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It is assumed that interventions to improve the adherence to insulin by allied health professionals discussing adherence to insulin will improve this adherence. However, there is little evidence to support this, as interventions by a pharmacist or nurse educator have not been shown conclusively to improve adherence to insulin.

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 × 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.

Mean LDL-C levels during treatment were 104mg/ dL in the simvastatin group and 81mg/dL in the atorvastatin group. There was no significant difference between groups in major coronary events (10.4% simvastatin vs 9.3% atorvastatin; hazard ratio 0.89, 95% CI 0.78–1.01, p 1⁄4 0:07). Atorvastatin was associated with fewer non fatal acute myocardial infarctions (7.2% vs 6%, haard ratio 0.83, 95% CI 0.71–0.98, p 1⁄4 0:02). People receiving atorvastatin had higher rates of drug

1. The effects of several potassium channel blockers on the action potentials and contractile force of the electrically driven rat right ventricle have been determined. 2. Glibenclamide, which blocks the ATP-sensitive potassium channels, had no effect on the ventricular action potentials or contractile force responses. 3. 4-Aminopyridine, which blocks the Na(+)-activated potassium channels in ventricles, at 0.3-3 mM increased the amplitude and prolonged the action potentials, and also augmented the force responses to cardiac stimulation and to isoprenaline. 4. Clofilium, a selective blocker of the delayed outward rectifying potassium channel, at 0.1 and 0.3 microM prolonged the action potentials. At 0.1 microM, clofilium augmented the cardiac stimulation responses and, at 0.3 microM, clofilium augmented the maximal responses to isoprenaline. At 1 and 3 microM, clofilium had a lesser ability to prolong action potentials and did not alter force responses. 5. Procaine blocks the Na(+)-activated and the delayed outward rectifying potassium channels and, at higher concentrations, sodium channels. Procaine, at 30 microM, prolonged the action potentials and augmented the force responses to isoprenaline, presumably by blocking potassium channels. Procaine, at 1 mM, had no effect on action potentials but reduced the maximal force responses to isoprenaline, probably by blocking sodium channels. 6. Tetraethylammonium blocks the inward rectifying and delayed outward rectifying potassium channels. Tetraethylammonium, at 1 and 3 mM, prolonged the action potentials and augmented all of the force responses; these effects are likely to be predominantly due to blocking the outward rectifying potassium channel. Thus, in the presence of procaine, the effects of tetraethylammonium are predominantly due to the additional blockade of the inward rectifying potassium channel and there were no effects. 7. None of the potassium channel blockers at any of the concentrations tested had arrhythmogenic effects alone or in the presence of isoprenaline. 8. In summary, this study has shown that blockade of the Na(+)-activated and the delayed outward rectifying, but not the ATP-sensitive or inward rectifying, potassium channel is associated with prolongation of the action potentials, augments the contractile force responses, and is not arrhythmogenic on the rat right ventricle. New drugs that block the Na(+)-activated or delayed outward rectifying potassium channel may have potential as positive inotropes in the treatment of heart failure.

1. The effects of phenoxybenzamine treatment on the contractile responses of the aorta from WKY and SH rats to noradrenaline and adrenaline have been determined. 2. There was no change in sensitivity of the aorta to noradrenaline or adrenaline with hypertension. 3. Phenoxybenzamine treatment caused nonparallel rightward shifts of the concentration-response curves to the lower concentrations of noradrenaline and adrenaline. 4. The K A value for noradrenaline on the WKY rat aorta was 4.15 × 10 −8 M and noradrenaline produced a 95% maximum response by occupying 95% of the available α 1 -adrenoceptors. These parameters were significantly different on the SH rat aorta; thus the K A value for noradrenaline was 76.40 × 10 −8 M and noradrenaline produced a 95% maximum response by occupying 63% of the α 1 -adrenoceptors. 5. The K A value for adrenaline on the WKY rat aorta was 5.03 × 10 −8 M and adrenaline produced a 95% maximum response by occupying 95% of the available α 1 -adrenoceptors. These adrenaline parameters were not significantly different on the SH rat aorta. 6. In summary this study has demonstrated that although the sensitivities of the rat aorta to noradrenaline and adrenaline do not alter, there is a change in the K A and receptor reserve for noradrenaline, but not adrenaline in hypertension.

1. The effects of (+/-)- (+)- and (-)-metoprolol, (+/-)- (+)- and (-)-pindolol, (+/-)-mepindolol and (+/-)-bopindolol on the beta 1-adrenoceptor mediated responses of the rat left atria and the beta 2-adrenoceptor mediated responses of the rat portal vein to isoprenaline have been determined. 2. Racemic and (-)-metoprolol were selective beta 1-adrenoceptor antagonists. (+)-Metoprolol was devoid of beta-adrenoceptor antagonistic activity. 3. Racemic and (-)-pindolol were potent and (+)-pindolol was a modest beta-adrenoceptor antagonist. 4. (+/-)-Mepindolol and (+/-)-bopindolol were apparently competitive antagonists of the isoprenaline beta 1-adrenoceptor mediated responses of the rat left atria but non-competitive antagonists of the isoprenaline beta 2-adrenoceptor mediated responses of the rat portal vein. 5. It is suggested that (+/-)-mepindolol and (+/-)-bopindolol are slowly dissociating beta-adrenoceptor antagonists and the non-competitive antagonism can only be detected on tissues with modest receptor reserves for maximum responses to isoprenaline.

