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There is a small increase in the functional β2-adrenoceptor response on the spontaneously hypertensive rat (SHR) left atrium in the early stages of hypertension. In the present study, the functional β1 - and β2-adrenoceptors of the left and right atrium in SHR pre-hypertension and age-matched (5-week-old) Wistar Kyoto (WKY) rats were characterized. Contractility methods with isoprenaline, T-0509 (a selective β1-adrenoceptor agonist) and procaterol (a selective β2-adrenoceptor agonist) were used. At 5 weeks, the SHRs were pre-hypertensive. Isoprenaline was more potent on the left atrium of 5-week-old SHRs than WKY rats. Bisoprolol, a selective β1-adrenoceptor antagonist, was more potent against isoprenaline and T-0509 on the SHR than WKY rat left atrium. ICI 118,551, a selective β2-adrenoceptor antagonist, was more potent against procaterol and T-0509 on the SHR than WKY rat left atrium. The results with bisoprolol and ICI 118,551 suggest that there are more functional β1- and β2-adrenoceptors on the left atrium of 5-week-old SHRs than WKY rats. Isoprenaline, T-0509 and procaterol were equipotent on the right atrium of 5-week-old WKY rats and SHRs. Bisoprolol was more potent against isoprenaline, T-0509 and procaterol on the SHR than WKY rat right atrium. ICI 118,551 was more potent against T-0509, but not isoprenaline and procaterol, on the SHR than WKY rat left atrium. This suggests there are more functional β1-adrenoceptors, and probably more functional β2-adrenoceptors, on the right atrium of 5-week-old SHRs than WKY rats. These functional differences in β1 - and β2-adrenoceptor-mediated responses of the left and right atria of pre-hypertensive SHRs cannot be caused by hypertension, and may be associated with the onset of hypertension.

In the first part of this study, we characterized 24-month-old Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs), their heart weights, and the responses of the isolated left ventricles to electrical stimulation. In the main part of the study, we tested whether the positive inotropic effects of BDF 9198, which prevents the closure of the cardiac sodium channel, were present in senescence and heart failure. Thus, we studied the effects of BDF 9198 on the left ventricle strips of 24-month-old WKY rats (senescence) and SHRs using contractility methods. In comparison with WKY rats, the left ventricles of 24-month-old SHRs were hypertrophied and had prolonged times to peak contraction. BDF 9198 (10−8 to 10−6m) was a positive inotrope on the left ventricles of WKY rats, with a maximum augmenting effect of 122% with BDF 9198 at 10−7m. The magnitude of the augmenting effects of BDF 9198 were reduced in SHR heart failure, with a maximum augmenting effect of 26% at 10−7m. BDF 9198 at 10−6 m attenuated the responses of the SHR left ventricle to electrical stimulation. In conclusion, the potential of drugs that prevent closure of the sodium channel as positive inotropes in the treatment of heart failure should be further considered.

The aim was to test whether dofetilide has some potential for use in the treatment of heart failure. Dofetilide at ≤3 times 10−5 M had no effect on the quiescent Wistar Kyoto (WKY) rat aorta, mesenteric and intralobar arteries, or the spontaneous contractions of the WKY rat portal vein. Dofetilide at 10−6 to 3 times 10−5 M relaxed the KCl-contracted aorta. Dofetilide at 10−9-10−7 M augmented the force of contraction of left ventricle strips from 12- and 18-month-old WKY rats at 2 Hz. Spontaneously hypertensive rats (SHRs) at 12 and 17–21 months of age are models of cardiac hypertrophy and failure, respectively. The augmentation of force at 2 Hz with dofetilide was similar on 12-and 18-month-old WKY rats and 12-month-old SHRs but reduced on the 18-month-old SHR left ventricle. At a higher more physiological frequency, 4 Hz, the threshold concentration of dofetilide required to augment the force responses of 21-month-old SHR left ventricles was markedly increased and the maximum augmenting effect was decreased. Dofetilide at 10−7-10−5 M reduced the rate of the 17-month-old WKY rat right atrium, and had a similar effect on age-matched SHR right atrium. In summary, dofetilide is a positive inotrope and negative chronotrope in the rat. However, as the positive inotropic effect is not observed with clinically relevant concentrations at a physiological rate in heart failure, dofetilide is unlikely to be useful as a positive inotrope in the treatment of heart failure.

