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Biomedical subjects

S A Doggrell

Publications and source records attributed to S A Doggrell.

At least 37 records · Page 2Linked to original sources
PubMed2001

Gemfibrozil prevents major coronary events by increasing HDL-cholesterol and more.

A low concentration of plasma high-density lipoprotein (HDL)-cholesterol is a major risk factor for coronary heart disease (CHD). Gemfibrozil reduces the number of CHD events by 22% in 5 years. This marked beneficial effect can only partly be explained by the ability of gemfibrozil to increase HDL-cholesterol. Recently gemfibrozil has been shown to activate peroxisome proliferator-activated nuclear receptors. This activation leads to the increase in HDL-cholesterol and to a decrease in vascular wall inflammation and other changes in vascular function. These vascular effects of gemfibrozil may contribute to the beneficial effects in CHD.

Cholesterol, HDL↗
PubMed2001

ReoPro rules: results from the 'Do Tirofiban and ReoPro Give Similar Efficacy Trial' (TARGET).

In the treatment of atherosclerotic disease, stenting in the presence of a glycoprotein (GP) IIb/IIIa antagonist is becoming an increasingly common procedure. The 'Do Tirofiban and ReoPro Give Similar Efficacy Trial' (TARGET) was designed to determine whether the cheaper tirofiban was as effective and safe as abciximab in the prevention of ischaemic events with stenting. Unexpectedly, abciximab was shown to be superior to tirofiban. Tirofiban is a selective GP IIb/IIIa antagonist whereas abciximab has additional anti-inflammatory actions, which may contribute to its superiority.

Abciximab↗
PubMed2001

Pharmacology down under in 2001.

Every December, pharmacologists and toxicologists of Australia and New Zealand gather for the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists annual scientific meeting. The 2001 meeting highlighted the areas of cardiovascular research and neurodegeneration and neuroprotection. Cardiovascular researchers are investigating such areas as drugs for pulmonary hypertension, links between superoxide dismutase and cardiovascular disease, and angiogenesis. There was considerable discussion as to why neuroprotective agents that are so promising in animals fail in the clinic. Potential new agents and new targets for neuroprotection were also considered.

Journal Article↗
PubMed2000

Effects of BDF 9198 on action potentials and ionic currents from guinea-pig isolated ventricular myocytes.

BDF 9198 (a congener of DPI 201 - 106 and BDF 9148) was found to be a positive inotrope on guinea-pig isolated ventricular muscle strips. The effects of BDF 9198 on action potentials and ionic currents from guinea-pig isolated ventricular myocytes were studied using the whole cell patch clamp method. In normal external solution, at 37 degrees C, action potential duration at 50% repolarization (APD(50)) was 167.4+/-8.36 ms (n=37). BDF 9198 produced a concentration-dependent increase in APD(50) (no significant increase at 1x10(-10) M; and APD(50) values of 273.03+/-35.8 ms at 1x10(-9) M; n=6, P<0.01 and 694.7+/-86.3 ms at 1x10(-7) M; P<0.001, n=7). At higher concentrations in the range tested, BDF 9198 also induced early and delayed and after-depolarizations. Qualitative measurements of I(Na) with physiological [Na](o) showed prolongation of the current by BDF 9198, and the appearance of transient oscillatory inward currents at high concentrations. Quantitative recording conditions for I(Na) were established using low external [Na] and by making measurements at room temperature. The current - voltage relation, activation parameters and time-course of I(Na) were similar before and after a partial blocking dose of Tetrodotoxin (TTX, 1 microM), despite a 2 fold difference in current amplitude. This suggests that voltage-clamp during flow of I(Na) was adequately maintained under our conditions. Selective measurements of I(Na) at room temperature showed that BDF 9198 induced a concentration-dependent, sustained component of I(Na) (I(Late)) and caused a slight left-ward shift in the current - voltage relation for peak current. The drug-induced I(Late) showed a similar voltage dependence to peak current in the presence of BDF 9198. Both peak current and I(Late) were abolished by 30 microM TTX and were sensitive to external [Na]. Inactivation of control I(Na) during a 200 ms test pulse to -30 mV followed a bi-exponential time-course. In addition to inducing a sustained current component, BDF 9198 left the magnitude of the fast inactivation time-constant unchanged, but increased the magnitude of the slow inactivation time-constant. Additional experiments with a longer pulse (1 s) raised the possibility that in the presence of BDF 9198, I(Na) inactivation may be comprised of more than two phases. No significant effects of 1x10(-6) M BDF 9198 were observed on the L-type calcium current, or delayed and inward rectifying potassium currents measured at 37 degrees C. It is concluded that the prolongation of APD(50) by BDF 9198 resulted from selective modulation of I(Na). Reduced current inactivation induced a persistent I(Na), increasing the net depolarizing current during the action potential. This action of the drug indicates a potential for 'QT prolongation' of the ECG. The observation of after-depolarizations suggests a potential for proarrhythmia at some drug concentrations.

