cyclic-gmp and Hypercapnia

Hypercapnic acidosis often occurs in critically ill patients and during protective mechanical ventilation; however, the effect of hypercapnic acidosis on endogenous nitric oxide (NO) production and hypoxic pulmonary vasoconstriction (HPV) presents conflicting results. The aim of this study is to test the hypothesis that hypercapnic acidosis augments HPV without changing endogenous NO production in both hyperoxic and hypoxic lung regions in pigs.. Sixteen healthy anesthetized pigs were separately ventilated with hypoxic gas to the left lower lobe (LLL) and hyperoxic gas to the rest of the lung. Eight pigs received 10% carbon dioxide (CO(2)) inhalation to both lung regions (hypercapnia group), and eight pigs formed the control group. NO concentration in exhaled air (ENO), nitric oxide synthase (NOS) activity, cyclic guanosine monophosphate (cGMP) in lung tissue, and regional pulmonary blood flow were measured.. There were no differences between the groups for ENO, Ca(2+)-independent or Ca(2+)-dependent NOS activity, or cGMP in hypoxic or hyperoxic lung regions. Relative perfusion to LLL (Q (LLL)/Q (T)) was reduced similarly in both groups when LLL hypoxia was induced. During the first 90 min of hypercapnia, Q (LLL)/Q (T) increased from 6% (1%) [mean (standard deviation, SD)] to 9% (2%) (p < 0.01), and then decreased to the same level as the control group, where Q (LLL)/Q (T) remained unchanged. Cardiac output increased during hypercapnia (p < 0.01), resulting in increased oxygen delivery (p < 0.01), despite decreased PaO(2) (p < 0.01)(.). Hypercapnic acidosis does not potentiate HPV, but rather transiently weakens HPV, and does not affect endogenous NO production in either hypoxic or hyperoxic lung regions.

Topics: Acidosis, Respiratory; Animals; Blood Gas Analysis; Carbon Dioxide; Cyclic GMP; Exhalation; Hypercapnia; Hyperoxia; Nitric Oxide; Pulmonary Artery; Regional Blood Flow; Respiration, Artificial; Swine; Vasoconstriction

Nitric oxide (NO) is an important vascular modulator in the development of pulmonary hypertension. NO exerts its regulatory effect mainly by activating soluble guanylate cyclase (sGC) to synthesize cyclic guanosine monophosphate (cGMP). Exposure to hypoxia causes pulmonary hypertension. But in lung disease, hypoxia is commonly accompanied by hypercapnia. The aim of this study was to examine the changes of sGC enzyme activity and cGMP content in lung tissue, as well as the expression of inducible nitric oxide synthase (iNOS) and sGC in rat pulmonary artery after exposure to hypoxia and hypercapnia, and assess the role of iNOS-sGC-cGMP signal pathway in the development of hypoxic and hypercapnic pulmonary hypertension. Male Sprague-Dawley rats were exposed to hypoxia and hypercapnia for 4 weeks to establish model of chronic pulmonary hypertension. Weight-matched rats exposed to normoxia served as control. After exposure to hypoxia and hypercapnia, mean pulmonary artery pressure, the ratio of right ventricle/left ventricle+septum, and the ratio of right ventricle/body weight were significantly increased. iNOS mRNA and protein levels were significantly increased, but sGC α(1) mRNA and protein levels were significantly decreased in small pulmonary arteries of hypoxic and hypercapnic exposed rat. In addition, basal and stimulated sGC enzyme activity and cGMP content in lung tissue were significantly lower after exposure to hypoxia and hypercapnia. These results demonstrate that hypoxia and hypercapnia lead to the upregulation of iNOS expression, downregulation of sGC expression and activity, which then contribute to the development of pulmonary hypertension.

Topics: Animals; Cyclic GMP; Guanylate Cyclase; Heart Ventricles; Hypercapnia; Hypertension, Pulmonary; Hypoxia; Lung; Male; Nitric Oxide; Nitric Oxide Synthase Type II; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Soluble Guanylyl Cyclase; Up-Regulation; Ventricular Function

The hypothesis was tested that vardenafil, a PDE5 inhibitor, specifically enhances coronary vasodilation during acidosis. In isolated constant pressure perfused guinea pig hearts, infusion of vardenafil (

