Pierre Schelling

Involvement of ATP-sensitive potassium channels in preconditioning protection

SummarySingle or multiple brief periods of ischemia (preconditioning, PC) have been shown to protect the myocardium from infarction during a subsequent more prolonged ischemic insult. To test the hypothesis that opening of ATP-sensitive potassium channels (KATP) is involved in this mechanism, either bimakalim, a KATP channel opener, or glibenclamide, a KATP channel blocker, were administered to mimic or to block preconditioning protection in barbital-anesthetized pigs. PC was elicited by a single period of 10 min left anterior descending coronary artery (LADCA) occlusion followed by 15 min of reperfusion before the LADCA was reoccluded for 60 min. Instead of PC, bimakalim infusion was started 15 min before the 60 min LADCA occlusion (TCO) and stopped with the onset of ischemia. Glibenclamide was administered either for 10 min prior to the PC protocol, before bimakakim infusion, or before TCO. Regional wall function was quantified with ultrasonic crystals aligned to measure wall thickening (%ΔWT). At the end of the protocol, infarct size was determined by incubating myocardium with p-nitrobluetetrazolium.In seven preconditioned pigs, infarct size was 9.9±5.1% of the risk region compared with 65.9±6.0% in the seven control pigs subjected to 60 min of ischemia only (p<0.001). In seven pigs treated with bimakalim, infarct size was reduced to 35.3±6.6 (p<0.05 vs. controls). Blocking ATP-sensitive potassium channels with glibenclamide prior to PC abolished its protective effect (infarct size, 62.2±4.5%;p<0.001 vs. PC alone). Glibenclamide also antagonized the protective effect of bimakalim (infarct size, 55.2±4.0%), but did not affect infarct size, when solely administered prior to the prolonged ischemic period (62.2±4.3%). We conclude that in swine myocardium KATP channels are involved in the protective effect of ischemic preconditioning, since glibenclamide completely abolished the protective effect of preconditioning, while bimakalim could — at least in part — mimic it.

High beta 1-selectivity and favourable pharmacokinetics as the outstanding properties of bisoprolol.

&NA; Bisoprolol, (±)1‐(4‐[(2‐isopropoxyethoxy)‐methyl]‐phenoxy)‐3‐isopropyl‐amino‐2‐propanol‐hemifumarate, is a new, highly selective &bgr;1‐adrenoceptor blocking agent without intrinsic sympathomimetic activity and low to moderate local anaesthetic activity. As demonstrated in binding experiments, and in classical pharmacological studies using rats, guinea pigs, cats, and dogs, bisoprolol markedly differentiated between &bgr;1‐adrenoceptors of the heart, or the renal juxtaglomerular apparatus, and the &bgr;2‐subtype in arterial blood vessels, bronchi, liver, or skeletal muscle. Up to concentrations nearly 100‐fold higher than the therapeutic plasma levels in humans, bisoprolol did not affect the functional refractory period of the heart, and was devoid of a direct suppressive effect on myocardial contractility and of calcium antagonistic properties in heart and vascular muscle. The pattern of haemodynamic effects of bisoprolol was typical of &bgr;‐blockers and included decreases in blood pressure (BP), heart rate (HR), and cardiac output, concomitant with an increase in calculated total peripheral resistance. In contrast to other &bgr;‐blockers, bisoprolol increased renal blood flow in anaesthetized dogs. Bisoprolol lowered BP in hypertensive dogs and rats, attenuated the development of spontaneous hypertension in rats, decreased plasma renin activity and protected the heart from the sequelae of transient ischemia. It did not block presynaptic &bgr;‐adrenoceptors in blood vessels. Serum lipids and the serum lipoprotein profile remained unaltered after bisoprolol. Bisoprolol was devoid of affinity for autonomic receptors other than &bgr;‐adrenoceptors or for autacoid receptors. This is probably one of the reasons why bisoprolol did not affect the function of the central nervous, respiratory, and gastrointestinal systems in an obvious way. The high &bgr;1‐selectivity of bisoprolol is linked with extremely favourable pharmacokinetic properties. These include nearly complete enteral absorption and virtual absence of liver first‐pass metabolism, both resulting in high bioavailability, long plasma half‐life, pharmacokinetics that are linear over a wide dose range and independent of age, food intake and hydroxylator status, low plasma protein binding, and a 1: 1 ratio of hepatic metabolization to renal elimination of the unaltered substance. This sum of favourable pharmacological and pharmacokinetic properties characterize bisoprolol as an optimized &bgr;‐blocker.

