Peripheral vascular resistance increases after termination of obstructive apneas.

The mechanisms by which obstructive apneas produce intermittent surges in arterial pressure remain poorly defined. To determine whether termination of obstructive apneas produce peripheral vasoconstriction, we assessed forearm blood flow during and after obstructive events in sleeping patients experiencing spontaneous upper airway obstructions. In all subjects, heart rate was monitored with an electrocardiogram and blood pressure was monitored continuously with digital plethysmography. In 10 patients (protocol 1), we used forearm plethysmography to assess forearm blood flow, from which we calculated forearm vascular resistance by performing venous occlusions during and after obstructive episodes. In an additional four subjects, we used simultaneous Doppler and B-mode images of the brachial artery to measure blood velocity and arterial diameter, from which we calculated brachial flow continuously during spontaneous apneas (protocol 2). In protocol 1, forearm vascular resistance increased 71% after apnea termination (29.3 +/- 15.4 to 49.8 +/- 26.5 resistance units, P < 0.05) with all patients showing an increase in resistance. In protocol 2, brachial resistance increased at apnea termination in all subjects (219.8 +/- 22.2 to 358.3 +/- 46.1 mmHg x l(-1) x min; P = 0.01). We conclude that termination of obstructive apneas is associated with peripheral vasoconstriction.     

Indomethacin increases plasma lithium.

The effects of indomethacin on plasma lithium concentrations and renal lithium clearance were investigated in three psychiatric patients and four normal volunteers. After steady-state plasma lithium concentrations had been reached, the subjects received indomethacin placebo for three to seven days, indomethacin (50 mg thrice daily) for seven days, and placebo again for three to seven days. Indomethacin increased plasma lithium concentrations by 59% in the psychiatric patients and 30% in the volunteers. Renal lithium clearance was reduced by indomethacin by 31% in the group as a whole, and prostaglandin synthesis, determined by measuring the major metabolite of PGE2 with mass spectrometry, was reduced by 55%. These results show that indomethacin reduces renal lithium clearance to an extent which may be clinically important. They also suggest that the renal clearance may be affected by a prostaglandin-dependent mechanism, possibly located in the distal tubule.     

Endotoxin increases pulmonary vascular protein permeability in the dog

Endotoxin increases pulmonary vascular permeability consistently in some species but fails to reliably cause injury in the dog. We wondered whether this phenomenon depended on the method of injury assessment, as others have relied on edema measurement; we quantified injury by monitoring the rate of extravascular protein accumulation. 113mIn-labeled protein and 99mTc-labeled erythrocytes were injected into anesthetized dogs and monitored by an externally placed lung probe. A protein leak index, the rate of extravascular protein accumulation, was derived from the rate of increase in lung protein counts corrected for changes in intravascular protein activity. After administration of Salmonella enteriditis endotoxin (4 micrograms/kg), the protein leak index was elevated 2.5-fold (41.1 +/- 4.6 X 10(-4) min-1) compared with control (16.0 +/- 2.8 X 10(-4) min-1). In contrast, wet-to-dry weight ratios failed to increase after endotoxin (4.6 +/- 0.8 vs. control values of 4.2 +/- 0.5 g/g dry bloodless lung). However, we observed that endotoxin increased lung dry weight (per unit body weight), which may have attenuated the change in wet-to-dry weight ratios. To determine whether low microvascular pressures following endotoxin attenuated edema formation, we increased pulmonary arterial wedge pressures in five dogs by saline infusion, which caused an increase in wet-to-dry weight ratios following endotoxin but no change in the five controls. We conclude that low dose endotoxin causes pulmonary vascular protein leak in the dog while edema formation is minimal or absent.     

Physical and adrenergic factors affecting systemic vascular resistance in the rainbow trout: a comparison with branchial vascular resistance.

