Tolerance to peripheral, but not central, effects of ropinirole, a selective dopamine D2-like receptor agonist.

Studies were conducted to determine possible development, and underlying mechanisms, of tolerance to the hypotensive effects of ropinirole (4-[2-(dipropylamino)ethyl]-1-3-dihydro-2H-indol-2-one HCl), a selective dopamine receptor agonist, following twice daily oral administration to cynomolgus monkeys and spontaneously hypertensive rats (SHR). Tolerance to the hypotensive effects of the compound developed in both species within one week of repeated dosing. Tolerance which developed in rats was dose-related and could not be attributed to altered plasma/drug concentrations or be overcome by increasing the i.v. challenge dose of ropinirole. Cross-tolerance was shown to the dopamine receptor agonist bromocriptine. Similar hypotensive responses to bethanidine were seen in rats treated with ropinirole or vehicle. Tolerance to hypolocomotor effects of the compound were not apparent in the same time frame. The dopamine D2 receptor antagonist, domperidone, caused hypertension in ropinirole-but not vehicle-treated rats. Results reported in this paper are not consistent with a down-regulation of peripheral dopamine D2-like receptors but suggest a compensatory increase in basal sympathetic tone.

The effect of SK&F 95654, a novel phosphodiesterase inhibitor, on cardiovascular, respiratory and platelet function.

1. SK&F 95654 inhibited the guanosine 3':5'-cyclic monophosphate (cyclic GMP)-inhibited phosphodiesterase (cGI-PDE) with an IC50 value of 0.7 microM. The IC50 values were greater than 100 microM for the other four phosphodiesterase isoenzymes tested. The R-enantiomer of SK&F 95654 (IC50 = 0.35 microM) was a more potent inhibitor of cGI-PDE than was the S-enantiomer (IC50 = 5.3 microM). 2. In the guinea-pig working heart, SK&F 95654 produced a positive inotropic response without altering heart rate. 3. Oral administration of SK&F 95654 to conscious dogs caused dose-dependent increases in left ventricular dp/dtmax in the range 10-50 micrograms kg-1. These positive inotropic responses were maintained for 3 h without simultaneous changes in heart rate or blood pressure. The peak effects on left ventricular dp/dtmax were similar for orally and intravenously administered compound, indicating good oral bioavailability. 4. SK&F 95654 caused a potent inhibition of U46619-induced aggregation in both a human washed platelet suspension (WPS) (IC50 = 70 nM) and in human platelet-rich plasma (PRP) (IC50 = 60 nM), indicating that the compound shows negligible plasma binding. 5. The R-enantiomer of SK&F 95654 was twenty fold more potent as an inhibitor of platelet aggregation than was the S-enantiomer. The similarity of this ratio to that obtained on the cGI-PDE suggests that SK&F 95654 inhibits platelet aggregation via its effects on cGI-PDE. This was also indicated by studies which showed that SK&F 95654 increased adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels and activated cyclic AMP-dependent protein kinase in human platelets. 6. Collagen-induced aggregation of rat PRP was also inhibited by SK&F 95654 (ICso = 65 nM). The effects of SK&F 95654, administered intravenously, on ex vivo platelet aggregation were studied in the conscious rat. At 1 mg kg-', SK&F 95654 inhibited aggregation for at least 4 h post dose and was more potent than the two other cGI-PDE inhibitors studied (siguazodan and SK&F 94120).7. In contrast to its potent effects on heart and platelets, SK&F 95654 caused only a modest relaxation of histamine- or U46619-induced bronchoconstriction in the anaesthetized, ventilated guinea-pig.8. Taken together, these results indicate that SK&F 95654 may be a suitable agent for the treatment of congestive heart failure.

Preclinical pharmacology of ropinirole (SK&F 101468-A) a novel dopamine D2 agonist.

These studies characterise the pharmacology of ropinirole, a selective D-2 agonist. High-affinity human caudate binding revealed a Ki for D2 receptors of 2.9 x 10(-8) M with no affinity for D1 at 10(-4) M in the rat. Ropinirole was weakly active at alpha 2-adrenoceptors and 5-HT2 receptors but inactive at 5-HT1, benzodiazepine and gamma-aminobutyric acid receptors or alpha 1 and beta-adrenoceptors. In rodents, ropinirole, like apomorphine, caused biphasic spontaneous locomotor activity and contralateral circling in 6-OHDA-lesioned mice with no tolerance to the latter after 14 days treatment. Amphetamine caused ipsilateral responses in the lesioned mice. Ropinirole did not cause marked stereotypies. In marmosets ropinirole (0.05-1.0 mg/kg SC or 0.1 mg/kg PO) reversed all motor and behavioural deficits induced by MPTP. This response started 10-20 minutes after dosing, and exceeded 2 hours. No tolerance was seen following chronic b.i.d. treatment. Similar results were obtained with 1-dopa plus benserazide; however, 1-dopa always caused emesis, whereas beneficial effects were shown with ropinirole in the absence of this side effect. These results support the continued clinical assessment of ropinirole for the treatment of Parkinson's disease.