The objective of this study was to determine the responsiveness, affinity constants and β-adrenoceptor reserves for isoprenaline on the isolated aorta in the maturation of normotensive and hypertensive rats. The effects of a very slowly reversible antagonist, bromoacetylalprenololmenthane (BAAM), on the relaxant responses of the aortae of 5- and 14-week-old Wistar kyoto normotensive rats (WkY) and spontaneously hypertensive rats (SHRs) to isoprenaline were determined. Five-week-old SHRs are pre-hypertensive and the aortic rings are less responsive to isoprenaline than age-matched WkY (pD2 values: WkY, 8.40; SHRs, 8.03). Similar relaxant responses to forskolin were obtained on the aortae of 5- and 14-week-old WkY and SHRs. The kA value for isoprenaline at the aortic β2-adrenoceptors of the 5-week-old WkY was 2.1 times 10−7 M, and similar values were obtained on the aortae of 5-week-old SHR and 14-week-old WkY and SHRs. In the maturation of the WkY aortae from 5 to 14 weeks, there was a reduction in the maximum response, a major loss of sensitivity and a loss of β2-adrenoceptor reserve for isoprenaline. On 5-week-old SHR aorta, the sensitivity to isoprenaline was 2.5-fold lower, and the β2-adrenoceptor reserve was less than on age-matched WkY. In the development of hypertension on the SHR aorta from 5 to 14 weeks, there was a reduction in the maximum response to isoprenaline. At 14 weeks, the sensitivity and the β2-adrenoceptor reserve to isoprenaline were similar, but the maximum responses were lower on the SHR than WkY. As there are differences in pre-hypertensive SHR and age-matched WkY aortic responses to isoprenaline, it is no longer valid to consider that the loss of responsiveness to isoprenaline in hypertension is solely owing to the hypertension. There are no changes in affinity, but major changes in the sensitivity, maximum responses and aortic β2-adrenoceptor reserves to isoprenaline in the maturation of normotensive and pre-hypertensive aortae.

Previously we have determined the potency, affinity constants (KA values), and α1-adrenoceptor reserves for noradrenaline and adrenaline on the thoracic aortae of 20-week-old Wistar Kyoto normotensive (WKY) and spontaneously hypertensive rats (SHRs). This study has investigated whether these parameters were altered on the thoracic aortae by ageing, and in hypertension/heart failure. The effects of phenoxybenzamine on the contractile responses of the aortae of 20-month-old WKYs and SHRs were determined. The pD2 values for noradrenaline and adrenaline were 7.1 and 7.0, respectively, on the aortae of 20-month-old WKYs, and similar values were obtained on age-matched SHRs. On the aortae of 20-month-old WKYs, the KA values for noradrenaline and adrenaline were 1.85 and 1.95 × 10−6 M, and the receptor occupancies required for 50% maximum responses were 16 and 24%, respectively. There were lower affinities, by approximately twofold, but similar receptor reserves for noradrenaline and adrenaline on the aortae of age-matched SHRs. In comparison with the aortae of 20-week-old WKYs and SHRs, there was a 5-fold loss of sensitivity to noradrenaline and adrenaline between 20 weeks and 20 months. Between 20 weeks and 20 months there was a 50-fold loss of affinity with ageing and a further twofold loss with hypertension/heart failure, and an increase in α1-adrenoceptor reserves for noradrenaline and adrenaline between 20 weeks and 20 months. There were no differences in the sensitivity and affinity, and minor changes in the α1-adrenoceptor reserves for noradrenaline and adrenaline between the aortae of 20-month-old WKYs and SHRs. In contrast there were major changes in these parameters in the ageing of the WKY aorta from 20 weeksto 20 months. There were no additional changes in the sensitivity and α1-adrenoceptor reserves, but a small additional change in affinity for noradrenaline and adrenaline in hypertension/heart failure on the aortae of 20-month-old SHRs.