The rat portal vein has spontaneous mechanical activity. The effects of β-adrenoceptor agonists and antagonists and verapamil alone and together on this mechanical activity have been determined. Isoprenaline, but not dobutamine, attenuated the contractile activity. Three successive challenges to isoprenaline produced identical attenuation curves. The responses to isoprenaline were antagonized by propranolol, metoprolol, and ICI 118,551, and the pA 2 values, derived by Schild analysis, were 9.12, 6.78, and 9.33, respectively. Thus, the rat portal vein contains predominantly β 2 -adrenoceptors. Verapamil attenuated the contractile activity of the rat portal vein, and this attenuation was not altered by the presence of propranolol at 10 −5 M. The potencies of isoprenaline and propranolol were not altered by the presence of a 30% attentuation of the contractile activity with verapamil at 10 −7 M. Thus, the rat portal vein may be used to determine the potencies of drugs as β 2 -adrenoceptor antagonists and as voltage dependent calcium channel blockers. In addition, the potency of drugs as β 2 -adrenoceptor antagonists on the rat portal vein may be determined in the presence of some voltage dependent calcium channel blockade.

1. The membrane stabilizing and beta 1-adrenoceptor blocking activities of (+)- and (-)-propranolol have been determined using the rat left atria. 2. (+)- And (-)-propranolol have membrane stabilizing activity. Thus a low concentration of (-)-propranolol, 10(-8) M, and a higher concentration of (+)-propranolol, 10(-6) M, inhibited the responses to electrical stimulation. A high concentration of (+)- and (-)-propranolol, 10(-5) M, also inhibited the maximal combined response to electrical stimulation and isoprenaline. 3. As competitive beta 1-adrenoceptor antagonists, (-)-propranolol was over a 100 times more potent than (+)-propranolol.

Three consecutive challenges of the rat isolated left atria with electrical stimulation and then electrical stimulation and isoprenaline were made. The responses to electrical stimulation decreased and the responses to isoprenaline increased with consecutive challenges such that the maximal combined response to electrical stimulation and isoprenaline remained constant. The sensitivity (pD2) to isoprenaline decreased with successive challenges. Thus, in studies of the effects of drugs on the responses to electrical stimulation and isoprenaline, it is necessary to perform parallel experiments with untreated atria to monitor changes in the responses unrelated to the addition of drug. Analysis of the effects of procaine, metoprolol, and propranolol on the responses to electrical stimulation and/or isoprenaline demonstrated distinct contractile manifestations of beta-adrenoceptor blocking and membrane stabilizing activity. The beta-adrenoceptor blocking activity of metroprolol at 10(-7) M and propranolol (3 X 10(-9)-10(-6) M) consisted of parallel rightward shifts of the concentration-response curves to isoprenaline alone. There were three components to the membrane-stabilizing action of drugs: first, there was a decrease in the responses to electrical stimulation alone, which was observed with procaine at greater than or equal to 10(-4) M and propranolol at greater than or equal to 3 X 10(-9) M, second, there was a small parallel rightward shift of concentration-response curve to isoprenaline alone with metoprolol at 10(-6) M and propranolol at 3 X 10(-6) M (that the inhibitory effects of metoprolol at 10(-6) M or propranolol at 3 X 10(-6) M are greater than can be explained by beta-adrenoceptor blockade only may be detected either by determining pA2 values from the formula pA2 = pAx + log(x - 1) or by Schild analysis); third, the highest concentrations of procaine (3 X 10(-4) M) and propranolol (10(-5) M) tested decreased the maximal combined response to electrical stimulation and isoprenaline.

Two methods for determining pA2 values, the Schild regression and the use of the formula pA2 = pAx + log(x − 1), have been reassessed. The effects of propranolol on the contractile responses of the rat isolated right ventricle to isoprenaline were studied. The inhibitory effect with the lower concentrations of propranolol tested (3 × 10−9–10−7 M) was solely competitive. Thus there was a parallel dextral displacement of the concentration-response curves to isoprenaline with no depression of the maximal responses. Dual antagonism was observed with the higher concentrations of propranolol tested (10−6 and 3 × 10−6 M), thereby showing a parallel displacement of the concentration-response curve to the lower concentrations of isoprenaline with a depression of the maximal responses. Without analysis of data for individual concentrations of propranolol on concentration-response curves to isoprenaline, Schild regression did not clearly illustrate that the antagonism was not solely competitive with the higher concentrations of propranolol. We suggest that data for individual concentrations of antagonist should always be analyzed to ascertain whether there has been a parallel shift of the concentration-response curves to agonist prior to determining pA2 values.