Topics: Acidosis; Animals; Coronary Circulation; Cromakalim; Cyclic GMP; Dose-Response Relationship, Drug; Guinea Pigs; Hypercapnia; Imidazoles; In Vitro Techniques; Male; Nitric Oxide; omega-N-Methylarginine; Phosphodiesterase Inhibitors; Piperazines; Signal Transduction; Sulfones; Triazines; Vardenafil Dihydrochloride; Vasodilation

We investigated the role of the NO/cGMP system in the vasodilatory response to hypercapnia after cortical spreading depression (CSD) in barbiturate anesthetized rats in vivo. Regional cerebral blood flow (rCBF) was measured by laser Doppler flowmetry (LDF). Hypercapnia (arterial pCO2 50-60 mm Hg) increased rCBF by 2.8+/-1.0%/mm Hg (n = 34). Fifteen minutes after CSD, resting rCBF was reduced to 87%, and rCBF response to hypercapnia was abolished (p < 0.001, n = 28). Within 1 h after CSD, only little restoration of vascular reactivity occurred. Topical application of the NO-donors S-nitroso-N-acetylpenicillamine (SNAP), 3-morpholinosydnonimine (SIN1), or spermine/NO complex (Sperm/NO), or of the cell permeable guanosine 3',5'-cyclic monophosphate (cGMP) analogue 8-Br-cGMP reestablished resting rCBF to values measured before CSD, and reversed CSD-induced attenuation of the cerebrovascular response to hypercapnia. Restoration of resting rCBF to pre-CSD level by the NO-independent vasodilator papaverine had no effect on the attenuated hypercapnic response. In conclusion, we have shown that the compromised vascular reactivity to hypercapnia after CSD can be reversed to normal reactivity by restoration of the basal NO or cGMP concentration in the cortex, suggesting a reduction of the cerebrovascular NO or cGMP concentration following CSD.

Topics: Analysis of Variance; Animals; Cerebral Cortex; Cerebrovascular Circulation; Cerebrovascular Disorders; Cortical Spreading Depression; Cyclic GMP; Drug Interactions; Hypercapnia; Laser-Doppler Flowmetry; Male; Molsidomine; Nitric Oxide; Nitric Oxide Donors; Penicillamine; Rats; Rats, Wistar; Spermine; Thionucleotides; Time Factors

We hypothesize that inhibitory effects exist between prostanoids and nitric oxide (NO) in their contributions to cerebral circulation. Piglets (1-4 days old) were divided into three chronically treated (6-8 days) groups: control piglets, piglets treated with indomethacin (75 mg/day), and piglets treated with N(omega)-nitro-L-arginine methyl ester (L-NAME, 100 mg x kg(-1) x day(-1)). Pial arterioles dilated in response to hypercapnia similarly among the three groups (41 +/- 4, 40 +/- 6, and 45 +/- 11%). Cerebrospinal fluid cAMP increased in control piglets, while cGMP increased in indomethacin-treated piglets. L-NAME, but not 7-nitroindazole, inhibited the response to hypercapnia only in indomethacin-treated piglets (40 +/- 6 vs. 17 +/- 5%). Topical sodium nitroprusside or iloprost restored dilation in response to hypercapnia. Similar results were obtained when the dilator was bradykinin. Pial arterioles of control and L-NAME-treated piglets constricted in response to ACh (-24 +/- 3%). However, those of indomethacin-treated piglets dilated in response to ACh (15 +/- 2%). This dilation was inhibited by L-NAME. NO synthase activity, but not endothelial NO synthase expression, increased after chronic indomethacin treatment. These data suggest that chronic inhibition of cyclooxygenase can increase the contribution of NO to cerebrovascular circulatory control in piglets.

Topics: Acetylcholine; Animals; Animals, Newborn; Bradykinin; Cardiovascular Agents; Cells, Cultured; Cerebrovascular Circulation; Cyclic AMP; Cyclic GMP; Cyclooxygenase Inhibitors; Endothelium, Vascular; Enzyme Inhibitors; Hypercapnia; Indazoles; Indomethacin; Microcirculation; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Pia Mater; Swine; Vasodilator Agents

