition of efflux was procaine = 4-AP greater than TEA. The K+ channel blockers did not discriminate between cromakalim, pinacidil or nicorandil on efflux but demonstrated preferential inhibition of vasorelaxation to cromakalim greater than pinacidil greater than nicorandil. In addition, the maximum response to cromakalim was depressed but that to pinacidil and nicorandil was not. The results confirm the role of K+ channel activation in vasorelaxation to cromakalim, pinacidil and nicorandil, but suggest that additional mechanisms may be involved for pinacidil and, in particular, for nicorandil.

Effect of intracerebroventricular 5,6-dihydroxytryptamine on blood pressure of spontaneously hypertensive rats

The effects of intracerebroventricular injections of 5,6-DHT on the development and maintenance of hypertension in spontaneously hypertensive rats has been investigated. 5,6-DHT, injected into 6 week old rats, retarded the development of hypertension for at least 6 weeks; this effect was not accompanied by inhibition of the pressor response produced by stimulation of the total peripheral sympathetic outflow. 5,6-DHT, injected into 14-15 week old rats with established hypertension, produced a short-lived fall in blood pressure. These findings suggest that central 5-HT neurones are involved in the development of hypertension in spontaneously hypertensive rats.

Intrinsic sympathomimetic activity of β-adrenoceptor blocking drugs at cardiac and vascular β-adrenoceptors

Abstract In the anaesthetised, reserpinised rat isoprenaline causes tachycardia and depressor responses: these effects are due to stimulation of β 1 (cardiac) and β 2 (vascular) adrenoceptors. Salbutamol also produces tachycardia and depressor responses. (±) and (−) bufuralol, and its carbinol and ketone metabolites, produce similar responses indicating intrinsic sympathomimetic activity (ISA) at β 1 and β 2 adrenoceptors; (+) bufuralol lacks ISA. Pindolol and oxprenolol also cause tachycardia and a depressor effect; oxprenolol is weakly active in producing the latter response. Propranolol is devoid of ISA; 4-hydroxypropranolol causes tachycardia with a negligible fall in blood pressure. Practolol causes only tachycardia. These results demonstrate that the reserpinised rat is a suitable experimental model for the demonstration of ISA at β 1 and β 2 adrenoceptors. Non-selective β-adrenoceptor blocking drugs produce stimulation at β 2 (vascular) adrenoceptors as well as β 1 (cardiac) adrenoceptors.

Diminishing hypotensive effect of increasing doses of pindolol in DOCA/saline hypertensive rats.

In DOCA‐saline hypertensive rats, pindolol (4, 20 or 50 mg/kg orally) produced a hypotensive effect which was inversely related to dose. Following adrenal demedullation, a hypotensive response to the highest dose of pindolol was unmasked and the magnitude of the responses to lower doses was increased. The results suggest that adrenal catecholamines moderate the hypotensive effects of high doses of pindolol.

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 μg i.c.v.) or 6‐hydroxydopamine (6‐OHDA; 3 × 250 μg intracerebroventricularly). 4 It is concluded that the hypotensive response to PCPAME in normotensive rats is 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 DOCA/saline hypertensive rats has yet to be defined.

Hypotensive responses following oral administration of β-adrenoceptor blocking drugs to the conscious cat

On oral administration, the non-selective beta-adrenoceptor blocking drugs (+/-)-bufuralol, (-)-bufuralol, propanolol, oxprenolol, pindolol and alprenolol produced hypotensive responses in the conscious cat; (+)-bufuralol was without effect. The selective beta-adrenoceptor blocking drugs practolol and atenolol had no effect on blood pressure but tolamolol elicited a hypotensive response. All the drugs tested reduced the tachycardia due to intravenous isoprenaline in the conscious cat; however, not all doses of these drugs reduced blood pressure. (+)-Bufuralol was devoid to beta-adrenoceptive blocking activity. Only tolamolol reduced the pressor response to i.v. phenylephrine in the conscious cat, indicating that alpha-adrenoceptive blocking activity may contribute to its hypotensive action. The results suggest that beta-adrenoceptive blocking activity is necessary for the hypotensive responses of these drugs. However, for the different drugs, there was no correlation between peripheral beta-adrenoceptive blocking activity and hypotensive response.

