There is no information comparing the ability to reverse the cardiotoxic effects associated with incremental overdosage of bupivacaine (BUP) to levobupivacaine (LBUP), ropivacaine (ROP), or lidocaine (LIDO). Open-chest dogs were randomized to receive incremental escalating infusions of BUP, LBUP, ROP, and LIDO to the point of cardiovascular collapse (mean arterial pressure [MAP] ≤45 mm Hg). Hypotension and arrhythmias were treated with epinephrine, open-chest massage, and advanced cardiac life support protocols, respectively. Outcomes were defined as the following: successful (stable rhythm and MAP ≥55 mm Hg for 20 min), successful with continued therapy (stable rhythm and MAP <55 mm Hg after 20 min), or death. Continued therapy was required in 86% of LIDO dogs compared with only 10%–30% of the other dogs (P < 0.002). Mortality from BUP, LBUP, ROP, and LIDO was 50%, 30%, 10%, and 0%, respectively. Myocardial depression was primarily responsible for the profound hypotension, as the occurrence of lethal arrhythmias preceding resuscitation was not different among local anesthetics. Epinephrine-induced ventricular fibrillation occurred more frequently in BUP-intoxicated dogs than in dogs given LIDO or ROP (P < 0.05). The unbound plasma concentrations at collapse were larger for ROP, 19.8 μg/mL (10–39 μg/mL), compared with BUP, 5.7 μg/mL (3–11 μg/mL); whereas the concentrations of LBUP, 9.4 μg/mL (5–18 μg/mL) and BUP were not significantly different from each other. There were consistent differences among the local anesthetics, the sum of which suggests that larger doses and blood concentrations of ropivacaine (ROP) and lidocaine will be tolerated as compared with bupivacaine (BUP) and levobupivacaine (LBUP). Lidocaine intoxication results in myocardial depression from which resuscitation is consistently successful but will require continuing drug support. After BUP, LBUP, or ROP, resuscitation is not always successful, and the administration of epinephrine may lead to severe arrhythmias. The unbound plasma concentrations at collapse were larger for ROP compared with BUP, whereas the concentrations of LBUP and BUP were not significantly different from each other. Furthermore, larger plasma concentrations of ROP than BUP are present after resuscitation, suggesting a wider margin of safety when large volumes and large concentrations are used to establish upper or lower extremity nerve blocks for surgical anesthesia and during long-term infusions for pain management.

The prevalence of left ventricular diastolic dysfunction (LVDD) sharply increases in women after menopause and may lead to heart failure. While evidence suggests that estrogens protect the premenopausal heart from hypertension and ventricular remodeling, the specific mechanisms involved remain elusive. Moreover, whether there is a protective role of estrogens against cardiovascular disease, and specifically LVDD, continues to be controversial. Clinical and basic science have implicated activation of the renin-angiotensin-aldosterone system (RAAS), linked to the loss of ovarian estrogens, in the pathogenesis of postmenopausal diastolic dysfunction. As a consequence of increased tissue ANG II and low estrogen, a maladaptive nitric oxide synthase (NOS) system produces ROS that contribute to female sex-specific hypertensive heart disease. Recent insights from rodent models that mimic the cardiac phenotype of an estrogen-insufficient or -deficient woman (e.g., premature ovarian failure or postmenopausal), including the ovariectomized congenic mRen2.Lewis female rat, provide evidence showing that estrogen modulates the tissue RAAS and NOS system and related intracellular signaling pathways, in part via the membrane G protein-coupled receptor 30 (GPR30; also called G protein-coupled estrogen receptor 1). Complementing the cardiovascular research in this field, the echocardiographic correlates of LVDD as well as inherent limitations to its use in preclinical rodent studies will be briefly presented. Understanding the roles of estrogen and GPR30, their interactions with the local RAAS and NOS system, and the relationship of each of these to LVDD is necessary to identify new therapeutic targets and alternative treatments for diastolic heart failure that achieve the cardiovascular benefits of estrogen replacement without its side effects and contraindications.

