The effects of substance P on the preconstricted pulmonary vasculature of the anesthetized dog

Substance P is a vasoactive peptide. Nerve fibers containing substance P are present in the media of pulmonary arteries but the physiologic function of substance P in the pulmonary vasculature is unknown. Several doses of substance P were infused intravenously in the anesthetized dog to ascertain its effects on the pulmonary vasculature, both during normoxia and following preconstriction with hypoxia (F1O2 0.1) or prostaglandin F2 alpha (PGF2 alpha 5 mug/kg/min). Substance P resulted in systemic vasodilation during normoxia but had minimal effect on the pulmonary vasculature. During hypoxia and PGF2 alpha-induced pulmonary vasoconstriction, substance P significantly lowered pulmonary artery pressure, pulmonary vascular resistance, mean aortic pressure, and total systemic resistance. It had no effect on cardiac output, wedge pressure, and arterial blood gases. To investigate possible mechanisms for substance P-induced vasodilation, substance P was studied following pretreatment with N-acetylcysteine (a radical scavenging agent), methylene blue (an inhibitor of guanylate cyclase), meclofenamate (a cyclooxygenase inhibitor), and atropine (a muscarinic receptor antagonist). None of these agents impaired substance P-induced vasodilation. Substance P given intravenously is a nonselective vasodilator in the dog but the mechanism of its action remains uncertain.     

Respiratory effects of brief baroreceptor stimuli in the anesthetized dog

To quantify the immediate isocapnic respiratory response to baroreceptor stimulation, pressure in the isolated externally perfused carotid sinuses (CS) of 24 vagotomized alpha-chloralose-anesthetized dogs was increased selectively during either inspiration or expiration as a step (from time of onset to end of respiratory phase) or a pulse (500 ms). The rise time (150 ms), base-line pressure (80 mmHg), and stimulus magnitude (40 mmHg) were similar for the two stimuli. The time of stimulus onset (delay), expressed as a percent of control time of inspiration (TI) or expiration (TE), was varied. TI, TE, and tidal volume (VT) were expressed as percent changes from control. Stimuli delivered early in inspiration lengthened TI [23.5 +/- 6.4% (SE) for step and 11.7 +/- 6.3% for pulse stimuli at 5% delay] more effectively than late stimuli. VT was essentially unaltered. In contrast, step stimuli delivered during expiration caused a lengthening of TE (32.7 +/- 6.3% at 5% delay) that did not depend on the delay (up to 75%). Very late (85%) pulse stimuli lengthened TE (15.2 +/- 5.7%) more effectively than early stimuli. For both stimuli, the expiratory VT was unaltered. When the responses are compared before and after separation of the blood supply of the carotid bodies from the CS region and when they are compared before and after inhibition of reflex systemic hypotension by ganglionic blockade, the observed responses were shown to be due solely to CS baroreceptor stimulation and not to alterations in carotid body blood flow or reflex changes in systemic cardiovascular variables.     

Biphasic effects of platelet-activating factor on coronary blood flow in anesthetized dog

Platelet-activating factor (PAF), modulates vascular tone by influencing prostaglandin release and vascular permeability. To determine its coronary effects we administered RAF (0.3 to 10 ug) into the left main coronary artery of anesthetized dogs with patent left circumflex (LCx) and narrowed left anterior descending (LAD) coronary arteries. RAF produced an initial increase followed by a decrease in coronary blood flow (CBF). The CBF increase was greater in the patent LCx than in the narrowed LAD, but the decrease was similar in both. These effects of RAF on CBF were dose-dependent, and associated with an increase in prostacyclin and thromboxane A₂ metabolites. To examine the contribution of prostaglandin release in coronary effects of PAF, dogs were pretreated with indomethacin (5 mg/kg) followed by administration of PAF. In indomethacin-pretreated animals, the coronary effects of RAF were significantly attenuated. This study shows that RAF has biphasic effects on CBF in the normal coronary artery, but the major effect in the narrowed coronary is decrease in CBF. These effects of RAF can be attenuated by prior treatment of dogs with indomethacin.     

Parameters of tubulo-glomerular function in anesthetized rabbits with acute kidney insufficiency

We have induced acute renal failure (ARF) in barbiturate anesthetized rabbits, through warm ischaemia of 30 or 60 min duration caused by transient bilateral occlusion of renal arteries. In this model we have monitored some renal performance parameters, before and 4 hours after reperfusion, aiming to characterize ARF in this animal species. Glomerular filtration rate (determined by the inulin clearance technique) was of 9.74 +/- 0.48 ml min-1 in 4 rabbits before injury and declined by 91% (60 min ischemia) during the first reperfusion hour. In 6 rabbits undergoing 30 min occlusion, pre-ARF values of 10.70 +/- 0.98 ml min-1 declined by 47%. In both groups no recovery was observed in the following hours. Tubular enzymes (alanine-amino-peptidase, AAP and N-acetyl-beta-glucosaminidase, NAG) were released into urines before injury at the rate of 1.11 +/- 0.18 and 1.32 +/- 0.41 mU min-1, respectively, in the 30 min model (3 animals/group). During ARF, maximal AAP output was five-fold increased (5.83 +/- 0.35 mU min-1), whereas NAG was unmodified. On the other hand, renal haemodynamics in 5 rabbits did not change after the ischaemic procedure: total renal blood flow (44 +/- 5 ml min-1) and renal vascular resistances (225 +/- 26 Pa ml-min) displayed less than 10% variations throughout the reperfusion period. We concluded that ARF in rabbits can be reliably and reproducibly monitored and that the pathogenesis of the disease, in our situation, is attributable mainly to tubular cell damage and not to impairment of the vascular component of renal performance.     