In the middle cerebral artery (MCA), the presence of nitric oxide (NO) is responsible for maintaining a more dilated state than in its absence during increases in extracellular K(+) and osmolality. The purpose of the present study was to determine whether the involvement of NO was due to (a) a direct effect of the K(+)/osmolality (K(hyper)) on the endothelium or (b) a 'permissive' role of NO. MCAs (approximately 210 microm o.d.) were isolated, cannulated with glass micropipettes, and pressurized to 85 mmHg. When K(+) (KCl) in the extraluminal bath was increased to 21 mM, the diameter increased by 15-20% with the magnitude of dilation diminishing with further increases in K(hyper). The addition of N(G)-nitro-L-arginine methyl ester (L-NAME, 10(-5) mM), an inhibitor of nitric oxide synthase, had no significant effect on dilations at lower K(hyper) concentrations but constricted the arteries relative to the control at 51, 66, and 81 mM K(hyper). In the presence of L-NAME, the addition of an exogenous NO donor, S-nitroso-N-acetylpenicillamine (SNAP, 10(-8) M) or an analog of cGMP, 8-bromo-cGMP (6x10(-5) M), tended to restore the response of K(hyper)to near the original response. We conclude that the basal release of NO from the endothelium plays a permissive role in the K(hyper)-induced response.

Topics: Animals; Cerebrovascular Circulation; Cyclic GMP; Endothelium, Vascular; Enzyme Inhibitors; Hypercapnia; Iloprost; In Vitro Techniques; Male; Middle Cerebral Artery; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Penicillamine; Potassium; Rats; Rats, Long-Evans; S-Nitroso-N-Acetylpenicillamine; Vasodilator Agents

Specific cerebrovascular dilatory responses in newborn piglets are entirely prostanoid dependent, but require both nitric oxide (NO) and prostanoids in juveniles. We examined endothelial dependency and mechanisms of NO- and prostanoid-mediated cerebrovascular responses in anesthetized newborn and juvenile pigs implanted with closed cranial windows. Light/dye endothelial injury inhibited newborn and juvenile hypercapnic and bradykinin (BK) responses and inhibited dilation to acetylcholine in juveniles. Iloprost and NO act permissively in restoring light/dye inhibited newborn and juvenile responses, respectively. Differences in sensitivity to iloprost and sodium nitroprusside were not observed. Juvenile (not newborn) hypercapnic and BK cerebrovascular responses were sensitive to soluble guanylyl cyclase inhibition. Pial arteriolar diameter and cortical production of prostacyclin, cAMP, and cGMP in response to BK were measured under control conditions, after treatment with indomethacin and/or N(omega)-nitro-L-arginine methyl ester (L-NAME). Indomethacin inhibited BK responses in newborns. Juvenile responses were inhibited by L-NAME, and mildly by indomethacin. Cortical 6-keto-PGF(1 alpha), cAMP, and cGMP increased in response to BK in both age groups. Newborn cerebrovascular responses are largely NO independent, but NO becomes more important with maturation.

Topics: 6-Ketoprostaglandin F1 alpha; Acetylcholine; Age Factors; Animals; Animals, Newborn; Arterioles; Bradykinin; Cardiotonic Agents; Cardiovascular Agents; Cerebrovascular Circulation; Cyclic AMP; Cyclic GMP; Endothelium, Vascular; Enzyme Inhibitors; Epoprostenol; Female; Hypercapnia; Iloprost; Indomethacin; Isoproterenol; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitroprusside; Pia Mater; Swine; Vasodilation; Vasodilator Agents

Current evidence suggests that nitric oxide (NO) and vasodilating prostanoids, possibly via the actions of cGMP and cAMP, play permissive roles in hypercapnic cerebral vasodilation. The present study examined whether cGMP and cAMP have obligatory functions in hypercapnia. Using a closed cranial window in adult rats, we measured pial arteriolar diameters and periarachnoid cerebrospinal fluid (pCSF) cyclic nucleotide levels during normo- and hypercapnia and in the presence or absence of inhibitors of neuronal NO synthase (nNOS) or cyclooxygenase (COX). Also, we measured cGMP and cAMP contents in primary neuronal and astrocyte cultures, at different levels of CO2. Hypercapnia (arterial PCO2 65 mmHg)-induced pial arteriolar dilation was accompanied by 70-80% elevations in pCSF cGMP and cAMP. Inhibition of nNOS with 7-nitroindazole (7-NI) significantly reduced both the CO2-induced arteriolar dilation (by 77%) and the pCSF cGMP and cAMP increases (by 60-70%). Inhibition of COX with indomethacin reduced arteriolar CO2 reactivity (by 83%) and pCSF cyclic nucleotide increases (by 80-100%). In neuronal cultures a transient NO-dependent increase in cGMP, but not cAMP, was seen when the CO2 level was raised from 5 to 14%. No changes were seen in astrocytes. The 7-NI and indomethacin-inhibitable increases in pial arteriolar diameter and cyclic nucleotide production during hypercapnia suggest a link between these two responses. One possible, although not exclusive, interpretation of these findings is that the cyclic nucleotides have an obligatory function in the CO2 response. The large overlap in the abilities of nNOS and COX inhibitors to elicit those effects further implies interactions ("cross talk") between the cGMP and cAMP vasodilating pathways. The in vitro data suggest that hypercapnia stimulates NO production in neurons.

