Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Platelet hyperactivity plays an important role in the pathogenesis of cardio-vascular diseases. In patients with stable angina pectoris, we have recently demonstrated that nitroglycerin suppressed the increased platelet aggregability. The anti-aggregating effect of NTG and other nitrovasodilators is mediated by platelet guanylate cyclase, which generates cyclic GMP (cGMP) in response to nitric oxide (NO) liberated from the nitrovasodilator molecule. In the current study we utilised a more "direct" NO donor, sodium nitroprusside (SNP), to examine reversal of ADP-induced platelet aggregation in comparison with intraplatelet cGMP elevation in platelets from normal subjects (n = 22) and patients with stable angina pectoris (n = 23). Concentrations of SNP associated with 50% reversal of aggregation were 2.7 +/- 0.4 x 10(-7) mol/L with normal subjects and 4.5 +/- 0.5 x 10(-6) mol/L with patients (P < 0.01). SNP produced a concentration-dependent elevation of intraplatelet cGMP content: with 10(-4) mol/L SNP this was 17-fold for normals and 5-fold for patients (P < 0.01). An increase in cAMP content was seen only with 10(-4) mol/L SNP, and was 157 +/- 11% of baseline in platelets from normal subjects and 138 +/- 14% in patients. There was a strong interrelationship between cGMP-stimulating and anti-aggregating effects of SNP. The decrease in cGMP responsiveness to SNP was not related to a dysfunction of platelet guanylate cyclase; neither basal nor SNP-stimulated activity of the enzyme varied significantly between normal subjects and patients. Lipophilic derivatives of cGMP (db-cGMP) and cAMP (db-cAMP) caused reversal of aggregation; there was a nonsignificant trend towards decreased responsiveness of platelets from patients to both db-cGMP and db-cAMP. The observed decrease in responsiveness of platelets from angina patients to anti-aggregating effects of the exogenous NO donor, SNP, can therefore be attributed to suppressed cGMP accumulation. These results imply reduced platelet sensitivity to endogenous NO (endothelium-derived relaxing factor): this might contribute to platelet hyperaggregability observed in angina pectoris.
 ...
PMID:Suppressed anti-aggregating and cGMP-elevating effects of sodium nitroprusside in platelets from patients with stable angina pectoris. 889 57

Because nitroglycerin (NTG, an organic nitrate) and isoamyl nitrite have similar chemical structures and a common mechanism of vascular relaxation (i.e., conversion to nitric oxide in vascular tissues and activation of guanylyl cyclase), it has often been assumed that organic nitrates and nitrites have identical pharmacologic actions. Because recent studies have shown that the vascular enzymes responsible for nitric oxide generation from organic nitrates and nitrites are distinct, we hypothesized that the in vitro vascular actions, in vivo hemodynamic effects and tolerance properties (both in vitro and in vivo) would be different as well. Isolated blood vessel studies showed that NTG provided more stable relaxation effects than ISAN, was more potent and caused greater in vitro vascular tolerance. Because the mechanism(s) of vascular tolerance in vitro may not be the same as those occurring in vivo, we also compared the left ventricular hemodynamic effects and tolerance properties of NTG vs. isoamyl nitrite and in congestive heart failure rats. Constant NTG infusion (10 micrograms/min) caused initial reductions in left ventricular end-diastolic pressure of 45 to 55%, which returned to baseline within 10 hr (tolerance development). In contrast, isobutyl nitrite and isoamyl nitrite (45 micrograms/min) caused initial reductions in left ventricular end-diastolic pressure similar to NTG (42-58%), but these hemodynamic effects of organic nitrites were maintained even when infusions were carried out to 22 hr. These results show that organic nitrites and organic nitrates are not pharmacologically identical (in vitro or in vivo), and may suggest a therapeutic advantage for organic nitrites in the treatment of some cardiovascular diseases.
 ...
PMID:Vascular and hemodynamic differences between organic nitrates and nitrites. 899 13

PF9404C ((2'S),(2S)-3-isopropylamine, 1-[4-(2,3-dinitroxy)propoxymethyl]-phenoxy-2'-propranol) is the S-S diesteroisomer of a novel blocker of beta-adrenergic receptors with vasorelaxing properties. It causes a concentration-dependent relaxation of rat aorta helical strips precontracted with 10(-6) M norepinephrine (NE; IC50 33 nM). It is equipotent to nitroglycerin (NTG; IC50 49 nM), but much more potent than isosorbide dinitrate (ISD; IC50 15,000 nM). In rat aorta smooth muscle cells, at 10 microM, PF9404C increased the formation of cGMP from 3 pmol/mg protein in basal conditions to 53 pmol/mg protein, suggesting that the mechanism of its vasorelaxing effects involves the slow generation of NO. This is supported by the facts that (i) ODQ (a blocker of guanylate cyclase) inhibited the vasodilatory effects of PF9404C; and (ii) PF9404C generates NO, as indirectly measured by the Griess reaction. In the electrically driven guinea pig left atrium, PF9404C blocks the inotropic effects of isoproterenol in a concentration-dependent manner. Its IC50 (30 nM) was similar to that of S-propranolol (22.4 nM) and lower than that of metoprolol (120 nM) or atenolol (192 nM). The beta adrenergic ligand (-)-[3H]-CGP12177 (4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride) (0.2 nM) is displaced from its binding sites in rat brain membranes with a K(i) of 7, 17, 170, and 1200 nM for PF9404C, S-(-)propranolol, metoprolol, and atenolol, respectively. PF9404C blocks 45Ca2+ entry into bovine adrenal chromaffin cells induced by direct depolarization with 70 mM K+ or by the nicotinic agonist dimethylphenylpiperazinium (DMPP). PF9404C exhibits about 3-fold higher potency than NTG to relax the majority of the vessels studied, especially when they were contracted with K+, and shows a certain selectivity of action for the renal artery. It produces auto-tolerance that is ca. 20-fold less pronounced than that observed with NTG. Cross-tolerance in preparations pre-exposed to PF9404C and later relaxed with NTG, was much greater than auto-tolerance. This makes PF9404C a useful pharmacological tool for the development of novel NO-donor compounds with a lesser degree of vascular tolerance than those currently available.
 ...
PMID:Preclinical profile of PF9404C, a nitric oxide donor with beta receptor blocking properties. 1600 31