Stimulators and Activators of Soluble Guanylate Cyclase: Review and Potential Therapeutic Indications

The heme-protein soluble guanylyl cyclase (sGC) is the intracellular receptor for nitric oxide (NO). sGC is a heterodimeric enzyme with α and β subunits and contains a heme moiety essential for binding of NO and activation of the enzyme. Stimulation of sGC mediates physiologic responses including smooth muscle relaxation, inhibition of inflammation, and thrombosis. In pathophysiologic states, NO formation and bioavailability can be impaired by oxidative stress and that tolerance to NO donors develops with continuous use. Two classes of compounds have been developed that can directly activate sGC and increase cGMP formation in pathophysiologic conditions when NO formation and bioavailability are impaired or when NO tolerance has developed. In this report, we review current information on the pharmacology of heme-dependent stimulators and heme-independent activators of sGC in animal and in early clinical studies and the potential role these compounds may have in the management of cardiovascular disease

A Review of the Pathophysiology and Novel Treatments for Erectile Dysfunction

Erectile dysfunction (ED) affects up to 50% of men between the ages of 40 and 70. Treatment with PDE-5 inhibitors is effective in the majority of men with ED. However, PDE-5 inhibitors are not effective when levels of nitric oxide (NO), the principle mediator of erection, are low. The pharmacologic actions of three new potential treatments for ED are discussed in this paper: (1) sGC stimulators/activators, (2) Rho-kinase inhibitors, and (3) sodium nitrite

Analysis of Responses to Leukotriene D 4 in the Pulmonary Vascular Bed

SUMMARY. Pulmonary vascular responses to leukotriene D 4 were investigated in the intact-chest animal under conditions of controlled pulmonary blood flow. Intralobar injections of leukotriene D 4 in the sheep caused dose-dependent increases in' lobar arterial and small vein pressures without influencing left atrial or systemic arterial pressure. Leukotriene D 4 was very potent in increasing pulmonary vascular resistance in the sheep, with activity similar to that of U-46619, a thromboxane A 2 mimic. Pulmonary vascular responses to leukotriene D 4 in the sheep were similar when the lung was ventilated and when lobar ventilation was arrested. Responses to leukotriene D 4 were similar when the lung was perfused with blood or with dextran. Pulmonary vascular responses to leukotriene D 4 but not U-46619 in the sheep were reduced by inhibitors of cyclooxygenase and thromboxane synthesis. In contrast, leukotriene D 4 had modest pressor activity in the pulmonary vascular bed of the cat whereas U-46619 had marked activity in this species. Responses to leukotriene D 4 in the cat were not altered by cyclooxygenase inhibitors. It is concluded that leukotriene D 4 has marked pulmonary vasoconstrictor activity in the sheep, increasing pulmonary vascular resistance by constricting intrapulmonary veins and upstream segments. In this species, responses to leukotriene D 4 were independent of changes in ventilation or interaction with formed elements but were dependent on the formation of cyclooxygenase products including thromboxane A2. However, in the cat, leukotriene D 4 had very modest pressor activity, and this activity was not dependent on the integrity of the cyclooxygenase pathway. These data suggest considerable species difference in responses to leukotriene D 4 , a major component of the slow-reacting substance of anaphylaxis, in the pulmonary vascular bed. (Circ Res 55: 707-717, 1984

Chronic inhibition of endoplasmic reticulum stress and inflammation prevents ischaemia-induced vascular pathology in type II diabetic mice

Endoplasmic reticulum (ER) stress and inflammation are important mechanisms that underlie many of the serious consequences of type II diabetes. However, the role of ER stress and inflammation in impaired ischaemia-induced neovascularization in type II diabetes is unknown. We studied ischaemia-induced neovascularization in the hind-limb of 4-week-old db - /db- mice and their controls treated with or without the ER stress inhibitor (tauroursodeoxycholic acid, TUDCA, 150 mg/kg per day) and interleukin-1 receptor antagonist (anakinra, 0.5 microg/mouse per day) for 4 weeks. Blood pressure was similar in all groups of mice. Blood glucose, insulin levels, and body weight were reduced in db - /db- mice treated with TUDCA. Increased cholesterol and reduced adiponectin in db - /db- mice were restored by TUDCA and anakinra treatment. ER stress and inflammation in the ischaemic hind-limb in db - /db- mice were attenuated by TUDCA and anakinra treatment. Ischaemia-induced neovascularization and blood flow recovery were significantly reduced in db - /db- mice compared to control. Interestingly, neovascularization and blood flow recovery were restored in db - /db- mice treated with TUDCA or anakinra compared to non-treated db - /db- mice. TUDCA and anakinra enhanced eNOS-cGMP, VEGFR2, and reduced ERK1/2 MAP-kinase signalling, while endothelial progenitor cell number was similar in all groups of mice. Our findings demonstrate that the inhibition of ER stress and inflammation prevents impaired ischaemia-induced neovascularization in type II diabetic mice. Thus, ER stress and inflammation could be potential targets for a novel therapeutic approach to prevent impaired ischaemia-induced vascular pathology in type II diabetes

Atrial Natriuretic Peptide Levels Reflect Hemodynamic Changes Under Pacemaker Stimulation

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73244/1/j.1540-8159.1990.tb02142.x.pd