1. 1. Atriopeptin had no effect, whereas angiotensin increased the force of the electrically stimulated ventricle muscle. 2. 2. Atriopeptin and angiotensin had no effect on the combined response to muscle stimulation and isoprenaline. 3. 3. Following incubation of the ventricle with [ 3 H]noradrenaline, atriopeptin and angiotensin had no effect on the spontaneous or nerve-evoked outflow of radioactivity.

1. Procaine, a membrane stabilizer, depresses the maximal responses of the electrically driven rat right ventricle to isoprenaline. 2. Esmomol is a competitive β-adrenoceptor antagonist as it causes parallel rightward shifts of isoprenaline response curves. 3. Atenolol, bufuralol and prizidilol were dual antagonists of the responses to isoprenaline. 4. The competitive component of the dual antagonism (parallel rightward shift of response curve) is due to β-adrenoceptor antagonism whereas the noncompetitive component (depression of isoprenaline maximal response) is probably due to membrane stabilization. 5. This membrane stabilizing activity of β-adrenoceptor antagonists may be clinically relevant.

The effects of cocaine and nortriptyline on contractile responses to field stimulation, (−)-noradrenaline and methoxamine in the rabbit aorta were studied. The method used allowed detection of changes in maximal responses. Cocaine (3.3 × 10−5 M) potentiated all, responses, including maximal responses, to field stimulation, (−)-noradrenaline and methoxamine. Nortriptyline (10−6 M) had no effect on maximal responses to field stimulation, (−)-noradrenaline and methoxamine. The submaximal responses in the presence or absence of nortriptyline were plotted either as a percentage of an initial maximal response to (−)-noradrenaline in the absence of the drug or as a percentage of the maximal response of the individual maximal response. Depending on the method used to express the results, nortriptyline (10−6 M) had no effect or potentiated submaximal responses to field stimulation and had no effect or inhibited submaximal responses to (−)-noradrenaline; this matter is discussed. Nortriptyline (10−6 M) inhibited submaximal responses to methoxamine. The results illustrate that, in the rabbit aorta, inhibition of neuronal uptake is an insufficient explanation of the potentiating effect of cocaine on maximal responses and, furthermore, support the suggestion that cocaine has a postsynaptic action in this tissue.

1. 1.|Desipramine at 10−7 M inhibited the neuronal uptake of noradrenaline and at 10−6 M was also a α1-adrenoceptor blocker. 2. 2.|Desipramine potentiated and inhibited the responses of the epididymal and other portions to field stimulation, respectively, probably because the increased concentration of noradrenaline in the synapse was stimulating postjunctional α1- and prejunctional α2-adrenoceptors, respectively. 3. 3.|Qualitatively the effects of prazosin, phentolamine and yohimbine on responses to added noradrenaline and to field stimulation were consistent with their being α1-selective, nonselective and α2-selective adrenoceptor antagonists. 4. 4.|Quantitatively the effects of phentolamine and/or yohimbine on fast and slow responses to field stimulation and the modification of these effects by desipramine were dependent on the portion of vas, the response, the frequency of stimulation and the concentration of desipramine used.

1. The inability of blood vessels to relax to acetylcholine is often used as the sole test of endothelial removal. 2. Following blotting of the intimal surface of the rat aorta with filter paper, the tissue did not relax to acetylcholine and the contractions to alpha 2-adrenoceptor agonists and to the lower concentrations of noradrenaline, adrenaline, phenylephrine and KCl were enhanced. 3. However the responses to the higher concentrations of noradrenaline, adrenaline, phenylephrine and KCl were reduced. 4. These results show that blotting with filter paper destroys the endothelium and some smooth muscle.

1. 1. The inhibitory effects of atropine and pirenzepine (nonselective and M1-selective antagonists, respectively) on the contractile responses of the epididymal half of the rat vas deferens to methacholine included a depression of the maximal response. 2. 2. In the presence of pirenzepine, atropine was a competitive antagonist of the responses to methacholine. However in the presence of atropine, pirenzepine remained a non-competitive inhibitor of the response. 3. 3. It is suggested that low concentrations of methacholine predominantly stimulate M2-receptors and that at high concentrations, methacholine also stimulates M1-receptors.

Cromakalim alone at 1 microM had no effect and at 10 microM hyperpolarized the rat aorta. The rat aorta was depolarized by KCl (20 mM), noradrenaline (0.3 microM) and 5-hydroxytryptamine (1 microM). In the presence of depolarization with KCl, noradrenaline or 5-hydroxytryptamine, cromakalim at 1 and 10 microM hyperpolarized the rat aorta. Thus the antispasmogenic actions of modest concentrations of cromakalim is compatible with potassium channel opening.