Action Potentials↗
PubMed2000

Effects of clofilium on cardiovascular tissues from normo- and hypertensive rats.

1. The overall aim was to test whether clofilium has some potential as a positive inotrope for heart failure. We used Wistar Kyoto normotensive rats (WKY) and spontaneously hypertensive rats (SHRs) and studied the effects of clofilium on isolated blood vessels, left ventricular action potentials and left ventricular contractility. 2. Clofilium at < or = 10(-6) M had no effect on WKY portal vein contractions and at < or = 3 x 10(-4) M had no effect on WKY or SHR quiescent mesenteric and intralobar pulmonary arteries. 3. Clofilium at 10(7) - 10(-5) M prolonged the WKY left ventricular action potentials and with 10(-6) and 10(-5)M this included after-depolarizations. 4. Clofilium at < or = 3 x 10(-5) M augmented the peak force, prolonged the contractions and did not cause arrhythmias in the absence and presence of isoprenaline on left ventricle strips from 12-month-old WKY. 5. The 12-month-old SHR has hypertrophy of the left ventricle with reduced peak force and prolongation of relaxation. The effects of clofilium on 12-month-old SHR left ventricle contractility were similar to those in the age-matched WKY. 6 In summary, clofilium has positive inotropic effects on the rat left ventricle that are maintained in hypertrophy. Clofilium does not have effects on blood vessels that would be detrimental in heart failure. Clofilium prolongs the rat left ventricle action potential and causes after-depolarizations. The pro-arrhythmic potential of clofilium, however, makes it unlikely that it could be used as a positive inotrope in the treatment of heart failure.

Action Potentials↗
PubMed2000

The heart as a target for oestrogens.

Observational studies have consistently shown a markedly decreased risk of cardiovascular disease in postmenopausal women when treated with oestrogens. This review discusses plausible mechanisms for the physiological effects of oestrogens in healthy and diseased hearts. Oestrogens have well-documented effects on blood lipids and the regulators of the cardiovascular system, which should reduce risk. In addition, the heart is a primary target for oestrogens with functional oestrogen receptors in the coronary vasculature and on cardiac myocytes and fibroblasts. Rapid oestrogen effects include vasodilatation and anti-arrhythmic effects by actions on ion channels, and some of these effects may be pharmacological rather than physiological. Longer term responses to physiological levels of oestrogen include an increased expression of nitric oxide synthase in myocytes and endothelial cells as well as proinflammatory and pro-arrhythmic effects. Oestrogens induce growth of non-proliferating fibroblasts but inhibit the replication of proliferating fibroblasts. In contrast to the observational studies, two randomised, controlled studies of oestrogen and progestins in postmenopausal women with coronary heart disease have now shown increased coronary events, especially in the first year of study, and no change in the progression of coronary atherosclerosis. Further studies of the complex effects of oestrogens on healthy and diseased animal models are essential. Large clinical trials of the newer selective oestrogen receptor modulators to lower cardiovascular risk in both males and females should be considered as a priority.

Journal Article↗
PubMed2000

Effects of azimilide on cardiovascular tissues from normo- and hypertensive rats.

