No abstract

Rational treatment of primary hypertension remains elusive, owing to a lack of knowledge about the pathogenesis of blood pressure elevation. Established hypertension is associated with well-described cardiovascular hemodynamic changes. Because the cardiovascular system is self-regulating, the action of an antihypertensive on one of the regulatory mechanisms induces changes in others. A drug-induced decrease of the elevated peripheral resistance leads to compensatory reflex mechanisms. The use of centrally acting drugs avoids compensatory neural reflexes. Furthermore, the participation of the central and autonomic nervous systems in the pathogenesis of hypertension is probable. The development of drugs aimed at controlling the central nervous system (CNS) would, therefore, be reasonable. The use of a,-adrenoceptor agonists, such as clonidine, as antihypertensive agents has declined. The mean reason being a high rate of side effects such as sedation, dry mouth with marked reduction in salivary flow, and other nonspecific effects. The mode of action was explained by stimulation of both pre-and postsynaptic a,-adrenoceptors within the CNS . However, recent investigations have clearly demonstrated that centrally acting drugs like clonidine and moxonidine induce their antihypertensive effects primarily by high affinity binding at the imidazoline receptors. Most of the side effects are induced by an action at aw,-receptors. The difference between clonidine and moxonidine is moxonidine's pronounced selectivity for imidazoline rather than ctzreceptors. Moxonidine and other related compounds may reestablish the use of centrally active drugs in antihypertensive therapy.~ ~~~

Ten healthy volunteers daily received 30 ml linseed oil for 4 weeks in addition to the "normal" diet. The influence of linseed oil diet on the fatty acid pattern of plasma phospholipids and thromboxane formation in platelets was investigated. The fatty acid pattern was analysed by gas liquid chromatography. The alpha-linolenic, eicosapentaenoic and docosahexaenoic acids were increased (p less than 0.01), whereas linoleic and arachidonic acids were decreased (p less than 0.05) after 4 weeks of the linseed oil diet. The thromboxane formation of platelets were unchanged. Additionally the influence of HDL and LDL on PGI2 biosynthesis in pig aortic microsomes (PAM) was investigated. HDL taken from serum before and after 3 weeks of linseed oil diet and LDL taken after 3 weeks of diet stimulated the PGI2 formation in PAM, whereas LDL taken from serum before the diet period inhibited the PGI2 formation in PAM.

No abstract

Sulfonylureas stimulate insulin secretion independent of the blood glucose concentration. This can lead to hypoglycaemia in type 2 diabetic patients. Over the last years a number of imidazoline derivatives have been identified that stimulate insulin secretion in a more glucose-dependent way. In agreement with this, our aim was to generate imidazoline derivatives with a potential for the treatment of type 2 diabetic patients. We developed the compound 2-[4-(4-chlorophenyl)-3-(2-methoxyethoxy)-2-naphthalenyl]-4,5-dihydro-1-H-imidazole monohydrochloride (LY389382) with an imidazoline moiety and investigated its effects on glucose-dependent insulin secretion in a beta-cell line, isolated rat islets and in vivo. We could demonstrate that LY389382 induces insulin secretion in MIN6 cells and rat islets in a glucose-dependent manner (EC50=1.1 microM and 0.3 microM, respectively). Furthermore during hyperglycaemia LY389382 increased insulin secretion in a dose-dependent manner in healthy rats, whereas the compound had no effect at euglycemia in a tenfold higher dosage. After 7 days of treatment of Zucker Diabetic Fatty [ZDF/ (Gmi/fa)] rats with LY389382 with a dose of 15 mg/kg twice daily the blood glucose concentration was reduced from 22.7 +/- 1.7 mM to 16.6 +/- 2.3 mM. During the same time period the glucose concentration increased from 21.7+/-1.7 mM to 28.9 +/- 1.3 mM in the vehicle-treated group (P<0.05). The drop of the insulin level was also inhibited by LY389382 in ZDF rats. In contrast to other well-characterised imidazolines that have been shown to induce a glucose-dependent insulin secretion only within a limited range of concentrations, LY389382 stimulates insulin secretion over a concentration range of at least two log units in a glucose-dependent manner. These data suggest that this imidazoline compound has a potential for the treatment of type 2 diabetes.