Myocardial stiffness is attributed to alterations in cross-linked collagen rather than total collagen or phenotypes in spontaneously hypertensive rats.
BACKGROUND
The relative contributions of increases in myocardial collagen, collagen cross-linking, and the ratio of type I to type III collagen to the stiff myocardium in hypertension were determined.


RESULTS
We compared the action of hydralazine (0.07 mmol x kg(-1) x d(-1)) with that of captopril (0.22 mmol x kg(-1) x d(-1)) on the left ventricular end-diastolic (LVED) myocardial stiffness constant, k (g x cm(-2)) and LV myocardial interstitial characteristics in spontaneously hypertensive rats (SHRs) and Wistar Kyoto (WKY) control rats. LVED k (SHR, 27.9+/-1; WKY, 19.5+/-1.2; P<.01), myocardial hydroxyproline concentrations (HPRO; microg/mg dry wt) (SHR, 4.19+/-0.16; WKY, 3.17+/-0.09; P<.001), and collagen type I/III ratios (SHR, 7.1+/-0.7; WKY, 2.1+/-0.2; P<.001) were increased, whereas the percentage of myocardial collagen extracted after cyanogen bromide digestion (an index of cross-linked collagen) was decreased (SHR, 17+/-3; WKY, 41+/-4; P<.001) in SHRs compared with WKY controls. Captopril therapy reduced LVED k, myocardial HPRO, collagen type I/III, and augmented collagen solubility (43+/-4) in SHRs to values similar to those measured in WKY controls. Hydralazine therapy, despite a favorable effect on LVED k in SHRs (20.+/-1.6, P<.01 compared with untreated SHRs), failed to influence either myocardial HPRO (4.18+/-0.18) or collagen type I/III (8+/-1) but did improve collagen solubility (31+/-2).


CONCLUSIONS
An association between alterations in LVED k and collagen solubility but not between changes in LVED k and total collagen or phenotype ratios after antihypertensive therapy in SHRs suggests that myocardial stiffness in hypertension is the consequence of an enhanced myocardial collagen cross-linking rather than of an increase in total collagen or type I phenotype concentrations.
Norton
G R
GR
Department of Physiology, University of the Witwatersrand Medical School, Johannesburg, South Africa. 057nort@chiron.wits.ac.za
Tsotetsi
J
J
Trifunovic
B
B
Hartford
C
C
Candy
G P
GP
Woodiwiss
A J
AJ
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001835:Body Weight; D002216:Captopril / Q000494:pharmacology; D003094:Collagen / Q000032:analysis* / Q000235:genetics; D003432:Cross-Linking Reagents / Q000032:analysis*; D003971:Diastole / Q000502:physiology; D004195:Disease Models, Animal; D006830:Hydralazine / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D009206:Myocardium / Q000737:chemistry*; D009929:Organ Size; D010641:Phenotype; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012995:Solubility; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000503:physiopathology*; D018497:Ventricular Dysfunction, Right / Q000188:drug therapy / Q000503:physiopathology
D000959:Antihypertensive Agents; D003432:Cross-Linking Reagents; D006830:Hydralazine; D003094:Collagen; D002216:Captopril