We tested whether azimilide has potential for use in the treatment of heart failure. Azimilide, > or =3 x 10(-5) M, had no effect on the quiescent Wistar-Kyoto (WKY) rat aorta, or mesenteric and intralobar pulmonary arteries. Azimilide > or =3 x 10(-5) M relaxed the KCl-contracted aorta and portal vein. Azimilide, 10(-7)-10(-5) M, prolonged the WKY left ventricular action potential and augmented the force of contraction of left ventricle strips from 12- and 22-month-old WKY rats. Spontaneously hypertensive rats (SHRs), at ages 12 and 22 months, are models of cardiac hypertrophy and failure, respectively. The augmentation of force with azimilide was similar on 12- and 22-month-old WKY rats and 12-month-old SHRs but reduced on the 22-month-old SHR left ventricle. Azimilide, 3 x 10(-6) and 10(-5) M, augmented the force responses of the 22-month-old SHR left ventricle by 40 and 50%, respectively. As azimilide is a vasodilator and positive inotrope in the rat, and the positive inotropic effect is present in heart failure, azimilide should undergo further testing as a positive inotrope for the treatment of heart failure.

Action Potentials↗
PubMed2000

D-Sotalol: death by the SWORD or deserving of further consideration for clinical use?

D-Sotalol is the dextro-rotatory isomer of sotalol and a class III anti-arrhythmic. D-Sotalol prolongs cardiac repolarisation by inhibiting the fast component of the delayed outward rectifying potassium channel. In animal studies, D-sotalol has been shown to be more effective in prolonging atrial, rather than ventricular, action potentials, suggesting that D-sotalol may be more effective against supra-ventricular than ventricular arrhythmias. Furthermore, in animal studies, D-sotalol induces after-depolarisations, which are predictors of pro-arrhythmic activity. D-Sotalol shows little or no reverse use dependence in animal and humans and has slow offset kinetics. This suggests that, in addition to being a preventative treatment for arrhythmias, D-sotalol may be effective at the start or during arrhythmia. As D-sotalol does not block the slow component of the delayed outward rectifying potassium channel, which is activated by the sympathetic nervous system, D-sotalol will not protect against sympathetic hyperactivity. D-Sotalol also has no effect on the K(ATP) channel, which is activated in ischaemia to shorten the action potential. Thus D-sotalol is less effective in ischaemia. Anti-arrhythmic activity with D-sotalol has been demonstrated in dog models of ventricular tachycardia and sudden death. Arrhythmias with D-sotalol have been demonstrated in an ischaemic guinea-pig ventricle model in the absence of action potentials. D-Sotalol is a weak beta-adrenoceptor antagonist and may also be a positive inotrope. In humans, D-sotalol has 100% systemic oral bioavailability, a terminal half-life of 7.2 h and is mainly excreted unchanged in the urine. Preliminary, mainly hospital-based, clinical trials showed that D-sotalol was effective in a variety of supraventricular and ventricular arrhythmias. However, a large clinical trial of D-sotalol as a preventative treatment for arrhythmias and sudden death after myocardial infarction, the SWORD trial, was terminated early because of increased mortality with D-sotalol. The group at greatest risk was those with a remote myocardial infarction and relatively good left ventricular function, the group that showed the lowest mortality when untreated. It is assumed that excessive prolongation of the action potential leading to pro-arrhythmia with D-sotalol, underlies the increased risk of death. However, there is little objective evidence in the SWORD trial to support this. Obviously D-sotalol should not be used in humans with a remote myocardial infarction and relatively good left ventricular function. D-Sotalol could still be considered for short-term hospital use in resistant arrhythmias and for longer-term use to prevent atrial fibrillation in those with remote myocardial infarction and poor left ventricular function.

Animals↗
PubMed2000

Pharmacology down under in 2000.

In December the pharmacologists and toxicologists of Australia and New Zealand get together for their annual scientific meeting, which is made up of pre-meeting workshops followed by invited lectures, symposia and free communications. This year, one of the pre-meeting workshops was on "Animal Models for the Development of Molecular Pharmaceuticals." Symposia included "Models and New Therapies for Traumatic Brain Injury" and "New Targets for Rheumatoid Arthritis." Novel medicines being developed in Australia revealed at the meeting included potassium channel blockers, C5a receptor agonists and antagonists, brain-derived neurotrophic factor mimetics and AM-36.

