saralasin and Cardiomegaly

Hypertensive cardiac hypertrophy is associated with the accumulation of collagen in the myocardial interstitium. Previous studies have demonstrated that this myocardial fibrosis accounts for impaired myocardial stiffness and ventricular dysfunction. Although cardiac fibroblasts are responsible for the synthesis of fibrillar collagen, the factors that regulate collagen synthesis in cardiac fibroblasts are not fully understood. We investigated the effects of angiotensin II on cardiac collagen synthesis in cardiac fibroblasts of 10-week-old spontaneously hypertensive rats and age-matched WKY rats. Basal collagen synthesis in cardiac fibroblasts from spontaneously hypertensive rats was 1.6-fold greater than that in the cell of WKY rats. Angiotensin II stimulated collagen synthesis in cardiac fibroblasts in a dose-dependent manner. The responsiveness of collagen production to angiotensin II was significantly enhanced in cardiac fibroblasts from spontaneously hypertensive rats (100 nM angiotensin II resulted in 185 +/- 18% increase above basal levels, 185 +/- 18 vs 128 +/- 19% in WKY rats, P < .01). This effect was receptor-specific, because it was blocked by the competitive inhibitors saralasin and MK 954. These results indicate that collagen production is enhanced in cardiac fibroblasts from spontaneously hypertensive rats, that angiotensin II has a stimulatory effect on collagen synthesis in cardiac fibroblasts, and that cardiac fibroblasts from spontaneously hypertensive rats are hyper-responsive to stimulation by angiotensin II. In the hearts of spontaneously hypertensive rats, mRNA of the renin-angiotensin system (renin, angiotensinogen, angiotensin converting enzyme) was expressed. Levels of angiotensinogen and renin mRNA expressed in ventricles, and angiotensinogen mRNA expressed in fibroblasts from SHR were higher than those from WKY. ACE mRNA was also more strongly expressed in the ventricles and fibroblasts from SHR compared with those of WKY. These findings suggest that the cardiac reninangiotensin system may play an important role in collagen accumulation in hypertensive cardiac hypertrophy (fig.4).

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Cardiomegaly; Cells, Cultured; Collagen; Fibroblasts; Imidazoles; Losartan; Male; Myocardium; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin-Angiotensin System; RNA, Messenger; Saralasin; Signal Transduction; Tetrazoles

We have previously shown that mechanical stress induces activation of protein kinases and increases in specific gene expression and protein synthesis in cardiac myocytes, all of which are similar to those evoked by humoral factors such as growth factors and hormones. Many lines of evidence have suggested that angiotensin II (Ang II) plays a vital role in cardiac hypertrophy, and it has been reported that secretion of Ang II from cultured cardiac myocytes was induced by mechanical stretch. To examine the role of Ang II in mechanical stress-induced cardiac hypertrophy, we stretched neonatal rat cardiac myocytes in the absence or presence of the Ang II receptor antagonists saralasin (an antagonist of both type 1 and type 2 receptors), CV-11974 (a type 1 receptor-specific antagonist), and PD123319 (a type 2 receptor-specific antagonist). Stretching cardiac myocytes by 20% using deformable silicone dishes rapidly increased the activities of mitogen-activated protein (MAP) kinase kinase activators and MAP kinases. Both saralasin and CV-11974 partially inhibited the stretch-induced increases in the activities of both kinases, whereas PD123319 showed no inhibitory effects. Stretching cardiac myocytes increased amino acid incorporation, which was also inhibited by approximately 70% with the pretreatment by saralasin or CV-11974. When the culture medium conditioned by stretching cardiocytes was transferred to nonstretched cardiac myocytes, the increase in MAP kinase activity was observed, and this increase was completely suppressed by saralasin or CV-11974. These results suggest that Ang II plays an important role in mechanical stress-induced cardiac hypertrophy and that there are also other (possibly nonsecretory) factors to induce hypertrophic responses.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Benzimidazoles; Biphenyl Compounds; Cardiomegaly; Cells, Cultured; Electrophoresis, Polyacrylamide Gel; Enzyme Activation; Mitogen-Activated Protein Kinase Kinases; Myocardium; Phenylalanine; Protein Kinases; Rats; Rats, Wistar; Receptors, Angiotensin; Saralasin; Signal Transduction; Stress, Mechanical; Tetrazoles

In an earlier study of guinea pigs with constriction of the pulmonary artery (PA) for 30 days, hindquarters' vascular resistance was maintained primarily by humoral mechanisms. In the present study, we investigated the contribution of circulating catecholamines, angiotensin II, and other constrictor stimuli to hindquarters' vascular resistance by observing vasodilator responses to specific competitive antagonists. Pressure-flow curves indicated vascular resistances in isolated, perfused, sympathectomized hindquarters of anesthetized guinea pigs. Phentolamine produced significantly greater (P less than 0.05) vasodilatation in animals with constriction of pulmonary artery than in sham animals [Sar1-Ala8]angiotensin II produced no vasodilation in either group. After alpha-adrenergic blockade, papaverine produced similar vasodilatation and similar final perfusion pressures in both groups. It appears that circulating catecholamines and augmented vasoconstrictor responsiveness to norepinephrine are totally responsible for the increased humoral regulation of vascular resistance in this experimental model of right ventricular hypertrophy.

Topics: Angiotensin II; Animals; Cardiomegaly; Catecholamines; Dopamine; Epinephrine; Guinea Pigs; Heart Failure; Norepinephrine; Papaverine; Phentolamine; Phenylephrine; Saralasin; Sympathetic Nervous System; Tyrosine 3-Monooxygenase; Vascular Resistance

1. Angiotensin II (AII) antagonists, namely Sar1,Ile8-AII, Sar1,Ala8-AII and Sar1,Thr8-AII, were administered daily for 4 weeks to normotensive rats to study their effect on cardiac hypertrophy. 2. None of the antagonists altered blood pressure significantly but Sar1,Ile8-AII and Sar1,Ala8-AII produced a significant increase in heart weight, as compared with untreated age-matched control rats. Administration of Sar1,Thr8-AII did not produce cardiac hypertrophy. 3. A significant increase in catecholamine concentration was observed in the ventricles of rats treated with Sar1,Ile8-AII and Sar1,Ala8-AII but no change was found in the group treated with the Sar1,Thr8-AII analogue. The production of cardiac hypertrophy by Sar1,Ile8-AII was prevented by bilateral adrenalectomy, suggesting an important role for catecholamines in modulating cardiac hypertrophy.

Topics: Angiotensin II; Animals; Blood Pressure; Cardiomegaly; Catecholamines; Rats; Saralasin