Topics: Animals; Arteries; Arterioles; Astrocytes; Carbon Dioxide; Cells, Cultured; Cerebrovascular Circulation; Cyclic GMP; Hypercapnia; Male; Neurons; Nucleotides, Cyclic; Pia Mater; Rats; Rats, Sprague-Dawley; Vasodilation

Previous experimental findings have led to the suggestion that guanosine 3',5'-cyclic monophosphate (cGMP) plays a permissive role in hypercapnic cerebral vasodilation. However, we recently reported that the technique used to reveal a permissive role for cGMP [cGMP repletion in the presence of nitric oxide synthase (NOS) inhibition] created a situation where CO(2) reactivity was normalized but where different mechanisms (i.e., K(+) channels) participated in the response. In the present study, we examined whether that nascent K(+)-channel dependence is related in any way to an increase in the influence of the miconazole-inhibitable cytochrome P-450 epoxygenase pathway. Using intravital microscopy and a closed cranial window system in adult rats, we measured pial arteriolar diameters during normo- and hypercapnia, first in the absence and then in the presence of a neuronal NOS (nNOS) inhibitor [7-nitroindazole (7-NI)]. This was followed by suffusion of a cGMP analog and then cGMP plus miconazole. Separate groups of rats were used to evaluate whether miconazole either alone or in the presence of 8-bromoguanosine 3', 5'-cyclic monophosphate (8-BrcGMP) or its vehicle (0.1% ethanol) had any effect on CO(2) reactivity and whether miconazole affected K(+)-channel opener-induced dilations. Hypercapnic (arterial PCO(2), congruent with65 mmHg) pial arteriolar dilations, as expected, were reduced by 70-80% with 7-NI and restored with cGMP repletion. CO(2) reactivity was again attenuated after miconazole introduction. Miconazole, with and without 8-BrcGMP, and its vehicle had no influence on pial arteriolar CO(2) reactivity in the absence of nNOS inhibition combined with cGMP repletion. Miconazole alone also did not affect vasodilatory responses to K(+)-channel openers. Thus present results suggest that the nascent K(+)-channel dependence of the hypercapnic response found in our earlier study may be related to increased epoxygenase activity. The specific reasons why the pial arteriolar CO(2) reactivity gains a K(+)-channel and epoxygenase dependence only under conditions of nNOS inhibition and cGMP restoration remain to be identified. These findings again call into question the interpretations applied to data collected in studies evaluating potential permissive actions of cGMP or NO.

Topics: Animals; Arterioles; Carbon Dioxide; Cyclic GMP; Drug Combinations; Enzyme Inhibitors; Hypercapnia; Indazoles; Miconazole; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Pia Mater; Potassium Channels; Rats; Rats, Sprague-Dawley; Reference Values; Vasodilation