Journal Article↗
PubMed1999

Functional effects of 4-aminopyridine (4-AP) on pulmonary and systemic vessels from normoxic control and hypoxic pulmonary hypertensive rats.

The effects of the outward rectifying potassium channel blocker, 4-aminopyridine, on contractile tone and on contractile responses to the spasmogens, 5-hydroxytryptamine and endothelin-1, were examined in pulmonary arteries (main and intralobar) and systemic vessels (aorta and mesenteric artery) from rats with and without hypoxic pulmonary hypertension. Hypoxic pulmonary hypertension was induced by exposure of rats to 10% oxygen for 1 week. The development of pulmonary hypertension was associated with (i) depolarization of the cell membrane in intralobar pulmonary artery, but not aorta, and (ii) an increase in sensitivity to 5-hydroxytryptamine in pulmonary, but not systemic, vessels; sensitivity to endothelin-1 was unchanged. 4-Aminopyridine contracted all of the vessels studied. In pulmonary hypertension the sensitivity to 4-aminopyridine was increased ten-fold in pulmonary vessels but was unchanged in systemic vessels. Threshold concentrations of 4-aminopyridine (< or =3x10(-3) M) augmented contractions to 5-hydroxytryptamine in main pulmonary artery and aorta from control rats but failed to augment contractions to 5-hydroxytryptamine in main pulmonary artery from pulmonary hypertensive rats. Responses to endothelin-1 were not augmented by 4-aminopyridine. The membrane depolarization and the increases in sensitivity to 4-aminopyridine and 5-hydroxytryptamine seen in pulmonary hypertension are compatible with the concept that potassium channel function is altered in pulmonary, but not systemic, vessels from pulmonary hypertensive rats. Our data suggest that in main pulmonary artery a common mechanism is responsible for (i) the augmentation of 5-hydroxytryptamine responses by 4-aminopyridine in control rats, and (ii) the sensitization to 5-hydroxytryptamine seen in pulmonary hypertensive, compared with control, rats in the absence of 4-aminopyridine. Hence, we conclude that the sensitization to 5-hydroxytryptamine may be due to downregulation of 4-aminopyridine-sensitive potassium channels.

4-Aminopyridine↗
PubMed1999

The effects of lignocaine and tetrodotoxin on the action potentials and contractions of left ventricles from normo- and hypertensive rats.

The objective was to test the hypothesis that the effects of the sodium channel blockers lignocaine and tetrodotoxin are modified in the presence of hypertension-induced hypertrophy. We describe the effects of lignocaine and tetrodotoxin on the action potentials and contractions of left ventricles isolated from 6-month-old Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). The upstroke velocity, amplitude, and overshoot of the action potential were reduced; action potentials were prolonged; and the contractions were reduced on the hypertrophied left ventricles of the SHRs. Lignocaine and tetrodotoxin reduced the upstroke velocity, amplitude, and overshoot and prolonged the left ventricular action potentials. These effects of lignocaine and tetrodotoxin on the SHR were less than those on the WKY left ventricle, possibly because the action potential was already modified by hypertrophy. Lignocaine also reduced the left ventricular contractions and the concentrations producing this reduction were lower for the hypertrophied than those for the normal left ventricle. Tetrodotoxin at 3 x 10(-6)-10(-5) M caused similar attenuation of the WKY and SHR left ventricle contractions. Our study shows that the effects of lignocaine on contraction are enhanced in the hypertrophied left ventricle of the SHR, which suggests that the binding is increased or the access of lignocaine to the receptor is enhanced in hypertrophy. In contrast, the effects of tetrodotoxin on contractions are similar, and thus the binding or access of tetrodotoxin to the receptor is not altered in the hypertrophied left ventricle of the SHR.

Action Potentials↗
PubMed1999

Effects of BDF 9148 on the action potentials and contractions of left ventricles from normo- and hypertensive rats.

