Prevention by blockade of angiotensin subtype1-receptors of the development of genetic hypertension but not its heritability.
1. We determined whether early inhibition of angiotensin II subtype1 (AT1) receptors by the newly synthesized nonpeptidic antagonist, A-81988, can attenuate the development of hypertension in spontaneously hypertensive rats (SHR) and if the altered blood pressure phenotype can be passed on to the subsequent generation, not exposed to the antagonist. 2. Pairs of SHR were mated while drinking tap water or A-81988 in tap water, and the progeny was maintained on the parental regimen until 14 weeks of age. At this stage, A-81988-treated rats showed lower systolic blood pressure and body weight values (136 +/- 5 versus 185 +/- 4 mmHg and 247 +/- 4 versus 283 +/- 4 g in controls, P < 0.01); while heart rate was similar. In addition, mean blood pressure was reduced (101 +/- 7 versus 170 +/- 7 mmHg in controls, P < 0.01), and the pressor responses to intravenous or intracerebroventricular angiotensin II were inhibited by 27 and 59%, respectively. Heart/body weight ratio was smaller in A-81988-treated rats (3.2 +/- 0.1 versus 3.8 +/- 0.1 in controls, P < 0.01). 3. The antihypertensive and antihypertrophic effect of A-81988 persisted in rats removed from therapy for 7 weeks (systolic blood pressure: 173 +/- 4 versus 220 +/- 4 mmHg, heart/body weight ratio: 3.4 +/- 0.1 versus 4.1 +/- 0.1 in controls at 21 weeks of age, P < 0.01 for both comparisons), whereas the cardiovascular hypertensive phenotype was fully expressed in the subsequent generation that was maintained without treatment. 4. These results indicate that chronic blockade of angiotensin AT1-receptors attenuates the development of hypertension in SHR but it does not prevent the transmission of hypertension to the following generation. Thus, heritability of the SHR's hypertensive trait is not affected by pharmacological manipulation of the cardiovascular phenotype.
Madeddu
P
P
Clinica Medica and Farmacologia, University of Sassari, Italy.
Anania
V
V
Varoni
M V
MV
Parpaglia
P P
PP
Demontis
M P
MP
Fattaccio
M C
MC
Palomba
D
D
Pollock
D
D
Glorioso
N
N
D000284:Administration, Oral; D000804:Angiotensin II / Q000008:administration & dosage / Q000633:toxicity; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers / Q000652:urine; D001794:Blood Pressure / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D004231:Diuresis / Q000187:drug effects; D005260:Female; D030342:Genetic Diseases, Inborn / Q000235:genetics; D006321:Heart / Q000187:drug effects; D006973:Hypertension / Q000235:genetics / Q000517:prevention & control*; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D008297:Male; D009539:Nicotinic Acids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D009929:Organ Size / Q000187:drug effects; D010641:Phenotype; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D015415:Biomarkers; D009539:Nicotinic Acids; D013777:Tetrazoles; D000804:Angiotensin II; C081174:A 81988