Potential use of selective phosphodiesterase inhibitors in the treatment of asthma.

Selective inhibitors of the cyclic nucleotide phosphodiesterase (PDE) isoenzymes have been studied to assess the potential for such agents in the treatment of asthma. A novel selective PDE V inhibitor, SK&F 96231, reversed the bronchoconstriction induced in anaesthetised guinea pigs by histamine, a thromboxane-mimetic or by ovalbumin challenge. There was no effect of SK&F 96231 on heart rate or blood pressure in conscious dogs. Siguazodan (SK&F 94836, a selective PDE III inhibitor) caused bronchodilation but also had cardiovascular effects in conscious dogs. Studies on the PDE profile of various inflammatory cells have indicated that inhibition of PDE IV would be beneficial in the treatment of the inflammatory aspects of asthma and this is briefly reviewed.

The role of DA1- and DA2-receptors in the control of blood pressure.

1. Endogenous dopamine, acting through specific receptors on blood vessels, renal tubules and adrenal cortical cells, may play a role in the development and maintenance of the hypertensive state. 2. In hypertensive patients, activation of the DA1-receptor with intravenous fenoldopam produces a rapid and sustained reduction in blood pressure, in contrast to the tachyphylaxis seen in some rat models. 3. Activation of the DA2-receptor also represents a viable antihypertensive approach, based on the chronic efficacy of hydergine. However, none of the recently developed selective DA2-receptor agonists has been shown to reduce blood pressure in man. 4. Since animal experiments suggest qualitatively different antihypertensive profiles for quinpirole and SK&F 101468, both presumed to be selective agonists at the DA2-receptor, it may be possible to design new DA2-receptor agonists more effective as antihypertensive drugs. 5. Dopamine receptors at different sites, even if of the same subtype, can be differentially regulated; this may be a consequence of activation of multiple second messenger systems by receptor occupation.

Autonomic and haemodynamic responses to SK & F 101468 (ropinirole), a DA2 agonist, in anaesthetised cats.

The haemodynamic and autonomic nervous system effects of the DA2 agonist, SK & F 101468, have been studied in anaesthetised cats. SK & F 101468 inhibited the tachycardia response to cardiac accelerans nerve stimulation. The inhibition, reversed by L-sulpiride a selective DA2 receptor antagonist, was dose-dependent over the dose range 10-50 micrograms.kg-1 and there was proportionally greater inhibition of the responses to low rather than high frequency stimulation. There was evidence that SK & F 101468-A inhibited sympathetically mediated reflexes, but even at high doses, of up to 500 micrograms.kg-1, there was no inhibition of end-organ responsiveness to noradrenaline, isoprenaline or acetylcholine nor of the bradycardia caused by vagus nerve stimulation. SK & F 101468-A produced falls in blood pressure and heart rate at 50 and 500 micrograms.kg-1, but stroke volume, aortic blood flow and total peripheral resistance, were only slightly affected. These effects of SK & F 101468 in the intact cardiovascular system are consistent with an action on presynaptic receptors at sympathetic nerve endings to reduce transmitter release and thereby selectively reduce responses to sympathetic nerve stimulation.

In vivo pharmacological studies with SK&F 94836, a potent inotrope/vasodilator with a sustained duration of action.

1. SK&F 94836 (racemate) was studied in vivo for its cardiovascular properties in cats and dogs. 2. In anaesthetized cats and dogs SK&F 94836 administered intravenously caused increases in left ventricular contractility and decreases in peripheral vascular resistance at similar doses, thus demonstrating the compound to be a mixed acting positive inotropic/vasodilator agent. 3. In conscious instrumented dogs SK&F 94836 was active via the oral as well as intravenous route. 4. The inodilator activity of SK&F 94836 in conscious and anaesthetized animals occurred in association with minimal changes in either blood pressure or heart rate. 5. Detailed studies carried out on anaesthetized cats indicated that SK&F 94836 caused a balanced dilatation of both resistance and capacitance blood vessels. 6. Haemodynamic studies in anaesthetized cats indicated that as a consequence of the inotropic/vasodilator actions, SK&F 94836 caused significant increases in cardiac output and stroke volume. 7. Detailed studies in anaesthetized dogs indicated that significant inodilator activity occurred in the absence of an increase in myocardial oxygen consumption. 8. The duration of action of SK&F 94836 was sustained following both i.v. and oral administration. 9. We conclude that SK&F 94836, as an orally active inotropic/vasodilator agent with a sustained duration in vivo, has potential utility in the treatment of congestive heart failure.