1. The aim of the present study was to test the hypothesis that responses to BDF 9148, which prolongs the opening of sodium channels, are reduced in the spontaneously hypertensive rat (SHR) left ventricle in the presence of hypertrophy and failure. 2. We studied the effects of BDF 9148 on the action potentials and contractions of left ventricles from 5-week-old prehypertensive, 14-week-old hypertensive, 6- and 12-month-old hypertension-associated hypertrophy and 18-month-old hypertension-induced heart failure SHR and age-matched Wistar-Kyoto normotensive (WKY) rats. 3. Action potentials and left ventricular contractions did not alter in the early stages of hypertension (14-week-old SHR). The diastolic membrane potential did not change with hypertension-associated hypertrophy, but there was a reduction in amplitude and a prolongation of action potentials in the left ventricles of 6-18-month-old SHR. Cardiac stimulation responses and maximum contractions to 10(-6) mol/L isoprenaline were reduced at 6 months, whereas the maximum contractions to 10(-2) mol/L CaCl2 were only reduced in left ventricles of 18-month-old SHR. 4. At concentrations ranging from 10(-7) to 3 x 10(-6) mol/L, BDF 9148 increased the amplitude and prolonged the duration of action potentials and augmented the force in WKY rat left ventricles. The augmenting effects of BDF 9148 at 3 x 10(-6) mol/L were smaller than at 10(-6) mol/L, possibly because the high concentration of BDF 9148 was also blocking calcium channels. Similar effects were observed with BDF 9148 in the early stages of hypertension (14-week-old SHR). 5. In the presence of persistent hypertension-associated hypertrophy of the SHR left ventricle at > or = 6 months, the effects of BDF 9148 on action potentials and contractions were significantly reduced to a small extent. This impairment of the response to BDF 9148 may reflect the reduced contractility of the SHR left ventricle and/or it may indicate that the response to the opening of sodium channels is altered from 6 months of age. 6. In summary, most of the response of BDF 9148 is maintained in the presence of hypertrophy and failure. Thus, BDF 9148 may have some potential for the treatment of heart failure.

Action Potentials↗
PubMed1999

Effects of tetraethylammonium, 4-aminopyridine and bretylium on cardiovascular tissues from normo- and hypertensive rats.

Our objective was to test whether potassium-channel blockade is a potential positive inotropic mechanism for heart failure. Thus we studied the effects of tetraethylammonium, 4-aminopyridine and bretylium on left ventricular action potentials, left ventricular contractility in the absence and presence of hypertrophy, and on isolated blood vessels from Wistar Kyoto normotensive rats (WKY) and spontaneously hypertensive rats (SHRs). Tetraethylammonium at 10(-3)-10(-2) M, 4-aminopyridine at 10(-4)-10(-3) M and bretylium at 10(-6)-10(-4) M prolonged the action potentials of the WKY left ventricular strip. Similar concentrations of tetraethylammonium, 4-aminopyridine and bretylium augmented the peak force, prolonged the contractions, and did not cause arrhythmias in the absence or presence of isoprenaline on left ventricular strips from 12-month-old WKY. The 12-month-old SHR has hypertrophy of the left ventricle with reduced contractility and prolongation of relaxation. The effects of tetraethylammonium and bretylium were similar on WKY and SHR, whereas the effects of 4-aminopyridine were reduced on SHR left ventricular contractility, which suggests that the function of the transient outward-blocking potassium channel may be impaired in hypertrophy. Bretylium at < or = 10(-4) M had no effect on the portal vein, intralobar or mesenteric arteries. Tetraethylammonium and 4-aminopyridine at > or = 10(-5) M increased the duration or amplitude, or both, of the portal vein contractions. Tetraethylammonium at > or = 10(-2) M and 4-aminopyridine at > or = 3 x 10(-4) M contracted the mesenteric artery, and 4-aminopyridine also contracted the intralobar pulmonary artery. In summary, we have demonstrated that the action potential prolonging effects of potassium-channel blockade is associated with a positive inotropic effect on the rat left ventricle. The non-specific blockers, tetraethylammonium and 4-aminopyridine, do not have potential as positive inotropes in heart failure because of their widespread effects, including vasoconstriction. The potential of bretylium and some of the newer selective potassium-channel blockers as positive inotropes requires further evaluation.

