Concerns & Answers About Potential α1-Agonist Therapy
As summarized above, abundant evidence from cell, animal and human studies indicates that activating cardiac α1-ARs is beneficial. α1-ARs are highly "druggable", and recruit numerous downstream adaptive and protective signaling mechanisms. Thus, α1-AR agonists could represent a novel approach to the treatment of myocardial diseases and HF. α1-AR augmentation of adaptive hypertrophy, cardioprotection, and positive inotropy might have multiple clinical applications, including acute myocardial ischemia, cardiotoxicity with cancer therapy, and chronic systolic HF. As previously mentioned, multiple studies have shown that α1-AR levels are either unchanged or increased in human HF [56
]. Furthermore, myocardial α1-ARs are thought to be only 10% occupied by NE, even in HF [134
], indicating the potential for additional activation by an exogenous agonist. The safety of α1-AR activation by an exogenous agonist is well established, as oral (midodrine) and intravenous (PE) agents are already in clinical use. In fact, a recent small clinical trial demonstrated a significant benefit associated with the use of midodrine in patients with advanced HF already receiving contemporary therapy [170
Given the wealth of data in multiple models from many different labs over three-plus decades, it is important to consider reasons for possible resistance to the idea of α1-agonist therapy. Potential concerns and answers are summarized in .
First, α1B subtype over-expression in transgenic mice causes a maladaptive phenotype, or at least not adaptive, whereas the KO approach and pharmacology point to the α1A and α1B in adaptive effects. We believe that pharmacology and the KOs provide the more reliable evidence, for reasons noted in , but the role of the α1B requires more study.
Second, α1-ARs are irrefutably linked to smooth muscle contraction, for example, in the vascular and GU systems, raising concerns of hypertension, angina, or prostatism with α1-agonist therapy. Against these possibilities is the key observation, repeated in many labs, that adaptive cardiac effects of α1-agonists occur at doses that do not increase BP, or cause myocardial ischemia. Furthermore, the α1D subtype appears to have a key role in smooth muscle contraction, but is not involved in adaptive cardiac effects, and thus could be avoided with α1A and/or α1B agonists. As with any systemic therapy, other potential extra-cardiac effects of an α1-agonist still need to be determined. Some might be favorable. For example, in the brain, there is evidence that α1-ARs might be neuroprotective [182
]. KO of the α1B causes abnormal glucose metabolism and obesity [184
], implying that an α1B agonist might have favorable metabolic effects, opposite to the view that α1-blockers have favorable metabolic profiles [185
The proven efficacy of carvedilol in the treatment of HF [186
] would also seem to argue against the therapeutic benefit of an α1-AR agonist, since carvedilol blocks both α1- and β-ARs. However, it is important to recognize that the α1-blocking properties of carvedilol extinguish shortly after initiation of therapy [187
]. In fact, chronic carvedilol use actually increases the blood pressure response to PE infusion in HF patients [189
]. Thus the benefits associated with chronic carvedilol use are likely related to β-blockade, not α1-blockade, as well as to a number of salutary effects unrelated to ARs [155
Finally, α1-ARs are associated with "pathological" hypertrophy, because they are coupled to Gq, and induce fetal genes in rodent models. On the contrary, the studies reviewed here indicate clearly that α1-ARs stimulate adaptive and protective effects in heart, not pathological. For reasons outlined in , it is not appropriate to extrapolate from Gq over-expression to the conclusion that all cardiac Gq-coupled receptors mediate pathology. Likewise, induction of fetal genes, such as ANF, BNP, skeletal α-actin, and β-MyHC is considered a hallmark of pathological hypertrophy. However, it is not clear that induction of these genes is causal, or even maladaptive. For instance, one fetal gene, BNP is even used as therapy in HF (nesiritide, Natrecor). As another example, skeletal α-actin is increased by 5-fold in BALB/c mouse hearts, yet cardiac structure is normal and contractility is enhanced [195
]. Finally, recent work suggests that the prototypical fetal gene, β-MyHC, is induced by pressure overload only in a minor population of myocytes, and that the cells with β-MyHC are smaller than those without β-MyHC, not larger [196
]. The low fraction of myocytes expressing β-MyHC casts some doubt on contractile function significance, and the small cell size suggests that β-MyHC is not a marker for cell hypertrophy.