The passive distensibility and adrenergic reactivity of the systemic vascular resistance (Rs) in Salmogairdneri have been studied using perfused trunk preparations, and the data compared with previous results on the branchial resistance (Rg). At normal levels of efferent blood pressure, Rs is relatively more distensible than Rg in response to afferent pressure increases, but this difference may not be important in vivo. alpha-adrenegic constrictory receptors predominate in Rs, in contrast to beta-adrenergic dilatory receptors in Rg; a significant alpha-adrenergic tone in Rs is lost during perfusion. Rs is far less sensitive than Rg to circulatory catecholamine levels. It is suggested that the sympathetic nervous system, rather than plasma catecholamines, provides the effective adrenergic control of Rs in vivo.     

Resveratrol increases vascular oxidative stress resistance

Epidemiological studies suggest that Mediterranean diets rich in resveratrol are associated with reduced risk of coronary artery disease. However, the mechanisms by which resveratrol exerts its vasculoprotective effects are not completely understood. Because oxidative stress and endothelial cell injury play a critical role in vascular aging and atherogenesis, we evaluated whether resveratrol inhibits oxidative stress-induced endothelial apoptosis. We found that oxidized LDL and TNF-alpha elicited significant increases in caspase-3/7 activity in endothelial cells and cultured rat aortas, which were prevented by resveratrol pretreatment (10(-6)-10(-4) mol/l). The protective effect of resveratrol was attenuated by inhibition of glutathione peroxidase and heme oxygenase-1, suggesting a role for antioxidant systems in the antiapoptotic action of resveratrol. Indeed, resveratrol treatment protected cultured aortic segments and/or endothelial cells against increases in intracellular H(2)O(2) levels and H(2)O(2)-mediated apoptotic cell death induced by oxidative stressors (exogenous H(2)O(2), paraquat, and UV light). Resveratrol treatment also attenuated UV-induced DNA damage (comet assay). Resveratrol treatment upregulated the expression of glutathione peroxidase, catalase, and heme oxygenase-1 in cultured arteries, whereas it had no significant effect on the expression of SOD isoforms. Resveratrol also effectively scavenged H(2)O(2) in vitro. Thus resveratrol seems to increase vascular oxidative stress resistance by scavenging H(2)O(2) and preventing oxidative stress-induced endothelial cell death. We propose that the antioxidant and antiapoptotic effects of resveratrol, together with its previously described anti-inflammatory actions, are responsible, at least in part, for its cardioprotective effects.     

Effect of meclofenamate on renal vascular resistance in early Goldblatt hypertension in conscious and anesthetized dog

Blood pressure and renal blood flow were monitored in conscious normotensive (N) and 2-kidney Goldblatt hypertensive (H) dogs. Plasma renin activity was significantly increased 4–8 days after partial renal artery occlusion. At this time intravenous administration of meclofenamate, 5 mg/kg, had no effect on blood pressure in the N or H or on renal vascular resistance in the N or in the H (contralateral kidney). The renal vasoconstrictor response to angiotensin II was increased in duration by meclofenamate in both the N and H. In contrast to the absence of an effect of meclofenamate on renal vascular resistance in the conscious dog, the synthesis inhibitor caused a consistent increase in RVR in the N and H when they were anesthetized in the terminal experiment. These results suggest the lack of an influence of prostaglandins on renal vascular resistance in the unaffected kidney in Goldblatt hypertension.     

Indomethacin increases abortifacient effect of PGE2 in man.

Results of this study indicate that pretreatment with indomethacin significantly increases the abortifacient effect of an intravenous infusion of PGE2 in patients admitted for abortion as a result of fetal death in utero. Indomethacin pretreatment shortened the duration of PGE2-induced abortion in primigravid and multigravid groups of patients by about 4 and 2 hours respectively. When primigravid and multigravid groups were combined, the dose of PGE2 needed for complete delivery decreases in the indomethacin-treated group by 39.9%.     