4-Aminopyridine↗
PubMed1998

The relaxing effect of BDF 9148 on the KCl-contracted aorta isolated from normo- and hyper-tensive rats.

BDF 9148, a positive cardiac inotrope, relaxes the rat isolated portal vein and the KCl-contracted rat aorta. The aims of our study were to determine the mechanism of action of BDF 9148, and to ascertain whether the relaxing effect of BDF 9148 was maintained in the presence of the hypertrophy associated with hypertension, by investigating the effects of BDF 9148 on the contractility and electrophysiology of aortae of Wistar Kyoto normo-tensive rats (WKY) and Spontaneously Hypertensive Rats (SHRs). High concentrations of veratridine contracted the quiescent rat aorta. BDF 9148 had no effect on the quiescent, but relaxed the KCl-contracted WKY and SHR aorta by a tetrodotoxin insensitive mechanism, and these relaxations decreased with age but were not greatly altered by hypertrophy. The verapamil relaxations of the KCl-contracted aorta were not altered by age or hypertrophy. The ability of KCl to depolarise the aorta was reversed by verapamil, but not by BDF 9148. On the contracted rat aorta, the relaxant responses to acetylcholine were abolished by removal of the endothelium but potentiated by IBMX (10[-6] M), and the responses to isoprenaline were inhibited by propranolol (10[-6] M) but potentiated by forskolin (10[-7] M). The relaxation responses of the KCl-contracted aorta to BDF 9148 were not altered by removal of the endothelium, or by propranolol, forskolin and IBMX. In summary, the effects of verapamil and BDF 9148 on the aorta are different, and thus it is unlikely that the relaxant responses to BDF 9148 on the aorta are due to calcium channel blocking activity. The mechanism of the relaxant effect of BDF 9148 on the aorta remains unknown, but we have shown the response is endothelium-independent, and not mediated by sodium channel opening, hyperpolarization, beta-adrenoceptors, or by stimulating adenylate cyclase or guanylate cyclase.

Aging↗
PubMed1998

The offset of beta-adrenoceptor antagonism of the responses of the rat right ventricle to isoprenaline.

1. The aim of the study was to test the hypothesis that the offset of action of beta-adrenoceptor antagonists on the heart is related to their lipophilicity, with low and highly lipophilic drugs having a rapid and slow offset, respectively. The effects of beta-blockers with low (atenolol), moderate (celiprolol), high (propranolol) and very high (bopindolol) lipophilicity on the contractile responses of the rat right ventricle to isoprenaline were determined. 2. Atenolol at 10(-6) and 10(-5) M, celiprolol at 10(-7), 10(-6) and 10(-5) M, propranolol at 10(-8), 10(-7) and 10(-6) M and bopindolol at 2 x 10(-9) and 10(-8) M caused parallel rightward shifts of the isoprenaline response curves with no effect on maximum responses. The Schild plots for atenolol, celiprolol and propranolol had slopes that were not significantly different from 1, which is indicative of competitive reversible antagonism. The pKB values were 7.33, 7.78, and 8.79 for atenolol, celiprolol, and propranolol, respectively. The Schild plot for bopindolol had a slope that was significantly greater than 1. 3. Our hypothesis is supported as the effects of propranolol and bopindolol were more slowly offset than those of atenolol and celiprolol. Thus, the concentration-ratio of 141 in the presence of atenolol at 10(-5) M was reduced to 4 after the first wash, whereas the ratio of 100 in the presence of propranolol at 10(-7) M was only reduced to 45 after a similar wash. The ratio of 54 with celiprolol at 10(-6) M was reduced to 5, whereas the ratio of 70 with bopindolol at 10(-8) M was only reduced to 28 by the first wash. 4. The effects of bopindolol were very slowly or not reversible over two washes in the absence or presence of atenolol at 10(-6) M. It is suggested that bopindolol is a very slowly reversible beta-blocker, and that this contributes to its slow offset of action.