In vivo evidence of positive inotropism of EMD 57 033 through calcium sensitization

The previous separation of the racemic cardiotonic thiadiazinone derivative EMD 53998 yielded two enantiomers with different pharmacologic properties: EMD 57,033, a potent Ca2+ sensitizer with some residual phosphodiesterase III (PDE III) inhibition, and EMD 57,439, a pure PDE III inhibitor. Although numerous in vitro studies demonstrated the ability of EMD 57,033 to increase the responsiveness of cardiac contractile proteins to Ca2+, in vivo evidence for such an action is lacking. Because there is no possibility of directly proving Ca2+ sensitization in vivo, we attempted to exclude PDE III inhibition as a major contributing component of the positive inotropic action of EMD 57,033. In anesthetized rats, EMD 57,033 increased left ventricular (LV) first derivative of change in systolic pressure over time (dP/dt max) without affecting blood pressure. In contrast, the PDE III-inhibitory enantiomer EMD 57,439 decreased blood pressure. The pattern of hemodynamic effects in anesthetized dogs revealed similar differences between EMD 57,033 and PDE inhibitors. Thus the increase in LV dP/dt max in response to EMD 57,033 was not accompanied by changes of heart rate and blood pressure. As expected for PDE inhibitors, pimobendan and milrinone increased cardiac contractile force in dogs, concomitant, however, with tachycardia, hypotension, and a decrease in total peripheral resistance. When regional contractility was measured separately in two different areas of the dog myocardium, the positive inotropic action of the PDE inhibitors pimobendan and milrinone was antagonized by local coronary infusion of acetylcholine. The cardiotonic effect of the Ca2+ sensitizer EMD 57,033 was entirely resistant to inhibition by acetylcholine. In conscious dogs, beta-blockade markedly attenuated the increase in LV dP/dt max produced by two different doses of the PDE III inhibitor EMD 57,439. In contrast, a dose of EMD 57,033 equieffective in positive inotropic action with the lower dose of EMD 57,439 remained unaffected by < b tau-blockade. We concluded (a) that EMD 57,033 increases cardiac contractile force in two species in vivo, (b) that this action is independent of the cardiac cyclic adenosine monophosphate (AMP) system, (c) that EMD 57,033 does not reduce blood pressure and increase heart rate, an action indicative of PDE inhibition, and (d) that, on the basis of numerous previous in vitro findings, the mechanism of action of EMD 57,033, also in vivo, is consistent with sensitization of the cardiac myofibrils to Ca2+. Of special importance is the finding that this Ca2+ sensitizer at appropriate doses may be able to improve systolic function without adverse effects on diastolic function, as indicated by a slight decrease in left ventricular end-diastolic pressure.

In swine myocardium, the infarct size reduction induced by U-89232 is glibenclamide sensitive : Evidence that U-89232 is a cardioselective opener of ATP-sensitive potassium channels

We determined whether U-89232, a derivative of the ATP-sensitive potassium (KATP) channel opener cromakalim, is cardioselective and whether its action on the myocardium is still sensitive to glibenclamide. Experiments were performed in open-chest pigs subjected to a 60-min occlusion of the left anterior descending coronary artery (LADCA) and to 2 h of reperfusion. Four groups of animals were studied (n = 6 each). Animals received either U-89232, 3 mg/kg i.v. over a 15-min period (U), or glibenclamide, a selective KATP channel blocker, 1 mg/kg i.v. over a 15-min period (GLI) before the LADCA occlusion. In the GLI + U group, first glibenclamide (1 mg/kg/15 min) and then U-89232 (3 mg/kg/15 min) were infused before the 60 min of ischemia. Saline-treated animals served as controls (CON). Hemodynamic parameters were continuously monitored. Regional contractile wall function was quantified with ultrasonic crystals aligned to measure wall thickening. At the end of the protocol, infarct size (IS, as percentage of risk region) was determined by incubating the myocardium with p-nitrobluetetrazolium. With comparable myocardium at risk, infusion of U-89232 before 60 min of LADCA occlusion significantly reduced infarct size (IS, 18.5 +/- 3.7%; p < 0.001 vs. 63.2 +/- 3.3% for the controls), whereas glibenclamide had no effect on infarct size (IS, 69.5 +/- 4.4%). The administration of glibenclamide before U-89232 infusion blocked the infarct size-reducing effect of U-89232 [IS, 61.2 +/- 9.1 (NS) vs. controls and p < 0.001 vs. U]. Infusion of U-89232 had no effect on hemodynamic parameters or on regional wall function. At least in a pig model, U-89232 appears to be a cardioselective KATP channel opener, because in the absence of hemodynamic alterations, it exhibits a profound cardioprotective effect, which is fully reversible by blocking KATP channels.

(6-oxo-3-pyridazinyl)-benzimidazoles as potent angiotensin II receptor antagonists

The syntheses and angiotensin II antagonistic activities of novel (6-oxo-3-pyridazinyl)-benzimidazole derivatives are reported. Evaluation of the structure-activity relationships led to the discovery of potent orally active antihypertensive compounds.

URACIL-BASED ANGIOTENSIN II RECEPTOR ANTAGONISTS

1,2,3,4-Tetrahydro-2,4-pyrimidinedione (uracil) is a valuable nucleus for the construction of potent antagonists of the AT1 angiotensin II receptor. Various synthetic routes were applied in order to introduce a wide range of different groups at the N3-nitrogen and to obtain condensed uracil derivatives as well. 121 with a N,N-dimethylacetamide residue at N3 was the most potent compound with an IC50 of 0.65 nM.