SK & F 95018, a vasodilator/beta-adrenoceptor antagonist.

The pharmacological properties of a novel vasodilator/beta-adrenoceptor antagonist, SK & F 95018 6-[4-[3-(3-[4-(2-Cyclopropylmethoxyethyl)phenoxy]-2- hydroxypropylamino)propionamido]phenyl]-4,5-dihydro-5-met hylpyridazin- 3(2H)-one methanesulphonate] are described. SK & F 95018 lowered blood pressure and increased hindquarters blood flow in anaesthetised rats over the same dose range 1-5 mumol kg-1. Over a similar dose range SK & F 95018 inhibited isoprenaline-induced tachycardia in ganglion-blocked, anaesthetized cats. SK & F 95018 had minimal effect on bronchial beta 2-adrenoceptors, while simultaneously antagonizing cardiac beta 1-adrenoceptors in anaesthetized guinea-pigs. SK & F 95018 was demonstrated to be a potent antihypertensive agent in conscious spontaneously hypertensive rats over the dose range of 1.6-13 mumol kg-1 i.v. and 13-103 mumol kg-1 p.o. A marked and persistent hypotension was observed in conscious cats at a dose of 7.5 mumol kg-1 i.v. and 19 mumol kg-1 p.o., without reflex tachycardia. In anaesthetized cats, the hypotensive response to the compound was found to be via a reduction in total peripheral resistance with a maintained cardiac output. Vasodilatation and beta-adrenoceptor antagonism have been demonstrated in the same molecule (SK & F 95018) in a combination which would be suitable for effective treatment of hypertension.

Histamine H1-receptor antagonist activity assessed in conscious dogs.

A simple, minimally invasive technique is described which allows assessment of histamine H1-receptor antagonist activity in conscious dogs. The technique is based on the inhibition of the tachycardia caused by intravenous administration of the H1-receptor agonist, 2-pyridylethylamine. The response to 2-pyridylethylamine is dose dependent and is inhibited, in a dose-dependent manner by H1-receptor antagonists, such as temelastine, terfenadine, and chlorpheniramine. In contrast, cimetidine does not inhibit this response. This technique allows comparison of antagonist activity after either oral or intravenous administration of antagonists and also permits an assessment of the time course of antagonism.

Pharmacological properties of the stereoisomers of prizidilol: their use in analysis of reflex tachycardia and blood pressure control in normotensive cats, rats, and dogs.

Prizidilol, a combined vasodilator/beta-adrenoceptor antagonist, has two optical isomers. The pharmacological activities of these isomers have been established and heart rate/blood pressure responses to both isomers have been determined. Both the R and S isomers elicited similar blood pressure lowering and vasodilator activity in anaesthetised normotensive rats. S-Prizidilol was a substantially more potent beta-adrenoceptor antagonist in vitro and in vivo than R-prizidilol. Neither optical isomer showed any specificity for either beta 1- or beta 2-adrenoceptors. In conscious rats both isomers lowered blood pressure similarly with only marginal differences in heart rate. In conscious cats the importance of increased sympathetic drive in reflex tachycardia was emphasised by the incidence of tachycardia after R-prizidilol but not after S-prizidilol when administered at equieffective blood pressure lowering doses. In conscious dogs both isomers caused tachycardia although S-prizidilol tended to cause the greater fall in blood pressure.

Pharmacological studies with SK&F 94120, a novel positive inotropic agent with vasodilator activity.

The pharmacological properties of SK&F 94120 on the cardiovascular system have been studied in laboratory animal species. The compound was shown to have positive inotropic activity on hearts from guinea-pig, cat, dog and marmoset in-vitro and in cat and dog in-vivo. These responses in-vivo occurred in association with minimal changes in heart rate. Positive inotropic activity was not caused by SK&F 94120 in rat or hamster hearts in-vitro, thereby indicating a species dependence in myocardial response. SK&F 94120 was shown to have vasodilator activity in cats in-vivo. Detailed studies carried out on anaesthetized cats indicated that the compound caused a balanced dilatation of both resistance and capacitance blood vessels. Haemodynamic studies in anaesthetized cats indicated that, as a consequence of the positive inotropic and vasodilator actions, SK&F 94120 causes significant increases in cardiac output and stroke volume. Studies in conscious dogs showed the compound to be active as a positive inotrope after oral administration. The above properties suggest that this compound possesses useful haemodynamic properties for the treatment of congestive heart failure.