Adrenergic beta-Antagonists↗
PubMed1998

Affinity constants and beta-adrenoceptor reserves for isoprenaline on cardiac tissue from normotensive and hypertensive rats.

To determine whether there are differences in cardiac beta-adrenoceptor responsiveness, isoprenaline affinity constants and fractional beta-adrenoceptor occupancy-response relationships for isoprenaline in the early stages of established hypertension, we studied the effects of bromoacetylalprenololmenthane (BAAM) and ([3,5-diamino-6-chloro-N-(1[N-beta-(2-hydroxyl-3-alpha-naphthoxypropy lamino)ethylcarbamoyl]-1-methylethyl)-pyrazine-2-carboxamide (ICI 147 798), slowly reversible beta-adrenoceptor antagonists, on the isoprenaline responses of the left ventricular papillary muscle and the left and right atria of 6-month-old Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). The papillary muscles, but not the right and left atria, of the SHR were less responsive to isoprenaline than those of the WKY. The isoprenaline pD2 values (the negative logarithms of the molar concentrations of agonist producing 50% of the maximum response) were 7.72 and 8.00 on the SHR and WKY papillary muscles, respectively. On the WKY papillary muscle the isoprenaline KA values were 2-3 x 10(-6) M, which is as expected for isoprenaline at beta1 or beta2-adrenoceptors. Isoprenaline had 100-fold greater affinity on the WKY and SHR left atria than on the papillary muscles; the isoprenaline KA values were 2-4 x 10(-8) M. On the WKY papillary muscle and left atrium, isoprenaline had to occupy 3-4% of the beta-adrenoceptors to produce a 50% maximum response; on the WKY papillary muscle and left atrium isoprenaline had to occupy 25-35% and 55%, respectively, of the beta-adrenoceptors to produce a 90% maximum response. The SHR papillary muscles and left atrium had smaller beta-adrenoceptor reserves for isoprenaline than did the WKY tissues. We were unable to obtain isoprenaline KA values on the WKY right atrium. The isoprenaline KA value on the SHR right atrium was 1-4 x 10(-8) M. Because the isoprenaline KA values for the left and right atria are markedly different from those previously reported for isoprenaline at beta1 or beta2-adrenoceptors, we suggest that atypical beta-adrenoceptors might be present on the atria of WKY and SHR. We have also demonstrated a lower beta-adrenoceptor reserve on SHR papillary muscle and atria in the early stages of established hypertension.

Adrenergic beta-Agonists↗
PubMed1997

The effects of bromoacetylalprenololmenthane on the responses to isoprenaline of the left ventricle from normo-, prehyper- and hypertensive rats.

1. We have studied the effects of bromoacetylalprenololmenthane (BAAM), a very slowly reversible beta-adrenoceptor antagonist, on the responses of the left ventricle of 5 and 22 week old Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) to isoprenaline. At 5 weeks the SHRs were prehypertensive and at 22 weeks they had hypertension-induced hypertrophy of the left ventricle. 2. The mean potency of isoprenaline on the left ventricle from 5 week old WKY was similar to that obtained on left ventricle with BAAM at 10(-6) M for 30 min, there was a parallel rightward shift of the isoprenaline concentration-response curves. Treatment with a higher concentration of BAAM (10(-5)M) caused non-parallel rightward shifts of the concentration-response curves, with a depression of the isoprenaline maximum responses. These data were used to derive affinity (KA) values for isoprenaline. The mean isoprenaline KA value on the left ventricle from 5 week old WKY was 2.44 x 10(-6)M, and similar KA values were obtained on the left ventricles from 22 week old WKY and 5 and 22 week old SHRs. On all the left ventricles tested, isoprenaline produced a half maximal response by occupying less than 1%, and a near maximal response by occupying about 5% of the available beta(1)-adrenoceptors. 4. This study has shown that there are no differences in the cardiac responses to isoprenaline at beta(1)-adrenoceptors, isoprenaline KA values or the beta(1)-adrenoceptor reserve for isoprenaline on the SHR left ventricle in prehypertension or in the early stages of hypertension-induced hypertrophy.

Adrenergic beta-Agonists↗