Heart failure (HF) is one of the few cardiac conditions that is increasing. Despite a better understanding of how hormones and other signaling systems underlie the pathophysiology, and despite improved outcomes from pharmacologic therapy, many HF patients receive no effective treatment. Patients with HF commonly require medical diagnosis and management in operating rooms and critical care units; thus anesthesiologists are obliged to remain up-to-date both with advances in outpatient (chronic) medical management and with inpatient treatments for acute exacerbations of HF. Accordingly, we reviewed angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-adrenergic receptor blockers, and aldosterone antagonists because these drugs prolong life and are included in current clinical practice guidelines for treating patients with chronic HF. We also reviewed the implications of chronic HF for patients undergoing surgery and anesthesia and discuss how best to provide intensive treatment for acute exacerbations of symptoms, such as might be caused by excessive intravascular volume, inappropriate drug "holidays," or worsening of the underlying cardiac disease.

GPR30 is a novel oestrogen receptor expressed in various tissues, including the heart. We determined the role of GPR30 in the maintenance of left ventricular (LV) structure and diastolic function after the surgical loss of ovarian hormones in the female mRen2.Lewis rat, a model emulating the cardiac phenotype of the post-menopausal woman. Bilateral oophorectomy (OVX) or sham surgery was performed in study rats; the selective GPR30 agonist, G-1 (50 µg/kg/day), or vehicle was given subcutaneously to OVX rats from 13–15 weeks of age. Similar to the cardiac phenotype of sham rats, G-1 preserved diastolic function and structure relative to vehicle-treated OVX littermates independent of changes in blood pressure. G-1 limited the OVX-induced increase in LV filling pressure, LV mass, wall thickness, interstitial collagen deposition, atrial natriuretic factor and brain natriuretic peptide mRNA levels, and cardiac NAD(P)H oxidase 4 (NOX4) expression. In vitro studies showed that G-1 inhibited angiotensin II-induced hypertrophy in H9c2 cardiomyocytes, evidenced by reductions in cell size, protein content per cell, and atrial natriuretic factor mRNA levels. The GPR30 antagonist, G15, inhibited the protective effects of both oestradiol and G-1 on this hypertrophy. These data show that the GPR30 agonist G-1 mitigates the adverse effects of oestrogen loss on LV remodelling and the development of diastolic dysfunction in the study rats. This expands our knowledge of the sex-specific mechanisms underlying diastolic dysfunction and provides a potential therapeutic target for reducing the progression of this cardiovascular disease process in post-menopausal women.

The G protein-coupled estrogen receptor (GPER) is expressed in various tissues including the heart. Since the mRen2.Lewis strain exhibits salt-dependent hypertension and early diastolic dysfunction, we assessed the effects of the GPER agonist (G-1, 40 nmol/kg/hr for 14 days) or vehicle (VEH, DMSO/EtOH) on cardiac function and structure. Intact female mRen2.Lewis rats were fed a normal salt (0.5% sodium; NS) diet or a high salt (4% sodium; HS) diet for 10 weeks beginning at 5 weeks of age. Prolonged intake of HS in mRen2.Lewis females resulted in significantly increased blood pressure, mildly reduced systolic function, and left ventricular (LV) diastolic compliance (as signified by a reduced E deceleration time and E deceleration slope), increased relative wall thickness, myocyte size, and mid-myocardial interstitial and perivascular fibrosis. G-1 administration attenuated wall thickness and myocyte hypertrophy, with nominal effects on blood pressure, LV systolic function, LV compliance and cardiac fibrosis in the HS group. G-1 treatment significantly increased LV lusitropy [early mitral annular descent (e′)] independent of prevailing salt, and improved the e′/a′ ratio in HS versus NS rats (P<0.05) as determined by tissue Doppler. Activation of GPER improved myocardial relaxation in the hypertensive female mRen2.Lewis rat and reduced cardiac myocyte hypertrophy and wall thickness in those rats fed a high salt diet. Moreover, these advantageous effects of the GPER agonist on ventricular lusitropy and remodeling do not appear to be associated with overt changes in blood pressure.