Role of angiotensin-converting enzyme, adrenergic receptors, and blood pressure in cardiac gene expression of spontaneously hypertensive rats during development.
We undertook this study to investigate the regulatory mechanism of cardiac gene expression in spontaneously hypertensive rats (SHR) during development. We measured cardiac mRNAs by Northern blot analysis. In 9-week-old SHR at the very early stage of cardiac hypertrophy, the expression of various cardiac genes related to the regulation of cardiac contraction and relaxation was already significantly changed compared with control Wistar-Kyoto rats, indicating that cardiac molecular changes are responsible for cardiac remodeling or the modulation of cardiac performance in SHR. We gave various types of antihypertensive drugs, at oral doses causing a mild and comparable hypotensive effect, to 27-week-old SHR to examine the effects on the altered cardiac gene expression. Imidapril, an angiotensin-converting enzyme inhibitor, normalized the increased gene expression of atrial natriuretic polypeptide and collagen types I and III and the decreased expression of alpha-myosin heavy chain in SHR heart. Atenolol (a beta 1-blocker) combined with doxazosin did not affect cardiac ANP and alpha-myosin heavy chain expression of SHR but normalized the increased collagen expression. In contrast, despite a hypotensive effect comparable to these two drug treatments, doxazosin (an alpha 1-blocker) alone or manidipine (a calcium antagonist) did not normalize these altered gene expressions of SHR. These results show that the cardiac renin-angiotensin system is involved in the altered cardiac gene expression in SHR. The beta 1- but not alpha 1-adrenergic receptor is also responsible for the increased cardiac collagen expression in SHR.
Ohta
K
K
Department of Pharmacology, Osaka City University Medical School, Japan.
Kim
S
S
Iwao
H
H
D000199:Actins / Q000235:genetics; D000375:Aging / Q000502:physiology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D009320:Atrial Natriuretic Factor / Q000235:genetics; D001794:Blood Pressure; D003094:Collagen / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006339:Heart Rate; D006973:Hypertension / Q000378:metabolism*; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000502:physiology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011941:Receptors, Adrenergic / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics
D000199:Actins; D000959:Antihypertensive Agents; D011941:Receptors, Adrenergic; D016212:Transforming Growth Factor beta; D009320:Atrial Natriuretic Factor; D003094:Collagen; D007703:Peptidyl-Dipeptidase A