Antiischemic and antiarrhythmic activities of some novel alinidine analogs in the rat heart.

The antiischemic and antiarrhythmic effects of alinidine and a number of novel alinidine analogs were examined by using perfused rat-heart models. In the isolated working rat heart, the alinidine analog TH91:21 (10 microM; a butyl derivative) significantly increased the postischemic recovery of the heart in terms of both power and efficiency when compared with the control group. In the in situ perfused heart model, this same compound, along with TH91:22 (10 microM; a pentyl derivative) also significantly reduced the severity of both ischemia- and reperfusion-induced arrhythmias in both paced and unpaced hearts. Thus this study is the first to demonstrate the potent antiarrhythmic efficacy of two novel alinidine analogs TH91:21 and TH91:22, with TH91:21 also demonstrated to be a potent antiischemic agent in the isolated working rat heart. Although the mode of action of these compounds remains unclear, results from this study suggest that it is not simply a result of bradycardia or blockade of KATP channels, two actions these compounds possess. These compounds thus possess a novel and beneficial pharmacologic profile worthy of further study.

Structure-activity relationship of glibenclamide analogs: a comparison of potency as levcromakalim antagonists in rat aorta vs. affinity for [3H]-glibenclamide binding to membranes from rat cerebral cortex.

Glibenclamide and analogs were tested for their ability to antagonize the vasorelaxant actions of the K+ channel opener levcromakalim in rat thoracic aorta, and to displace [3H]-glibenclamide binding from rat cerebral cortex membranes. Aortic ring segments were suspended in organ baths to record isometric tension. Tissues were precontracted with K+ (20 mM), and full concentration-relaxation curves were constructed to levcromakalim (0.01-30 microM) in the absence and presence of glibenclamide or analog. The majority of the amidoethylbenzenesulfonylurea based compounds (exemplified by glibenclamide) caused parallel rightward shifts in the levcromakalim concentration-effect curves without effecting the maximum response to levcromakalim. Sulfonamide based compounds were generally inactive, with the exception of the compound DK#1 (laboratory code), which was unusually active as an antagonist of levcromakalim-mediated responses. The compounds were 1,000 to 10,000 times more potent at displacing [3H]-glibenclamide binding from rat cerebral cortex membranes. There was a strong correlation between the activity of amidoethylbenzenesulfonylurea based compounds as antagonists of the effects of levcromakalim and their ability to displace [3H]-glibenclamide binding. The slope of the regression line indicated that structural modification to these compounds has a more dramatic effect on their actions as levcromakalim antagonists than on their ability to displace [3H]-glibenclamide binding. This relationship of activity for the amidoethylbenzenesulfonylureas did not hold in the case of the sulfonamide derivatives. The results show that, for the processes characterized in this study (vascular levcromakalim antagonism vs. sulfonylurea receptor affinity), there are quantitative differences in their sensitivities to sulfonamide/sulfonylurea based compounds. Such differentiation may be important in the development of tissue-specific compounds.

Potassium channel openers and other regulators of KATP channels.

1. Interest in ATP-sensitive K (KATP) channels first arose when it was shown that hypoglycaemic sulphonylureas, such as glibenclamide, closed these channels in pancreatic beta-cells to cause insulin release. The demonstration that certain smooth muscle relaxants (K channel openers) may exert their actions through opening a similar channel in vascular smooth muscle fueled further investigation of these channels and their physiological role in a variety of tissue types, including various types of smooth muscle, cardiac and skeletal muscle and neural and endocrine organ function. 2. The K channel openers have a variety of potential therapeutic applications, including disorders of smooth muscle hyperreactivity, such as hypertension, and a great deal of research has focused on this field. More recently, attention has turned to the cardiac actions of these compounds and this area is discussed in detail. One of the current problems is the lack of selectivity of KATP channel regulators. However, there have been a number of recent encouraging reports suggesting that, under certain pathophysiological conditions, the action of the K channel openers may be enhanced, conferring upon them some degree of selectivity. 3. A number of endogenous regulators of these channels have been identified, particularly in the category of endogenous openers of these channels. At present though, the physiological role of these channels and the endogenous regulators identified, is unclear. 4. It is evident that, although advances have been made, much work is still required to increase our understanding and ultimately to allow selective pharmacological manipulation of these channels to become a therapeutic reality.

Comparison of the cromakalim antagonism and bradycardic actions of a series of novel alinidine analogues in the rat.

Alinidine, and eight derivatives, were synthesized and tested for their ability to antagonise the actions of the K+ channel opener cromakalim in rat thoracic aorta, and for their ability to induce bradycardia in rat isolated spontaneously beating right atria. Ring segments of rat thoracic aorta were suspended in organ baths to record isometric tension. Tissues were precontracted with K+ (20 mM), and full concentration-relaxation curves constructed to cromakalim (0.01-30 microM) in the absence and presence of increasing concentrations of alinidine/derivative. The majority of the compounds tested caused rightward shifts in the cromakalim concentration-effect curves. Rat spontaneously beating right atria were suspended in organ baths to record rate of contraction. Addition of alinidine/derivative caused a concentration-dependent negative chronotropic response. In terms of structure-activity relationships, increasing the length of the N-allyl side-chain on the alinidine molecule (from 3 carbon (3C), to 5C) resulted in a significant increase in the activity of the compounds as both bradycardic agents and cromakalim antagonists. The most potent compounds in both cases (bradycardic agent and cromakalim antagonist) had no double bond in the side chain. The results suggest that the carbon side-chain influences the activity of alinidine-related compounds both as cromakalim antagonists and as bradycardic agents. However, while similar structure-activity relationships appear to apply for both effects in some instances, there was no significant correlation between the two actions of the alinidine analogues. The results suggest that the ability of alinidine-derivatives to induce bradycardia or to block K+ channels opened by cromakalim can be differentiated on the basis of structure.