Table 3.

α1-AR Loss of Function Models

ANIMAL PHARMACOLOGY
Species	α1-Antagonist & Model	Findings & References
Rat	Prazosin & hemorrhage	↑ I-R injury with α1-blockade [154]
Rabbit	CEC & I-R	↑ I-R injury with α1B-blockade [153]
Rabbit	Doxazosin & rapid pacing	↓ Efficacy of β-blockade with α1-blockade [155]
Pig	Prazosin & I-R	↑ I-R injury with α1-blockade (second window of preconditioning) [132]
KNOCKOUT MICE
α1 Subtype or Gene	Model	Findings & References
A	In vivo: basal & agonist infusion	Mixed genetic background: normal heart size & function, ↓ resting BP and pressor response to α1A agonist [50]
		Congenic: normal heart size and BP [157]
B	In vivo: basal, agonist infusion, TAC	Mixed background: normal heart size, normal BP, ↓ pressor response [107, 158–160]; normal HT with TAC, but ↓ HT with subpressor PE [107]
		Congenic: small heart, normal BP, sinus bradycardia [157]
D	In vivo: basal, agonist infusion, salt loading	Mixed background: normal heart size, ↓ resting BP, ↓ pressor response, ↓ hypertension with salt loading [160, 161]; ↓ coronary vasoconstriction with PE [37]
		Congenic: normal heart size, ↓ resting BP (unpublished data)
A & B	In vivo: basal, exercise, TAC	Congenic: small heart & myocytes (males), normal BP, bradycardia, ↓ exercise, ↓ ERK [25]; ↓ myocardial contractility [162]; normal HT with TAC, but ↓ fetal gene induction, ↑ apoptosis and fibrosis, ↑ cardiomyopathy, ↑ HF, and ↑ death [26]
A & B	In vitro	↓ ERK activation with PE, but not ET or PMA [25]; ↑ apoptosis [26]; α1A but not α1B subtype rescues ABKO myocyte survival via ERK [27]
B & D	In vivo: basal, agonist infusion	Mixed: normal heart, ↓ BP, ↓ pressor response [160]
		Congenic: small heart, normal BP (unpublished data)
A & D	In vivo: basal	Congenic: normal heart size, normal BP (unpublished data)
A, B, & D	In vivo:basal	Congenic: small heart, normal BP (unpublished data)
TH, DBH	In vivo:basal	NE required for cardiac development in utero [198–200]
HUMAN RANDOMIZED CLINICAL TRIALS
Subtype	Test Drug	Findings & References
All ARs	moxonidine or bucindolol	Sympatholysis with ↓ NE (↓ α1 occupancy) increases HF [177–181]
A, B, D	prazosin	Non-selective α1-blocker trend toward ↑ mortality [173]
A, B, D	doxazosin	Non-selective α1-blocker ↑ incident HF [171, 172, 201]
A, B, D	phentolamine	Non-selective α-blocker ↓ preconditioning [175]

↑ and ↓ = relative to WT mice or control treatment; BP = blood pressure; CEC = chloroethylclonidine; DBH = dopamine beta-hydroxylase; ET = endothelin; HT = hypertrophy; I-R = ischemia-reperfusion; NE = norepinephrine; PE = phenylephrine; PMA = phorbol myristate acetate; TH = tyrosine hydroxylase