Soluble guanylate cyclase (sGC), a key enzyme of the nitric oxide (NO) signaling pathway, is attracting rapidly growing interest as a therapeutic target in cardiopulmonary disease, with several sGC agonists currently in clinical development. On binding of NO to a prosthetic heme group on sGC, the enzyme catalyzes synthesis of the second messenger cGMP, which produces vasorelaxation and inhibits...

NEUROTRANSMISSION, PLATELET FUNCTION, skeletal muscle and vascular and nonvascular smooth muscle, and numerous other cellular functions are significantly regulated by the principal enzyme initially transducing nitric oxide (NO) signals, soluble guanylyl cyclase (sGC) (8). The better-characterized active forms of this enzyme exist as a heterodimer, comprising an and a heme-containing -sGC subuni...

The nitric oxide (NO)/cGMP pathway plays a key role in the regulation of pulmonary vascular tone during the transition from the fetal to the neonatal circulation, and it is impaired in pathophysiological conditions such as pulmonary hypertension. In the present study, we have analyzed the changes in the function and expression of soluble guanylyl cyclase (sGC) in pulmonary arteries during early...

Soluble guanylyl cyclase (sGC), a ubiquitously expressed heme-containing receptor for nitric oxide (NO), is a key mediator of NO-dependent processes. In addition to NO, a number of synthetic compounds that target the heme-binding region of sGC and activate it in a NO-independent fashion have been described. We report here that dicyanocobinamide (CN2-Cbi), a naturally occurring intermediate of v...

Soluble guanylate cyclase (sGC) plays a central role in the cardiovascular system and is a drug target for the treatment of pulmonary hypertension. While the three-dimensional structure of sGC is unknown, studies suggest that binding of the regulatory domain to the catalytic domain maintains sGC in an autoinhibited basal state. The activation signal, binding of NO to heme, is thought to be tran...

The present study tests the hypothesis that chronic hypoxia enhances reactivity to nitric oxide (NO) through age-dependent increases in soluble guanylate cyclase (sGC) and protein kinase G (PKG) activity. In term fetal and adult ovine carotids, chronic hypoxia had no significant effect on mRNA levels for the beta1-subunit of sGC, but depressed sGC abundance by 16% in fetal and 50% in adult arte...

Vascular reactivity to nitric oxide (NO) is mediated by NO-sensitive soluble guanylyl cyclase (sGC). Since a diminished activity of vascular sGC has been reported in an animal model of type 2 diabetes, the sGC activity was assayed in vitro in internal mammary artery specimens obtained during bypass surgery from patients with and without type 2 diabetes. The sensitivity of sGC to NO, which is de...

Soluble guanylate cyclase (sGC), which is found in many cells and tissues, represents the receptor for the intra- and intercellular messenger molecule NO. Superoxide dismutase (SOD), an enzyme involved in the degradation of toxic superoxide radicals, has been proposed as a non-NO activator of sGC. Here we show that SOD stimulated sGC purified from bovine lung up to 10-fold. Activation by SOD wa...

The signaling molecule nitric oxide (NO) mediates many of its effects by the stimulation of soluble guanylyl cyclase (sGC). The activation process is initiated by high-affinity binding of NO to the enzyme's prosthetic heme group. Despite its poor sGC-activating properties, carbon monoxide (CO) has also been suggested as a physiological activator of sGC. Recently, we have shown that the substanc...

Nitrates such as nitroglycerin (GTN) and nitric oxide donors such as S-nitrosothiols are clinically vasoactive through stimulation of soluble guanylyl cyclase (sGC), which produces the second messenger cGMP. Development of nitrate tolerance, after exposure to GTN for several hours, is a major drawback to a widely used cardiovascular therapy. We recently showed that exposure to nitric oxide and ...