Veratridine and BDF 9148 both increase the force of myocardial contraction but their effects on the contractility of vascular smooth muscle are largely unknown. We have examined the effects of the drugs on the contractile force of the rat portal vein. The force responses of the rat portal vein were not altered by tetrodotoxin (≤ 30 μM) but were augmented by Bay K 8644 (10 nM-10 μM), and attenuated by nifedipine (10 nM-10 μM). Veratridine slightly reduced the force of spontaneous contractions at concentrations of 0.1−1 μM, then augmented the force at concentrations up to 100 μM. The reduction was prevented by 30 nM tetrodotoxin; a higher concentration of 3 μM prevented the effect of veratridine. Pretreatment with nifedipine at 30 nM reduced the maximum augmentation observed with veratridine. BDF 9148 (0.3−300 μM) attenuated the force and this attenuation was increased in the presence of tetrodotoxin at 3 μM but reversed to an augmentation in the presence of Bay K 8644 at 10 μM. The augmentation produced by BDF 9148 in the presence of Bay K 8644 was reduced by tetrodotoxin at 30 nM. These results suggest that veratridine predominantly opens sodium channels which in turn open voltage-dependent calcium channels to augment the force responses of the rat portal vein, but attenuate force in the presence of sodium-channel blockade with tetrodotoxin. BDF 9148 predominantly closes calcium channels to attenuate the force of the rat portal vein but in the presence of maximum calcium-channel opening with Bay K 8644 augments force probably by opening sodium channels.

Differing effects of labetalol and dilevalol on cardiovascular preparations have been reported. I have studied the effects of labetalol and dilevalol on the contractile responses of the rat and guinea-pig left atria and rat portal vein. On the guinea-pig left atria low concentrations of labetalol (≥ 10−8 m) and of dilevalol (≥ 10−7 m) inhibited to a small extent the responses to electrical cardiac stimulation, which is indicative of membrane stabilizing activity. Labetalol (≥ 3× 10−8 m) and dilevalol (≥ 10−8 m) caused surmountable antagonism of the isoprenaline responses of the atria and the pA2 values were 8·60 and 8·98 at the β1-adrenoceptors of the rat left atria and 7·90 and 8·31, respectively, on the guinea-pig left atria which has functional β1 and β2-adrenoceptors. Labetalol and dilevalol (both at ≥ 10−7 m) attenuated the spontaneous contractile activity of the rat portal vein and the attenuation to labetalol at 10−6 m was abolished by ICI 118,551 which illustrates that the labetalol-induced attenuation is β2-adrenoceptor mediated. The isoprenaline attenuation responses of the portal vein were inhibited by labetalol and dilevalol (both at ≥ 10−7 m) and the pA2 value for the labetalol at β2-adrenoceptors was 7·59. It is concluded that labetalol and dilevalol are β1-adrenoceptor selective antagonists.

Differing effects of (±)-celiprolol at β-adrenoceptors have been reported. The effects of (±)-, (+)- and (—)-celiprolol on the contractile responses of the rat left atria and portal vein have therefore been studied. (±)-Celiprolol did not augment the responses of the atria to electrical stimulation and is therefore not an agonist at β1-adrenoceptors. Prolonged treatment with (±)-celiprolol attenuated the contractile activity of the vein and this effect was blocked by ICI 118,551 and is therefore mediated by agonism at β2-adrenoceptors. The pA2 values for (±)-, (+)- and (–)-celiprolol at the β1-adrenoceptors of the atria were 8·0, 6·0 and 8·6, respectively. On the portal vein, (±)- and (–)-celiprolol produced non-parallel rightward shifts of log isoprenaline attenuation curves with a reduction in isoprenaline maximum responses. This effect of (±)-celiprolol on the vein was not due to slowly reversible antagonism, as the inhibitory effect of (±)-celiprolol was readily reversible.

The effects of (±)-, (+)- and (-)-celiprolol and of bromoacetylalprenololmentane (BAAM, an irreversible β-adrenoceptor antagonist) on the contractile responses of the electrically driven rat right ventricle strip to isoprenaline and on the relaxant responses of the rat aorta to procaterol, have been studied. Racemic and (-)-celiprolol or BAAM treatment of the ventricle produced non-parallel rightward shifts of the isoprenaline response curves with a reduction in the maximal response. Sotalol produced parallel rightward displacements of the procaterol response curves of the aorta with no effect on the maximal relaxations. Racemic and (+)- and (-)-celiprolol or BAAM treatment of the aorta produced non-parallel rightwards shifts of the procaterol relaxant curves with a reduction in the maximal relaxation. The BAAM data was used to demonstrate that the KA (dissociation constant) for isoprenaline at β1-adrenoceptors was 1.46 × 10−7 M and for procaterol at β2-adrenoceptors was 2.34 × 10−5 M. Calculation of receptor occupancy demonstrated that to produce a maximal response of the rat right ventricle, isoprenaline had to occupy 87% of the β1-adrenoceptors. Likewise, for a maximal response of the rat aorta, procaterol had to occupy 81 % of the β2-adrenoceptors. It is suggested that the use of tissues with small β-adrenoceptor reserves has shown that (±)- and (-)-celiprolol are slowly dissociating, rather than readily reversible, β-adrenoceptor antagonists.