Cigarette smoke acutely increases collateral resistance in excised dog lobes

The acute effects of cigarette smoke or drug inhalation on collateral conductance (Gcoll) were studied in freshly excised dog lobes held at fixed volumes. A double-lumen catheter was wedged into a segmental bronchus, and air, smoke, or aerosol flowed into the blocked segment at a constant pressure of 2 cmH2O. A capsule glued over a small area of perforated pleura of the segment was used to measure alveolar pressure; the capsule could also be used to measure small airway flow (Vcap) through the segment. Gcoll was almost linearly dependent on lung volume, rising about fivefold between 20 and 100% inflation (30 cmH2O). During smoke inhalation Gcoll began decreasing almost immediately, roughly halving with the first cigarette and falling to about 20% after two cigarettes. Similar proportions were obtained at other lung volumes. Pulmonary conductance (oscillator) in the remainder of the lobe decreased only modestly to 78% of control after two cigarettes. In lobes exposed to 4.5% CO2 after air Gcoll rose 25-50%, but Vcap increased only 5-10%. However, acetylcholine chloride aerosol reduced both flows by similar ratios. Isoproterenol did not prevent or reverse smoke-induced collateral constriction but did reverse the effects of acetylcholine on both pathways. These results suggest that in excised lungs aerosols acted on larger segmental airways in series with collateral channels and with peripheral airways, whereas CO2 and particularly cigarette smoke provoked more marked effects on the most distal smooth muscle.     

Forearm vascular resistance increases during static exercise in heart transplant recipients.

In heart transplant recipients but not in normal humans, total peripheral vascular resistance increases during static exercise. To determine whether this augmented vasoconstriction limits the vasodilation normally seen in the nonexercising forearm, we measured arterial pressure, heart rate, and forearm blood flow during 30% maximal static handgrip in 9 heart transplant recipients and 10 control subjects. Handgrip evoked comparable increases in mean arterial pressure in the transplant recipients and control subjects (+19 +/- 2 vs. +20 +/- 2 mmHg). Heart rates increased by 14 +/- 3 beats/min in the control subjects but did not change in the transplant recipients. Directionally opposite patterns of forearm vascular resistance were observed in the two groups. In the control subjects, forearm resistance fell during handgrip (-8.8 +/- 1.9 units, P less than 0.05). In contrast, in the transplant recipients, forearm resistance rose during this intervention (+9.0 +/- 2.9 units, P less than 0.05). Thus the vasodilation that normally occurs in the nonexercising forearm during static handgrip is reversed in heart transplant recipients. Vasoconstriction in the forearm contributes to the increase in total peripheral resistance that occurs during static exercise in these individuals.     

Thromboxane increases pulmonary vascular resistance and transvascular fluid and protein exchange after pulmonary microembolism

We compared the effects of inhibition of thromboxane synthetase with antagonism of thromboxane A2 (TxA2)/prostaglandin H2 receptors on the changes in pulmonary hemodynamics and pulmonary transvascular fluid and protein exchange following thrombin-induced pulmonary microembolism. Studies were made in chronically instrumented unanesthetized sheep prepared with lung lymph fistulas. Control thrombin challenged sheep (n = 5) were compared to animals pretreated with Dazoxiben (the Dazoxiben-thrombin group, n = 8) or animals pretreated with L-640,035 (the L-640,035-thrombin group, n = 5). In the control-thrombin sheep, plasma TxA2 concentration rose after thrombin and the response was inhibited in the Dazoxiben-thrombin group. The rise in the plasma TxA2 concentration was greater in the L-640,035-thrombin group than in the control-thrombin group. In the control-thrombin group, thrombin produced a sustained increase in the pulmonary transvascular protein clearance (pulmonary lymph flow x lymph/plasma protein concentration ratio) and pulmonary vascular resistance (PVR). In the Dazoxiben-thrombin group, increases in both pulmonary transvascular protein clearance and PVR after thrombin were less than in the control-thrombin group. In the L-640,035-thrombin group, thrombin initially increased pulmonary transvascular protein clearance and PVR to the same levels as the control group; however, both protein clearance and PVR declined with time, in contrast to the sustained responses in the control-thrombin group. These differences may be related to the initially greater increase in plasma TxA2 concentrations after thrombin in the L-640,035-treated animals. The results indicate that TxA2 plays a role in mediating the increases in PVR and contributes to increases in pulmonary transvascular fluid and protein exchange after thrombin-induced pulmonary microembolism.