The effect of secretin on pancreatic blood flow in the awake and anesthetized dog

The canine pancreatic blood flow was studied after iv secretin (resulting in a plasma level commensurate with the postcibal state), and also after larger iv doses and after duodenal acidification. We found that blood flow was unaffected by "physiological" doses of secretin, or by perfusion of duodenum at a pH as low as 2.0, but increased by bolus doses (0.5 CU/kg and above), and by acidification to pH 1.4. Anesthesia does not affect the blood flow response although the bicarbonate response appeared to be blunted under anesthesia. We conclude that increase in pancreatic blood flow is not a physiological effect of secretin.     

Chronic clonidine treatment and its termination: effects on penile erection and ejaculation in the dog.

The effects of chronic administration (4 weeks) of the alpha-2 adrenoceptor agonist clonidine (CL) and its termination on penile erection and ejaculation were investigated in male dogs. Penile erection and ejaculation were elicited by manual penile stimulation (for 5 min). CL (10 micrograms/kg/hr, s.c.) was delivered via osmotic minipump (Alza, 2ML-4). 3 or 7 days after the minipump implantation, CL caused a significant decrease in the amount of ejaculate produced by the genital stimulation without affecting the erectile potency. Ejaculatory ability returned to pretreatment levels despite continued CL administration, becoming evident in tests 14 days after initiation of treatment. Further, chronic CL (23 days) antagonized the inhibitory effects of acute administration of CL (0.05 mg/kg, i.p.). These data indicate tolerance to continued delivery of low doses as well as to acute administration of a higher dose. In the acute drug experiments, the ejaculatory inhibition elicited by CL (0.05 mg/kg, i.p.) was completely antagonized by pretreatment with yohimbine (0.05 and 0.10 mg/kg, i.p.), an alpha-2 adrenoceptor antagonist, but not with naloxone (1.0 mg/kg, i.p.), an opioid receptor antagonist. Furthermore, DG-5128 (1.0 and 2.0 mg/kg, i.p.), a selective alpha-2 adrenoceptor antagonist that poorly penetrates the blood-brain barrier, failed to antagonize the CL-induced ejaculatory inhibition. This study suggests that functional alterations in the central alpha-2 adrenoceptor mechanism may be related to the changes in the ejaculatory capacity during chronic treatment with CL.     

虫草多糖治疗家犬夹闭肾动脉引起的急性肾衰

探讨了虫草多糖对家犬夹闭肾动脉造成的急性肾衰的治疗作用。将实验动物家犬分为假手术组、阴性模型组、阳性组、虫草多糖高、中、低三个剂量组,观察治疗后犬的肾功能、血液生化指标、尿常规、肾脏病理的变化。发现虫草多糖组肾功能受损程度明显轻于阴性模型组（P〈0．01）,肾脏病理损伤明显减轻。实验证明虫草多糖能够治疗肾缺血诱发的急性肾功能衰竭,其机理可能与改善肾功能、增加肾血流量、纠正代谢紊乱、促进肾小管的修复与再生等作用有关。     

The effect of tubular damage by mercuric chloride on kidney function and some urinary enzymes in the dog

Alkaline and acid phosphatases, β-glucosidase, β-galactosidase, N-acetyl-β-glucosaminidase and lactate dehydrogenase were monitored in the urine and serum of dogs with renal tubular damage induced by a series of increasing doses of mercuric chloride. Isocitrate dehydrogenase, glutamate oxaloacetate transaminase and glutamate pyruvate transaminase were assayed in the serum. The functional capacity of the kidney was determined by creatinine, inulin and p-aminohippurate (PAH) clearances and tubular maxima tests. Serum urea levels, total protein in the urine and the specific gravity of the urine were monitored throughout the study. The extent and location of the kidney damage was determined by histological investigation. Evidence is presented that the assay of urinary alkaline and acid phosphatase is the most sensitive method of detecting renal tubular damage in the dog. The clearance of [¹⁴C]-propranolol was compared before and after the administration of mercuric chloride. In the presence of tubular damage the blood half-life of propranolol and the rate of excretion of metabolites in the urine were increased.     

Comparison of the protective effects by human and bovine superoxide dismutase against ischemia- and reperfusion-induced impairment of kidney function in anesthetized rats

In a rat model of ischemia- and reperfusion-induced kidney damage, the protective effects of human superoxide dismutase produced by genetic technology (hum-SOD) were compared to those of bovine superoxide dismutase (bov-SOD). The intravenous infusion of hum-SOD and bov-SOD, started concomitantly with the kidney reperfusion after a 60-min (or 30-min) period of ischemia, significantly improved the renal function (inulin and p-amino-hippuric acid clearance rates) as compared to the vehicle-treated control group. In contrast, inactive apoenzyme of superoxide dismutase (Apo-SOD) did not improve the impaired renal function after the kidney reperfusion. Therefore, the kidney protection by hum-SOD and bov-SOD may reasonably be ascribed to their specific enzymatic function--scavenging of oxygen radicals. In this respect, hum-SOD proved to be as effective as bov-SOD. To our knowledge this is the first report on a direct pharmacologic comparison of superoxide dismutases from natural and recombinant origin.