The endothelium-intact and -denuded rat aorta is hyperpolarized by racemic and (-)-pinacidil, probably by opening ATP-dependent potassium channels. (+)-Pinacidil caused depolarization of the endothelium-intact and -denuded rat aorta. The depolarization induced by 20 mm KC1 in the endothelium-intact rat aorta was reversed by racemic and (-)-, but not by (+)-pinacidil. On the endothelium-intact rat aorta, isoprenaline produced hyperpolarization and ICI 118 551 (erythro-(±)-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol) had no effect alone but prevented isoprenaline from causing hyperpolarization. The hyperpolarization induced by isoprenaline was reversed by racemic and (+)-, but not by (-)-pinacidil. Glibenclamide depolarized the endothelium-intact rat aorta and prevented the hyperpolarizing action of racemic pinacidil and (-)-pinacidil. (+)-Pinacidil prevented the hyperpolarizing action of (-)-pinacidil. Glibenclamide is probably preventing the hyperpolarization associated with opening of the ATP-dependent potassium channel by blocking this channel. Several mechanisms may underlie the depolarizing action of (+)-pinacidil, including blocking of ATP-dependent potassium channels.

Cromakalim at 50 μm and pinacidil at 0·1–10 μm had no effect, but pinacidil at 0·1 Mm had a negative inotropic effect on the rat electrically-driven left atria without altering the positive inotropic responses to isoprenaline or phenylephrine alone. Glibenclamide had no effect but 4-aminopyridine, procaine (30 μm) and tetraethylammonium (3 Mm) augmented the cardiac stimulation response. The ability of pinacidil to attenuate the cardiac stimulation response was not altered by glibenclamide, 4-aminopyridine or procaine but was prevented by pretreatment with tetraethylammonium. Thus, on the rat left atria, pinacidil has a negative inotropic effect which is unrelated to the opening of ATP-sensitive potassium channels, but may be due to opening the inward rectifying potassium channels.

The KCl contracted rat aorta is relaxed by procaterol, (±)-,(+)-and (—)-pindolol. The relaxations to procaterol, but not to (±)-pindolol, were prevented by ICI 118,551 at 10−6 M. The relaxations to (±)-pindolol are, therefore, not due to β-adrenoceptor agonism. At 10−7 M ICI 118,551, (±)-, (+)-and (-)-pindolol were β2-adrenoceptor antagonists as they inhibited the relaxant responses of the aorta to procaterol.

The KCl-contracted rat aorta is relaxed by labetalol, dilevalol, amosulalol and KF-4317. These relaxations are not reversed by ICI 118,551 at 10−6 M and, therefore, are not due to β-adrenoceptor agonism. At 10−7 M, labetalol, dilevalol, amosulalol and KF-4317 were β2-adrenoceptor antagonists as they inhibited the relaxant responses of rat aorta to procaterol.

The effects of antidepressants of tricyclic (amitriptyline, nortriptyline, protriptyline, doxepin, imipramine, and desipramine) and atypical (maprotiline, nomifensine, tandamine, viloxazine, CGP 6085A, and YM-08054-1) structures on contractile responses to exogenously applied acetylcholine and (−)-noradrenaline were studied in rat isolated anococcygeus muscle previously incubated with 6-hydroxydopamine. Atropine, amitriptyline, protriptyline, doxepin, imipramine, maprotiline and nortriptyline inhibited contractile responses to acetylcholine whereas desipramine, nomifensine, tandamine, viloxazine, CGP 6085A and YM 08054-1 did not. The contractile responses to (−)-noradrenaline were inhibited by low concentrations of tricyclic antidepressants and by higher concentrations of the atypical agents. These results illustrate that, in the preparation, the order of potency of antidepressants as muscarinic and as postsynaptic α-adrenoceptor antagonists is similar. The ability of tricyclic, but not atypical agents, to increase the concentration of noradrenaline bound to postsynaptic α-adrenoceptors may be severely limited by the antagonistic effect these agents have at this receptor.