The conclusion that cyclic 3'-5 guanosine monophosphate (cGMP) functions in a 'permissive' manner in promoting cerebrovasodilation during hypercapnia was based on findings showing that the nitric oxide synthase (NOS) inhibitor-induced repression of the CO2 response could be reversed upon addition of exogenous cGMP. We hypothesized that the action of cGMP revealed in those studies does not define its normal role in hypercapnic cerebral vasodilation, but rather is a unique function of the artificial situation of NOS inhibition coupled with cGMP repletion. Thus, although CO2 reactivity may be the same in normal versus cGMP-repleted animals, the factors contributing to that response may differ. To test that possibility, the effects of calcium-dependent (KCa) or ATP-sensitive (KATP) potassium channel blockers on pial arteriolar CO2 reactivity, in vivo, were evaluated in the presence and absence of NOS inhibition plus administration of a cGMP analogue. Pial arteriolar diameter changes in hypercapnia were measured in three principal groups of anesthetized rats: (I) KCa channel-inhibited (via iberiotoxin); (II) KATP channel-inhibited (via glibenclamide); and (III) controls. Group I and II rats were further divided into: (a) those treated with the neuronal NOS (nNOS) inhibitor, 7-nitroindazole (7-NI), followed by successive suffusions of the cGMP analogue, 8-bromo-cGMP (8Br-cGMP) and 8Br-cGMP+K-channel blocker; and (b) rats where 7-NI and 8Br-cGMP applications were omitted. Group III rats were divided into time and 8Br-cGMP controls. Hypercapnia (PCO2 congruent with60 mmHg, 3 min)-induced dilations were reduced by 70-80% following 7-NI and restored by 8Br-cGMP. That restoration was reversed by both K-channel blockers. In the absence of 7-NI and exogenous cGMP, CO2 reactivity was unaffected by K-channel inhibition. These findings confirmed that nNOS-derived NO is critically important to the hypercapnic reactivity of cerebral arterioles, and that cGMP repletion, following NOS inhibition, could restore CO2 reactivity. The observation that KCa and KATP channel blockade did not alter CO2 reactivity under baseline conditions, but attenuated CO2 reactivity only in the presence nNOS inhibition (and cGMP repletion), suggests that multiple, redundant, and interactive mechanisms participate in CO2-induced vasodilation. These results also imply that current strategies for revealing permissive actions of cGMP (or NO) may need to be re-evaluated.

Topics: Adenosine Triphosphate; Animals; Benzimidazoles; Blood Pressure; Calcium; Carbon Dioxide; Cerebral Arteries; Cromakalim; Cyclic GMP; Glyburide; Hydrogen-Ion Concentration; Hypercapnia; Indazoles; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Penicillamine; Peptides; Pia Mater; Potassium Channel Blockers; Potassium Channels; Rats; Rats, Sprague-Dawley; Substrate Specificity; Vasodilation

Topics: Animals; Argininosuccinic Acid; Cyclic GMP; Hypercapnia; Hypoxia; In Vitro Techniques; Male; Nitric Oxide; Perfusion; Pulmonary Circulation; Rabbits; Vasoconstriction

We sought to determine whether the attenuation of the hypercapnic cerebrovasodilation associated with inhibition of nitric oxide synthase (NOS) can be reversed by exogenous NO. Rats were anesthetized (halothane) and ventilated. Neocortical cerebral blood flow (CBF) was monitored by a laser-Doppler probe. The NOS inhibitor N omega-nitro-L-arginine methyl ester (L-NAME; 40 mg/kg iv) reduced resting CBF [-36 +/- 5% (SE); P < 0.01, analysis of variance] and attenuated the increase in CBF elicited by hypercapnia (partial pressure of CO2 = 50-60 mmHg) by 66% (P < 0.01). L-NAME reduced forebrain NOS catalytic activity by 64 +/- 3% (n = 10; P < 0.001). After L-NAME, intracarotid infusion of the NO donor 3-morpholinosydnonimine (SIN-1; n = 6) increased resting CBF and reestablished the CBF increase elicited by hypercapnia (P > 0.05 from before L-NAME). Similarly, infusion of the guanosine 3',5'-cyclic monophosphate (cGMP) analogue 8-bromo-cGMP (n = 6) reversed the L-NAME-induced attenuation of the hypercapnic cerebrovasodilation. The NO-independent vasodilator papaverine (n = 6) increased resting CBF but did not reverse the attenuation of the CO2 response. SIN-1 did not affect the attenuation of the CO2 response induced by indomethacin (n = 6). The observation that NO donors reverse the L-NAME-induced attenuation of the CO2 response suggests that a basal level of NO is required for the vasodilation to occur. The findings are consistent with the hypothesis that NO is not the final mediator of smooth muscle relaxation in hypercapnia.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acid Oxidoreductases; Animals; Arginine; Cerebrovascular Circulation; Cyclic GMP; Hypercapnia; Male; Molsidomine; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Papaverine; Rats; Rats, Sprague-Dawley; Vasodilation

