Beta Blockade and Clinical Outcomes in Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Aneurysmal subarachnoid hemorrhages are frequently complicated by hypertension and neurogenic myocardial stunning. Beta blockers may be used for management of these complications. We sought to investigate sympathetic nervous system modulation by beta blockers and their effect on radiographic vasospasm, delayed cerebral infarction, discharge destination and death. METHODS: Retrospective chart review of 218 adults admitted to the ICU between 8/2004 and 9/2010 was performed. Groups were identified relevant to beta blockade: 77 were never beta blocked (No/No), 123 received post-admission beta blockers (No/Yes), and 18 were continued on their home beta blockers (Yes/Yes). Records were analyzed for baseline characteristics and the development of vasospasm, delayed cerebral infarction, discharge destination and death, expressed as adjusted odds ratio. RESULTS: Of the 218 patients 145 patients developed vasospasm, 47 consequently infarcted, and 53 died or required care in a long-term facility. When compared to No/No patients, No/Yes patients had significantly increased vasospasm (OR 2.11 (1.06-4.16)). However, these patients also had significantly fewer deaths or need for long term care (OR 0.17 (0.05-0.64)), with decreased tendency for infarcts (OR 0.70 (0.32-1.55)). When compared to No/No patients, Yes/Yes patients demonstrated a trend toward increased vasospasm (OR 1.61 (0.50-5.29)) that led to infarction (OR 1.51 (0.44-5.13)), but with decreased mortality or need for long term care in a facility (OR 0.13 (0.01-1.30)). CONCLUSION: Post-admission beta blockade in aneurysmal subarachnoid hemorrhage patients was associated with increased incidence of vasospasm. However, despite the increased occurrence of vasospasm, beta blockers were associated with improved discharge characteristics and fewer deaths.

Chronic hypoxia modulates endothelium-dependent vasorelaxation through multiple independent mechanisms in ovine cranial arteries.

Acclimatization to chronic hypoxia involves numerous compensatory changes in many tissues, including blood vessels. The present data demonstrate that in addition to well-documented changes in contractility, chronic hypoxia also produces important changes in the mechanisms mediating endothelium-dependent vasodilatation. At the level of the endothelium, hypoxia attenuates endothelial release of NO and this appears to be mediated through reductions in eNOS specific activity; chronic hypoxia has little effect on eNOS abundance. In contrast, chronic hypoxia depresses the abundance of sGC, which functions as the downstream vascular receptor for NO released from the endothelium. The decreased abundance of sGC produced by chronic hypoxia occurs without changes in sGC specific activity and results in decreased rates of NO-induced cGMP synthesis. Nonetheless, the vasodilator efficacy of NO is enhanced in hypoxic arteries, which suggests that mechanisms downstream from sGC are upregulated by hypoxia. Consistent with this view, chronic hypoxia significantly depresses PDE activity, which serves to prolong cGMP half-life and enhance its vasodilator effects. It remains possible that chronic hypoxia may also enhance PKG activity and/or the abundance of its substrates; this possibility remains a promising topic for future investigation. Overall, it is important to recognize that the mechanisms of adaptation to chronic hypoxia identified in the present study may be somewhat unique to adult carotid arteries. Adaptive responses to chronic hypoxia can vary considerably between small and large arteries, and also between immature and adult arteries . Still, the present data clearly demonstrate that both the endothelium and vascular smooth muscle of major arteries are profoundly influenced by chronic hypoxia, and thereby participate fully in whole-body adaptation to reduced oxygen availability.

Chronic hypoxic decreases in soluble guanylate cyclase protein and enzyme activity are age dependent in fetal and adult ovine carotid arteries.

The present study tests the hypothesis that chronic hypoxia enhances reactivity to nitric oxide (NO) through age-dependent increases in soluble guanylate cyclase (sGC) and protein kinase G (PKG) activity. In term fetal and adult ovine carotids, chronic hypoxia had no significant effect on mRNA levels for the beta1-subunit of sGC, but depressed sGC abundance by 16% in fetal and 50% in adult arteries, through possible depression of rates of mRNA translation (15% in fetal and 50% in adult) and/or increased protein turnover. Chronic hypoxia also depressed the catalytic activity of sGC, but only in fetal arteries (63%). Total sGC activity was reduced by chronic hypoxia in both fetal (69%) and adult (37%) carotid homogenates, but this effect was not observed in intact arteries when sGC activity was measured by timed accumulation of cGMP. In intact arteries treated with 300 microM 3-isobutyl-1-methylxanthine (IBMX), chronic hypoxia dramatically enhanced sGC activity in fetal (186%) but not adult (89%) arteries. This latter observation suggests that homogenization either removed an sGC activator, released an sGC inhibitor, or altered the phosphorylation state of the enzyme, resulting in reduced activity. In the absence of IBMX, chronic hypoxia had no significant effect on rates of cGMP accumulation. Chronic hypoxia also depressed the ability of the cGMP analog, 8-(p-chlorophenylthio)-cGMP, to promote vasorelaxation in both fetal (8%) and adult (12%) arteries. Together, these results emphasize the fact that intact and homogenized artery studies of sGC activity do not always yield equivalent results. The results further suggest that enhancement of reactivity to NO by chronic hypoxia must occur upstream of PKG and can only be possible if changes in cGMP occurred in functional compartments that afforded either temporal or chemical protection to the actions of phosphodiesterase. The range and age dependence of hypoxic effects observed also suggest that some responses to hypoxia must be compensatory and homeostatic, with reactivity to NO as the primary regulated variable.

Maturation enhances fluid shear-induced activation of eNOS in perfused ovine carotid arteries.

The present study tests the hypothesis that age-dependent increases in endothelial vasodilator capacity are due to maturational increases in endothelial nitric oxide (NO) synthesis and release. Intact 4-cm carotid artery segments taken from term fetal lambs and nonpregnant adult sheep were perfused by using a closed system that enabled independent control of flow and inflow pressure and facilitated complete recovery of all NO released. Fluid shear stress induced a graded release of NO (in nmol NO x min x cm(-2) of luminal surface area) that was significantly greater in adult (890 +/- 140) than in fetal (300 +/- 40) carotid arteries at corresponding values of shear stress (5.9 +/- 0.3 dyn/cm2) but was independent of inflow pressure in both age groups. These age-related differences in NO release were not attributable to corresponding differences in endothelial NO synthase (eNOS) abundance, as eNOS protein levels (in ng of eNOS/cm2 of luminal surface area) were similar in adult (14 +/- 2) and fetal (12 +/- 1) arteries. Adult (80 +/- 15) and fetal (89 +/- 32) levels of eNOS mRNA (in 10(6) copies/cm2 of luminal surface area) were also similar. However, when NO release was normalized relative to the associated mass of eNOS protein to estimate eNOS-specific activity in situ, this value (in nmol NO x microg of eNOS(-1) x min(-1)) was significantly greater in adult (177 +/- 44) than in fetal (97 +/- 36) arteries when the endothelium was maximally activated by A-23187. Similarly, the slope of the relation between fluid shear stress and estimated eNOS-specific activity (in nmol NO x microg of eNOS(-1) x min(-1) per dyn/cm2) was also significantly greater in adult (6.8 +/- 0.1) than in fetal (2.9 +/- 0.1) arteries, which suggests that eNOS may be more sensitive to or more efficiently coupled to activating stimuli in adult compared with fetal arteries. We conclude that maturational increases in endothelial vasodilator capacity are attributable to age-dependent increases in NO release secondary to elevated eNOS-specific activity and involve more efficient coupling between endothelial activation and enhancement of eNOS activity in adult compared with fetal arteries.