Cardiotoxicity of a new inotrope/vasodilator drug (SK&F 94120) in the dog.

The cardiotoxicity and haemodynamic changes induced by IV administration of high doses of SK&F 94120, a novel positive inotrope/vasodilator, were studied in the dog. Inotropism was observed at a dose of 0.375 mg/kg. Mean blood pressure was reduced in a dose-related manner, reaching a nadir of 43.7 mm Hg at 24 mg/kg. Heart rate was increased at doses of 1.5 mg/kg and above. ECG examination revealed a shortening of PR interval and an increase in T-wave amplitude. At doses of 15 mg/kg and above, occasional AV dissociation with accrochage were sometimes seen shortly after the start of the infusion. Ventricular extrasystoles were only seen at doses of 120 mg/kg and above. A dose-related increase in severity and incidence of haemorrhages, deposition of haemosiderin and fibroplasia were seen in the left ventricular endocardium and atrioventricular valves at doses of 15 mg/kg and above. Focal myocardial necrosis, predominantly of the left ventricular papillary muscle, and mild periarteritis of medium-sized extramural arteries, mostly in the right atrium, were seen at doses of 45 mg/kg and above. Intimal proliferation of intra- and extramural coronary vessels was observed. A necrotising peri/panarteritis of these arteries was noted at doses of 200 and 400 mg/kg. The cardiotoxicity observed was considered to be due to the exaggerated pharmacologic effects seen at these high dose levels.

Studies on the autonomic nervous system with SK&F 92657, a new antihypertensive agent causing direct arterial vasodilatation and beta-adrenoceptor blockade.

The beta-adrenoceptor-blocking properties of SK&F 92657, D,L-3-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-6-hydrazinopyridazine, were studied in both in vivo and in vitro. The pA2 against isoprenaline tachycardia (beta 1 effect) in isolated guinea pig right atria was 7.16 (6.14-7.87). In contrast, histamine-induced tachycardia was unaffected by SK&F 92657. The pA2 against isoprenaline relaxation of guinea pig tracheal muscle (beta 2 effect) was 7.03 (6.28-7.61). In vivo ED50's against isoprenaline tachycardia (beta 1) and vasodilation (beta 2) in anesthetized cats were 5.7 x 10(-8) and 6.2 x 10(-8) mol/kg, i.v., respectively. Increases in heart rate caused either by activation of autonomic reflexes or by stimulation of efferent cardiac sympathetic nerves were also antagonized by SK&F 92657. The beta-adrenoceptor blockade caused by SK&F 92657 was shown to be competitive both in vivo an vitro and to be equally effective on beta 1- and beta 2-receptor populations. SK&F 92657 was a weak partial agonist in vivo and had only minimal local anesthetic activity. The compound had no direct effect on the functioning of the autonomic nervous system, apart from beta-blockade, but reflexes maintaining homeostasis were reduced because (1) SK&F 92657 is a beta-adrenoceptor antagonist preventing reflex increases in heart rate and cardiac output, and (2) it is a potent vasodilator counteracting reflex vasoconstriction. Postural reflexes were unaffected because SK&F 92657 selectively dilates arterial blood vessels.

Hemodynamic profile of a new antihypertensive agent D,L-3-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-6-hydrazinopyridazine (SK&F 92657).

The properties of a new antihypertensive agent, SK&F 92657, D,L-3-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-6-hydrazinopyridazine, have been studied. The compound, given intravenously, subcutaneously, or orally, caused a sustained fall in systemic blood pressure of conscious genetically hypertensive rats, normotensive cats, and renal hypertensive dogs. The fall in blood pressure of genetically hypertensive rats was maintained during 52 days of chronic dosing with no development of tolerance. The hemodynamic effects and mechanism of action of SK&F 92657 were investigated in anesthetized cats and dogs using a variety of techniques. Blood pressure was lowered by a direct vasodilator effect on precapillary blood vessels (arteries, arterioles), particularly in the renal, coronary, and skeletal muscle vasculatures, giving an overall decrease in total peripheral resistance with no significant change in cardiac output. In contrast, SK&F 92657 had no significant effect on capacitance blood vessel (veins, venules) tone or on vascular reactivity to vasoconstrictors and consequently did not cause postural hypotension. The beta-adrenoceptor-blocking actions of the drug prevented reflex increases in heart rate and cardiac output, except in the conscious dog, where vagal control of heart rate was predominant. It was also concluded that SK&F 92657 was not acting by alpha-adrenoceptor blockade, ganglion blockade, or inhibition of angiotensin II responses. A "central" action was unlikely, as SK&F 92657 caused vasodilatation in denervated autoperfused vascular beds.