K+ channel activators, acute glucose tolerance and glibenclamide-induced hypoglycaemia in the hypertensive rat

The effects of the K+ channel activators, levcromakalim, pinacidil and diazoxide, at comparable antihypertensive doses, on acute glucose tolerance and glibenclamide-induced hypoglycaemia were examined in conscious spontaneously hypertensive rats (SHR). Levcromakalim (0.15 mg.kg-1 p.o.) and pinacidil (1.0 mg.kg-1 p.o.) caused a slight, but short-lived, impairment of glucose tolerance following oral or s.c. administration of glucose (2.0 g.kg-1). This effect, although small, was abolished by the beta-adrenoceptor blocker, propranolol (2.0 mg.kg-1 p.o.). Diazoxide (30.0 mg.kg-1 p.o.) caused a marked and sustained impairment of oral glucose tolerance and s.c. glucose tolerance, the profile of which was quantitatively and qualitatively different from levcromakalim or pinacidil and was not significantly affected by propranolol. Glibenclamide (1.0-10. mg.kg-1 p.o.) elicited a dose-related hypoglycaemic response. Levcromakalim or pinacidil had little or no significant effect on the hypoglycaemic response elicited by glibenclamide (3.0 mg.kg-1). Conversely, diazoxide both abolished and reversed glibenclamide-induced hypoglycaemia. We conclude that levcromakalim and pinacidil have only marginal and transient effects on glycaemic control in conscious SHR and that these disturbances are probably mediated indirectly via reflex activation of the sympathetic nervous system in response to blood pressure lowering. In addition, at active antihypertensive doses neither levcromakalim nor pinacidil significantly interfered with the ability of glibenclamide to reduce blood glucose concentration. Diazoxides impairment of oral glucose tolerance, s.c. glucose tolerance and glibenclamide response confirms this drugs well known ability to activate pancreatic KATP channels.

Comparison of the vasodilator activity of acetylcholine, cholinomimetics and other vasodilators in two vascular beds of the cat.

Abstract The relative vasodilator activities of acetylcholine, isoprenaline, histamine and papaverine differ in the autoperfused hindquarters and splanchnic region of the chloralosed cat. The cholinomimetic agents acetylcholine, oxotremorine and arecoline were active as vasodilators over a lower dose range in the hindquarters than in the splanchnic region. The vasodilator response of the splanchnic region to acetylcholine-like agents is not normally influenced by changes of intestinal motility but, after neostigmine, increases of vascular conductance produced by these agents in the splanchnic region were reduced, whereas those in the hindquarters were augmented. The difference in sensitivity of the blood vessels of the hindquarters and splanchnic region to acetylcholine-like drugs is possibly due to a combination of increased acetylcholinesterase activity and lower sensitivity of cholinoceptors in the splanchnic region.

Evidence for the involvement of α-adrenoceptor blockade in the antihypertensive action of diazoxide in the renal hypertensive rat

The effects of diazoxide on the blood pressure and heart rate of conscious renal hypertensive rats have been investigated. The antihypertensive action of diazoxide has been studied in relation to the effects of diazoxide pretreatment on pressor responses to stimulation of the complete sympathetic outflow and to injections of noradrenaline, phenylephrine, angiotensin and serotonin in pithed rats. In pithed preparations, pressor responses to sympathetic nerve stimulation, and to injected noradrenaline and phenylephrine were significantly reduced by diazoxide pretreatment, at a time corresponding to maximal reduction of blood pressure in conscious animals. At this time there was no significant reduction of pressor responses to injected angiotensin or serotonin. These findings suggest a contribution of alpha-adrenoceptor blockade to the antihypertensive activity of diazoxide.