Changes in dopamine D(2)-receptor modulation of the hypoxic ventilatory response with chronic hypoxia.

Modulation of the hypoxic ventilatory response (HVR) by dopamine D(2)-receptors (D(2)-R) in the carotid body (CB) and central nervous system (CNS) are hypothesized to contribute to ventilatory acclimatization to hypoxia. We tested this with blockade of D(2)-R in the CB or CNS in conscious rats after 0, 2 and 8 days of hypoxia. On day 0, CB D(2)-R blockade significantly increased VI and frequency (fR) in hyperoxia (FI(O(2))=0.30), but not hypoxia (FI(O(2))=0.10). CNS D(2)-R blockade significantly decreased fR in hypoxia only. On day 2, neither CB nor CNS D(2)-R blockade affected VI or fR. On day 8, CB D(2)-R blockade significantly increased hypoxic VI and fR. CNS D(2)-R blockade significantly decreased hypoxic VI and fR. CB and CNS D(2)-R modulation of the HVR decreased after 2 days of hypoxia, but reappeared after 8 days. Changes in the opposing effects of CB and CNS D(2)-R on the HVR during chronic hypoxia cannot completely explain ventilatory acclimatization in rats.

Nitric oxide synthesis inhibition does not improve the hemodynamic response to hemorrhagic shock in dehydrated conscious swine.

Nitric oxide (NO) may influence the hemodynamic response to hemorrhage. To test this hypothesis, the NO synthesis inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) was administered to conscious, dehydrated swine during a 37% blood volume hemorrhage and a 180 min recovery period without fluid resuscitation. L-NAME (.75 mg/kg bolus plus constant infusion of .75 mg/kg/h) was given via a central intravenous catheter during the bleed. The selectivity and specificity of L-NAME as a NO synthesis inhibitor in pigs was validated in pilot studies. The present study shows that inhibition of NO synthesis with L-NAME had no significant effect on the major hemodynamic parameters during and after hemorrhage when compared to dehydrated and euhydrated control groups. Only stroke volume and A-VO2 were significantly different from controls. Mortality was 83% for the L-NAME group and 44% for controls at 180 min of recovery (NS). The results suggest that NO synthesis inhibition provides no hemodynamic benefit during hemorrhage in dehydrated, conscious swine.

Immune-based resistance to the formation of v-src-induced distal tumors.

Although v-src, the oncogene of Rous sarcoma virus, has been shown to be capable of inducing lethal tumors at visceral sites distal to the primary tumor mass, the mechanisms opposing visceral tumor formation remain to be elucidated. In the present study, we show that visceral tumors, many of which represent a metastasis spawned by the primary mass, are found only in hosts exhibiting reduced levels of tumor immunity. We conclude that it is the weakness of the tumor immune response, rather than a lack of expression of tumor antigen on visceral tumor cells, that is a major underpinning of the formation of v-src-induced visceral tumors.

Role of nitric oxide in hypoxic coronary vasodilatation in isolated perfused guinea pig heart.

To test the hypothesis that nitric oxide (NO) mediates hypoxic coronary dilatation in situ, isolated guinea pig hearts were perfused at constant pressure (Langendorff technique) with physiological salt solution. Switching from a control perfusate (95% O2-5% CO2) to one equilibrated with a lower O2 tension (20% O2) induced a large, but submaximal and reproducible, coronary dilatation. The NO synthase inhibitor NG-nitro-L-arginine (L-NNA) diminished baseline flow (3.67 +/- 0.24 vs. control 5.11 +/- 0.42 ml.min-1 x g-1; P < 0.05) and selectively blocked the coronary flow response to acetylcholine without reducing the response to papaverine. L-NNA reduced the absolute increase in coronary flow during hypoxia by 27 +/- 2% (delta flow = 5.83 +/- 0.49 vs. control delta flow = 8.04 +/- 0.74 ml.min-1 x g-1; P < 0.05). Hypoxic coronary dilatation was unaffected by infusion of the thromboxane mimetic U-46619, which decreased baseline coronary flow to the same extent as L-NNA. Prior addition of indomethacin did not alter the attenuating effect of L-NNA. Hypoxic coronary dilatation during constant flow perfusion at 14.7 +/- 0.28 ml/min was reduced by 65 +/- 5% after L-NNA. Therefore, the NO component of the response was not a consequence of the reduced baseline flow observed in the presence of L-NNA, did not depend on prostaglandin synthesis, and was not secondary to increased flow or intravascular shear stress. We conclude that hypoxic coronary vasodilatation in isolated guinea pig hearts is partially mediated by NO.

Mechanisms of coronary vasodilatation produced by ATP in guinea-pig isolated perfused heart.

1. Isolated hearts of guinea-pigs were perfused in vitro with a physiological salt solution via a retrograde aortic cannulation (Langendorff preparation) at constant perfusion pressure. Bolus intra-arterial injections of various vasodilator drugs were made and the coronary flow responses were measured with an electromagnetic flow probe placed in the arterial inflow circuit. Inhibitory drugs were infused intra-arterially. 2. Nitro-L-arginine (NLA; 500 microM), an NO synthesis inhibitor, decreased coronary baseline flow by 16 +/- 0.8%, converted acetylcholine-induced coronary vasodilatation to vasoconstriction and had no effect on coronary flow responses to adenosine or papaverine. Sodium nitroprusside-induced responses were enhanced during NLA infusion by 46 +/- 11%. 3. Adenosine 5'-triphosphate (ATP) increased coronary flow but coronary flow responses to ATP were not altered by infusion of NLA. 4. ATP-induced coronary dilatation was not significantly attenuated by infusion of the adenosine receptor antagonist XAC, (xanthine amine congener; 2 microM), whereas XAC decreased coronary flow responses to adenosine by 75% +/- 5%. 5. ATP-induced coronary flow responses were reduced by only 31 +/- 4% during indomethacin infusion (2.8 microM) whereas indomethacin completely eliminated the initial vasoconstriction phase and greatly attenuated the peak flow and duration of the later vasodilatation phase seen in response to arachidonic acid (0.75 nmol). Indomethacin had no effect on vasodilatations produced by adenosine or prostaglandin I2. 6. These results indicate that ATP-induced coronary dilatation in the isolated, perfused heart of the guinea-pig is not dependent upon NO production or upon degradation of ATP to adenosine. The coronary dilator action of ATP may be partially dependent (approximately 30%) upon the production of vasodilator prostaglandins.