The relaxant effect of hypercapnia (15% CO2) was studied in isolated circular segments of rat basilar arteries with intact endothelium. The nitric oxide synthase inhibitor nitro-L-arginine (L-NOARG) and the cytosolic guanylate cyclase inhibitor methylene blue (MB), significantly reduced this relaxation by 54% and 70%, respectively. The effect of L-NOARG was completely reversed by L-arginine. Blockade of nerve excitation with tetrodotoxin (TTX) had no affect on the 15% CO2 elicited vasodilatation. Measurements of cGMP in vessel segments showed no significant increase in cGMP content in response to hypercapnia. L-NOARG and MB, but not TTX, significantly reduced the basal cGMP content in cerebral vessels. Adding 1.5% halothane to the incubation medium did not result in a significant increase in cGMP content. Lowering the pH by cumulative application of 0.12 M HCl resulted in relaxation identical to that obtained by lowering the pH with 15% CO2. In vessel segments in which the endothelium had been removed beforehand 15% CO2 induced relaxation that was not different from that seen in vessels with intact endothelium. L-NOARG had no affect in endothelium denuded vessels. The results suggest that high CO2 elicits vasodilatation of isolated rat basilar arteries by a mechanism independent of nitric oxide synthase (NOS) activity. The markedly reduced basal cGMP levels in cerebral vessels by L-NOARG and MB suggest that there exists a basal NO formation in the cerebral vessel wall.

Topics: Amino Acid Oxidoreductases; Animals; Arginine; Basilar Artery; Cyclic GMP; Hydrogen-Ion Concentration; Hypercapnia; Male; Methylene Blue; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Wistar; Tetrodotoxin; Vasodilation

The role of nitric oxide (NO) in the response to 5% CO2 inhalation was investigated by measuring 1) regional cerebral blood flow (rCBF) by laser-Doppler flowmetry and pial vessel diameter through a closed cranial window after topical NG-nitro-L-arginine (L-NNA, 1 mM), and 2) the time-dependent changes in brain guanosine 3',5'-cyclic monophosphate (cGMP) levels after L-NNA (10 mg/kg ip). When L-NNA (but not NG-nitro-D-arginine) was applied topically for 30 or 60 min, the response to hypercapnia was significantly attenuated. A correlation was found between inhibition of brain NO synthase (NOS) activity and the rCBF response (r = 0.77; P < 0.01). However, L-NNA applied 15 min before hypercapnia did not attenuate the increase in rCBF but did attenuate the dilation to topical acetylcholine. Inhalation of CO2 (5%) elevated brain cGMP levels by 20-25%, and L-NNA reduced this response. These data from the rat suggest that 1) a product of NOS activity is associated with hypercapnic hyperemia and the attendant increase in brain cGMP levels, and 2) hypercapnic blood flow changes may not be dependent on endothelial NOS activity within pial vessels.

Topics: Acetylcholine; Administration, Inhalation; Administration, Topical; Animals; Arginine; Brain; Carbon Dioxide; Cerebral Cortex; Cerebrovascular Circulation; Cyclic GMP; Hypercapnia; Hyperemia; Male; Nitroarginine; Rats; Rats, Sprague-Dawley; Vasodilation

Relationships between cyclic nucleotides and cerebrovascular tone were investigated using closed cranial windows in anesthetized newborn pigs. Pial arteriolar diameter was monitored and cerebrospinal fluid (CSF) was collected from beneath the cranial window. Adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) concentrations in CSF were 1,690 +/- 200 and 730 +/- 40 fmol/ml, respectively. Topically applied isozyme-selective and nonselective inhibitors [3-isobutyl-1-methylxanthine (IBMX), theophylline, Ro 201724, dipyridamole, zaprinast, calmidazolium, and W-7] of cyclic nucleotide phosphodiesterases dilated pial arterioles with concomitant increases in cAMP and/or cGMP levels in CSF. Topical application of dibutyryl-cAMP and dibutyryl-cGMP also resulted in pial arteriolar dilation. Ten-minute hypercapnia, which results in pial arteriolar dilation, increased cAMP to 5,240 +/- 900 and cGMP to 1,350 +/- 200 fmol/ml. IBMX and zaprinast potentiated the increases in cAMP and cGMP as well as the cerebrovascular dilation in response to hypercapnia. These data suggest that cyclic nucleotides contribute to regulation of cerebral vascular tone during control conditions. Furthermore, cAMP and/or cGMP appears to be involved in arterial vasodilation in response to hypercapnia in newborn pigs.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Animals, Newborn; Cerebrovascular Circulation; Cyclic AMP; Cyclic GMP; Hypercapnia; Imidazoles; Phosphodiesterase Inhibitors; Sulfonamides; Swine; Vasomotor System

Topics: Adrenal Glands; Adrenalectomy; Animals; Cyclic AMP; Cyclic GMP; DNA; Female; Histamine; Hypercapnia; Lung; Rats