The incidence of obstructive sleep apnea (OSA) has reached epidemic proportions, and it is an often unrecognized cause of perioperative morbidity and mortality. Profound hypoxic injury from apnea during the postoperative period is often misdiagnosed as cardiac arrest due to other causes. Almost a quarter of patients entering a hospital for elective surgery have OSA, and >80% of these cases are undiagnosed at the time of surgery. The perioperative period puts patients at high risk of apneic episodes because of drug effects from sedatives, narcotics, and general anesthesia, as well as from the effects of postoperative rapid eye movement sleep changes and postoperative positioning in the hospital bed.

The T-tube model of systemic arterial circulation was examined with respect to the physiological relevance of model parameters. root aortic pressure [Pao(t)] and flow [Qao(t)] and descending aortic flow [Qb(t)] were measured in anesthetized, open-chest dogs under control conditions, during inflation of a balloon positioned in the left external iliac artery (n = 5), and during infusion of vasoactive drugs nitroprusside (NTP, n = 4) and phenylephrine (PHL, n = 5). With Pao(t) as the input, the model accurately predicted both Qao(t) and Qb(t) under all conditions (r2 > 0.96). The balloon inflation data established the ability of the model to discriminate between proximal and distal arterial mechanical properties. Furthermore, proximal properties (i.e., tube characteristic impedances and transit times) were independent of distal properties such as terminal compliances and resistances (or equivalently, wave reflections). The effects of NTP and PHL were pharmacologically consistent and served to further validate this model. NTP primarily affected distal (load) properties, whereas PHL altered both load and tube parameters. Physiological interpretation of model parameters, particularly compliance, is also discussed. The ability of the model to correctly discriminate between proximal and distal arterial properties is relevant because these properties may affect cardiovascular function differently.

Mutation of an invariant glutamate residue found within the catalytic domain of guanylyl cyclases resulted in a dramatic 14-fold increase in the activity of the guanylyl cyclase-A receptor. Even in the presence of Mn 2؉ ͞Triton X-100, a treatment previously thought to yield hormoneindependent and maximum cyclase activity, the mutant enzyme remained 7-fold more active; to our knowledge, this is the first example of a protein modification or of an added agent that significantly increases cyclase activity in the presence of Mn 2؉ ͞Triton X-100. Intracellular concentrations of cGMP in cells expressing the mutant (E974A) cyclase were only marginally elevated by the addition of atrial natriuretic peptide, and in broken-cell preparations, the mutant enzyme also was relatively insensitive to ligand͞regulatory nucleotide. The marked increase in cyclase activity was not due to a relief of protein kinase domain inhibition, since the point mutation caused 7-to 13-fold elevations in guanylyl cyclase-A activity when the protein kinase homology domain was deleted. The E974A mutation also altered the kinetics from positive cooperative to linear with respect to MnGTP, suggesting disruption of subunit-subunit interactions. Thus, a single point mutation within the catalytic domain of a guanylyl cyclase results in a constitutively hyperactive enzyme that is independent of protein kinase domain regulation.Guanylyl cyclases are classified into two broad families: the soluble forms activated by NO (nitric oxide) and the membrane-bound forms stimulated by peptide hormones. To date the soluble forms have been shown to exist as heterodimers and the membrane forms as homomers (1-5).Guanylyl cyclase-A (GC-A), the apparent receptor for atrial natriuretic peptide (ANP) and B-type natriuretic peptide, requires both the peptide ligand and an adenine nucleotide (ATP) for effective activation of the cyclase (6). Although the mechanisms by which the cyclases are activated upon ligand binding are not known, it appears that the guanylyl cyclase subunits are associated prior to ligand binding for either the membrane or soluble forms; thus, ligand-induced aggregation does not appear to explain the activation, although one report on the receptor for heat-stable enterotoxin has suggested that a ''functional'' dimerization occurs in response to ligand binding (7). With GC-A, ATP is thought to bind to the protein kinase homology domain, and deletion of this region yields a constitutively active guanylyl cyclase that is no longer regulated by ANP and ATP (8); point mutations within the domain can also eliminate ANP͞ATP regulation of the cyclase but activity remains low (9, 10). These results have led to suggestions that the protein kinase homology domain acts as a repressor of cyclase activity in the absence of peptide ligand and ATP and that catalytic domain activation, therefore, is a result of ANP͞ATP release of the inhibition (8).It was rationalized that if the protein kinase homology domain could serve as a repressor of the cyclase catalytic ...

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