Table 4.

Concerns & Answers About Potential α1-Agonist Therapy

Concerns	Answers & References
Transgenics: α1B-AR over-expression can be maladaptive (Table 2).	Pharmacology and KOs are congruent on adaptive effects (Tables 1 & 3), and germline KOs are predictive of drug effects in humans [19, 202]; high-level over-expression is non-physiological; over-expressed or constitutively activated α1- and β-ARs can signal differently from endogenous receptors [203–205]; over-expressed receptors can inhibit other GPCRs by "stealing" G proteins [206, 207]
Hypertension: α1-receptors cause vasoconstriction, and α1-agonists will cause hypertension.	Cardiac trophic effects occur at low, cardioselective doses that do not increase blood pressure [39, 103–107, 127]
Angina: α1-receptors constrict coronary arteries, and an agonist will cause angina.	α1-Receptors do not constrict normal coronary arteries [208]; smooth muscle contraction occurs at higher doses than required for cardiac trophic effects [36, 127]; the α1D is the subtype present in coronary smooth muscle, and could be avoided with selective agonists [36, 37, 55].
Prostatism: α1-receptors constrict prostate smooth muscle, and agonists will cause urinary retention or prostate symptoms.	Cardiac effects might occur at doses below those activating prostate smooth muscle, as with vascular; α1D antagonists are effective to treat prostate symptoms [209], and the α1D subtype could be avoided with α1A- and/or α1B-selective agonists.
Carvedilol: carvedilol blocks α1-receptors and is efficacious in heart failure.	Carvedilol in chronic therapy does not block α1-effects [187, 188], and might even enhance them [189].
Hypertrophy: α1-receptors cause hypertrophy, which is bad.	α1-Receptor agonists stimulate an adaptive or "physiological" hypertrophy, with no fibrosis, and normal or improved cardiac function [39, 103–107, 127].
Fetal genes: α1-receptors increase β-MyHC and other fetal genes in rodent models, and these are hallmarks of pathological hypertrophy.	It is arguable whether fetal gene induction is maladaptive, or causative in pathological hypertrophy [195, 196, 210, 211]
Gq: α1-receptors are coupled to Gq, and Gq over-expression in mice causes pathological hypertrophy.	Two-fold, life-long α-MyHC-driven Gq over-expression in mice has no phenotype [212, 213], and 5-fold adult myocyte over-expression does not cause pathology [214]; 2-fold increases in endogenous Gq are the maximum seen in heart failure [215, 216], and the Gq is shared among many cardiac cells and receptors in those cells.