It has been suggested that various agents induce relaxation of vascular smooth muscles through guanosine 3',5'-cyclic monophosphate (cGMP) and cGMP-dependent protein kinase (cGMP-PK). In this work, the activity of cGMP-PK was studied in the 30,000 g supernatant from aortae of 4, 6, 8 and 12-week-old spontaneously hypertensive (SHR) and age-matched normotensive Wistar-Kyoto (WKY) rats and also of 4 and 12-week-old normotensive Wistar (W) and Sprague Dawley (SD) rats. At 4 weeks of age, both basal and cGMP-stimulated activity were not different in SHR and WKY rats. Nevertheless, a greater basal activity was measured in W (+50%) and SD (+20%) rats than in SHR, while no difference was observed between stimulated activities. In contrast with observations in the three normotensive rat strains, cGMP-PK activity did not decrease in the aortae supernatant of SHR rats aged 4-12 weeks. This resulted in mean increases of 45 and 30% in the basal and the cGMP-stimulated activity, respectively, in the 12-week-old SHR rats. The abnormal evolution of cGMP-PK activity in the hypertensive strain was already detectable at 4-6 weeks of age. In apparent agreement with observations on protein kinase activity, cGMP binding activity attributable to cGMP-PK was 25% greater in 12-week-old hypertensive rats compared with age-matched WKY rats. These results indicate that in aortae of SHR rats, control of cGMP-PK activity is abnormal early in life.
[Show abstract][Hide abstract] ABSTRACT: Cyclic GMP (cGMP) kinase is intimately involved in the regulation of vascular smooth muscle tone. Its tissue concentration was determined in normotensive and hypertensive rats by use of monospecific anti-cGMP kinase antibodies. Hearts of spontaneously hypertensive rats and renovascular (Goldblatt II) hypertensive rats contained half the concentration of cGMP kinase than those of the respective normotensive animals. The increase in blood pressure and the resulting left ventricular hypertrophy were correlated inversely with the left ventricular cGMP kinase concentration. This decrease was specific for the left ventricle and was not observed in other tissues. In addition, the cardiac concentration of cGMP kinase was unchanged in hyperthyroid animals that had comparable left ventricular hypertrophy and mild hypertension. This suggested that in severe renovascular hypertension the decrease in cardiac cGMP kinase concentration is caused by a relative lack of cardiac vessel growth during the development of hypertrophy. In agreement with this conclusion, immunohistochemistry of cardiac cross sections showed that cGMP kinase was exclusively located in cardiac vessels. In support of this localization, the maximal arterial blood flow of heart, liver, skeletal muscle, and kidney correlated excellently with the cGMP kinase content of the respective organ. These results suggest that the cGMP kinase concentration of nonsmooth muscle tissues depends on the amount of organ-specific vascular smooth muscle and may be used as an index for the vascularization of these organs.
Circulation Research 12/1989; 65(5):1361-9. DOI:10.1161/01.RES.65.5.1361 · 11.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The state of the vasodilator systems in congestive heart failure is poorly defined. Plasma atrial natriuretic peptide is increased, whereas endothelium derived relaxing factor activity can be decreased. Atrial natriuretic peptide and endothelium derived relaxing factor both cause vascular relaxation by generating cyclic guanosine monophosphate (cGMP), by activating the particulate and the soluble guanylate cyclase, respectively. This study examines the biological effects of atrial natriuretic peptide and endothelium derived relaxing factor in experimental heart failure by assessing the plasma, urinary, and tissue concentrations of their common second messenger cGMP.
Myocardial infarctions (n = 31) were induced and sham operations (n = 25) were performed on Wistar rats, and the rats were monitored for three months. Aortic and pulmonary cGMP contents were measured, as the aorta is mainly matrix and smooth muscle cells, and the lung is particularly rich in capillaries, hence in endothelial cells. The concentrations of the other second messenger cyclic adenosine monophosphate (cAMP) was also determined, as were those of cGMP dependent protein kinase in the arteries.
17 of the 31 rats with myocardial infarction had oedema. The total heart weight to body weight ratio and the ratio of the myocardium haemodynamically upstream from the infarcted left ventricle to body weight were increased in proportion to the infarct size. Plasma atrial natriuretic peptide and plasma and urinary cGMP concentrations were increased in proportion to the degree of heart failure (p < 0.0001). The pulmonary cGMP concentration was significantly higher in the rats with myocardial infarction than in the control group (p < 0.0001). Pulmonary cGMP concentrations were correlated with the plasma concentrations of atrial natriuretic peptide and cGMP (r2 = 0.59 and 0.66 respectively, p < 0.0001). The cGMP, cAMP, and cGMP, and cGMP dependent kinase concentrations in the aortic wall of rats with myocardial infarctions were the same as in control rats.
The increase in plasma, urinary, and pulmonary cGMP in rats with myocardial infarctions were highly correlated with the increase in circulating atrial natriuretic peptide. By contrast, the aortic cGMP concentration was unchanged in these rats, despite high plasma atrial natriuretic peptide. In congestive heart failure, a discrepancy seems to exist between pulmonary (mainly endothelium) and aortic wall (mainly smooth muscle cells) cGMP.
Cardiovascular Research 06/1993; 27(6):1094-100. DOI:10.1093/cvr/27.6.1094 · 5.94 Impact Factor
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