Functional tolerance to alpha-adrenergic receptor blockade in the spontaneously hypertensive rat highlights the multifunctional role of vascular angiotensin II in the development of hypertension.
Treatment of spontaneously hypertensive rats (SHR) with alpha-adrenoceptor antagonists failed to alter the development of hypertension in this animal model. However, agents such as captopril (CAP) and losartan (LOS) which interfere with the renin-angiotensin system effectively prevented the development of hypertension. When tolerance occurred in the presence of doxazosin (DOX) or phenoxybenzamine, there was an enhanced sensitivity to the blood pressure lowering influence of LOS. In the presence of CAP, at a dose that did not retard the development of blood pressure in the SHR, DOX treatment significantly offset the development of hypertension in this strain. These results suggest that a functional tolerance to agents that interfere with the sympathetic nervous system is mediated by the renin-angiotensin system. Angiotensin-converting enzyme inhibition was associated with a normalization of the enhanced contraction of the mesenteric vascular bed seen in preparations from the SHR and a suppression in the development of the vascular amplifier. The results suggest that the sympathetic nervous system is unable to maintain an elevated blood pressure in the SHR during interference with the functioning of the renin-angiotensin system. Conversely, under conditions of alpha-adrenoceptor blockade, angiotensin II can maintain an elevated blood pressure in the SHR.
Smid
S D
SD
Department of Clinical and Experimental Pharmacology, University of Adelaide, Australia.
Frewin
D B
DB
Wyartt
C L
CL
Head
R J
RJ
D000317:Adrenergic alpha-Antagonists / Q000627:therapeutic use*; D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000627:therapeutic use; D001794:Blood Pressure; D002216:Captopril / Q000008:administration & dosage / Q000627:therapeutic use; D017292:Doxazosin / Q000008:administration & dosage / Q000627:therapeutic use; D004361:Drug Tolerance; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D007093:Imidazoles / Q000008:administration & dosage / Q000627:therapeutic use; D019808:Losartan; D009638:Norepinephrine / Q000494:pharmacology; D010643:Phenoxybenzamine / Q000008:administration & dosage / Q000627:therapeutic use; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013777:Tetrazoles / Q000008:administration & dosage / Q000627:therapeutic use
D000317:Adrenergic alpha-Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D010643:Phenoxybenzamine; D000804:Angiotensin II; D002216:Captopril; D019808:Losartan; D017292:Doxazosin; D009638:Norepinephrine