8-bromocyclic-gmp and Hypotension

Outcome of traumatic brain injury (TBI) is impaired by hyperglycemia, hypotension, and glutamate, and improved by insulin. Insulin reduces glutamate concentration, making it uncertain whether its beneficial effect accrues from euglycemia. Glucagon decreases CNS glutamate, lessens neuronal cell injury, and improves neurological scores in mice after TBI. In vitro, glucagon limits NMDA-mediated excitotoxicity by increasing cAMP and protein kinase A (PKA). NMDA receptor activation couples cerebral blood flow (CBF) to metabolism. Dilation induced by NMDA is impaired after fluid percussion brain injury (FPI) due to upregulation of endogenous tPA, which further disturbs cerebral autoregulation during hypotension after fluid percussion injury (FPI). We hypothesized that glucagon prevents impaired NMDA receptor-mediated dilation after FPI by upregulating cAMP, which decreases release of tPA. NMDA-induced pial artery dilation (PAD) was reversed to vasoconstriction after FPI. Glucagon 30 min before or 30 min after FPI blocked NMDA-mediated vasoconstriction and restored the response to vasodilation. PAD during hypotension was blunted after FPI, but protected by glucagon. Glucagon prevented FPI-induced reductions in CSF cAMP, yielding a net increase in cAMP, and blocked FPI-induced elevation of CSF tPA. Co-administration of the PKA antagonist Rp 8Br cAMPs prevented glucagon-mediated preservation of NMDA-mediated dilation after FPI. The pKA agonist Sp 8Br cAMPs prevented impairment of NMDA-induced dilation. These data indicate that glucagon protects against impaired cerebrovasodilation by upregulating cAMP, which decreases release of tPA, suggesting that it may provide neuroprotection when given after TBI, or prior to certain neurosurgical or cardiac interventions in which the incidence of perioperative ischemia is high.

Topics: Analysis of Variance; Animals; Brain Injuries; Cerebral Cortex; Cerebrovascular Circulation; Cyclic GMP; Enzyme-Linked Immunosorbent Assay; Glucagon; Homeostasis; Hypotension; Neurons; Receptors, N-Methyl-D-Aspartate; Swine; Up-Regulation; Vasodilation

The effects of myoglobin on renal microcirculation were studied in anesthetized rats subjected to hemorrhagic hypotension. Capillary flow distribution was determined by allowing two dyes to circulate for 3 and 1 min, respectively, freezing the left kidney and quantifying the dye distribution in histological sections by analyzing the distances of regularly spaced test points to the next dye-labeled capillary. Control experiments showed 88% of distances to be < 12 microns in the cortex [medullary outer stripe (OS): 77%, inner stripe (IS): 93%] and no distance to be > 60 microns. Myoglobin induced disturbances in intrarenal perfusion with a significantly higher potency of (Fe2+)- as compared to (Fe3+)-myoglobin. With the reduced species, the fraction of distances > 60 microns increased to 54% in the cortex (OS: 69%; IS: 67%). L-NAME, an inhibitor of nitric oxide synthesis, induced similar defects of perfusion. The cGMP analogue 8-Br-cGMP was able to nearly completely prevent these effects. The results support the view that myoglobin when released during hemorrhagic hypotension impairs renal microcirculation supposedly by scavenging the endogenous relaxing factor nitric oxide.

Topics: Anesthesia, Intravenous; Animals; Cyclic GMP; Enzyme Inhibitors; Hemorrhage; Hypotension; Iron; Kidney; Male; Microcirculation; Myoglobin; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Wistar; Renal Circulation

Cyclic GMP (cGMP) dependent vasodilating agents (natriuretic peptides, nitric oxide) inhibit secretion of endothelin-1 (ET-1) in cultured endothelial cells. However, in circulatory conditions associated with acute hypotension, a marked increase in plasma ET-1 has repeatedly been observed. Therefore, after administration of cGMP-dependent agents in hypotensive dose, the net effect of these opposing influences on ET-1 release may shed light on the mechanisms determining circulating levels of this peptide. We have studied the effect of a hypotensive dose of atrial natriuretic peptide (n = 16), 8-Br-cGMP (n = 5), and papaverin (n = 7) on plasma ET-1 in anesthetized dogs. All agents produced marked increases in the peptide level at the end of infusion (178, 280, and 240% of the last preinfusion level, respectively) and a mean arterial blood pressure (MAP) decrease of 19, 18, and 42 mmHg (1 mmHg = 133.3 Pa), respectively. In all three protocols, plasma ET-1 continued to rise when the hypotensive agent was discontinued and remained elevated for 2-3 h postinfusion, even though MAP was normalized. There was a close positive correlation between the maximal increment in plasma ET-1 and the maximal decrease in MAP (r = 0.67, p < 0.001). These results show that acute hypotension due to directly acting vasodilators is a potent stimulus for systemic release of ET-1, even when due to agents known to inhibit ET-1 production in cultured endothelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atrial Natriuretic Factor; Blood Glucose; Blood Pressure; Cyclic GMP; Dogs; Endothelins; Female; Glomerular Filtration Rate; Hypotension; Male; Papaverine