Biomedical subjects

P H MacDonald

Publications and source records attributed to P H MacDonald.

7 recordsLinked to original sources

PubMed2003

Hemodynamic and proinflammatory actions of endothelin-1 in guinea pig small intestine submucosal microcirculation.

The hemodynamic and proinflammatory effects of endothelin-1 (ET-1) in proximal (1st/2nd order) and terminal (3rd/4th order) arterioles and venules were examined in small intestine submucosa of anesthetized guinea pigs. Vessel diameter (D), red blood cell velocity, and blood flow (Q) were determined in eight proximal and eight terminal microvessels before and at 20 min of ET-1 suffusion (10(-10), 10(-9), and 10(-8) M) and then with endothelin-A (ET(A))-receptor blockade with BQ-123 (10(-5) M). This protocol was repeated with platelet-activating factor (PAF) inhibition (WEB-2086, 1.0 mg/kg iv; n = 16). The ET-1-mediated microvascular responses were also examined with endothelin-B (ET(B))-receptor blockade using BQ-788 (10(-5) M; n = 11) alone or with ET(A+B)-receptor blockade with BQ-123 + BQ-788 (n = 10). Microvascular permeability was assessed by FITC-albumin (25 mg/kg iv) extravasation in seven series: 1) buffered modified Krebs solution suffusion (n = 6), 2) histamine suffusion (HIS; 10(-3) M, n = 5), 3) ET-1 suffusion (10(-8) M, n = 5), 4) BQ-123 (10(-5) M) plus ET-1 suffusion (n = 5), 5) PAF inhibition before ET-1 suffusion (n = 5), 6) histamine-1 (H1)-receptor blockade (diphenhydramine, 20 mg/kg iv) before ET-1 suffusion (n = 5), and 7) ET(B)-receptor blockade before (BQ-788 10(-5) M; n = 3) or with ET-1 suffusion (n = 3). D and Q decreased at 10(-8) M ET-1 and returned to control values with BQ-123 and BQ-123+BQ788 but not with BQ-788 in proximal microvessels. D did not change in terminal microvessels with ET-1 (10(-8) M) but decreased with BQ-788 and increased with BQ-123. PAF inhibition did not affect the D and Q responses of proximal microvessels to ET-1 but prevented the fall in Q in terminal microvessels with ET-1. ET-1 increased vascular permeability to approximately 1/3 of that with HIS; this response was prevented with BQ-123 and WEB-2086 but not with H1-receptor blockade. This is the first evidence that submucosal terminal microvessel flow is reduced with ET-1 independent of vessel diameter changes and that this response is associated with increased microvascular permeability mediated via ET(A)-receptor stimulation and PAF activation.

Animals↗

PubMed2002

Ischaemic colitis.

The term colonic ischaemia was first coined approximately 40 years ago. Up until that point, the disease was only diagnosed in cases where the colon was completely gangrenous. In the 1960s reversible non-transmural ischaemia of the colon was described and much has been written about the disease since. Ischaemic colitis is usually a disease process that is seen in the elderly. However, the true incidence of the disease remains unknown since many cases are probably never diagnosed. We now know that the disease can occur both with occlusive and non-occlusive vascular disease, the latter being much more common. Although factors that contribute to non-occlusive disease have been identified, often the exact pathophysiology is unclear and this is an area where further research is needed. Known facts about the pathophysiology and aetiology of the disease will be discussed in this chapter. The key to diagnosis is often a high degree of clinical suspicion. Various diagnostic modalities are described, but colonoscopy remains the main instrument of accurate diagnosis. Fortunately the majority of patients will have self-limiting disease and, accordingly, they usually respond to conservative therapy. When the disease progresses to transmural infarction, surgery is required and the prognosis is guarded. Since many of the patients are elderly with other underlying diseases, it is unlikely that major treatment advances will allow us to significantly alter the prognosis in this group of patients with transmural ischaemia.

Aged↗

PubMed2002

Endothelial modulation of skeletal muscle blood flow and VO(2) during low- and high-intensity contractions.

In the present study, we determined whether endothelin (ET)-1 contributed to the observed reduction in muscle blood flow (Q) during contractions with nitric oxide synthase (NOS) inhibition and whether muscle O(2) uptake (VO(2)) would be affected by the decrease in muscle Q with NOS inhibition at different contraction intensities. Muscle Q, VO(2), O(2) extraction ratio (OER), and tension development (TD) were studied in the in situ gastrocnemius muscle preparation in anesthetized dogs. A decrease in the VO(2)-to-TD ratio (VO(2)/TD) was used as an indicator of O(2) limitation. Three contraction protocols were used: 1) isometric twitch contractions at 2 twitches (tw)/s, 2) the same contractions at 4 tw/s, and 3) pretreatment with an ET(A)-receptor antagonist (BQ-123) before 2 tw/s contractions. The muscle was stimulated to contract, and measures were obtained at steady state (approximately 5-8 min). NOS inhibition (N(omega)-nitro-L-arginine methyl ester) was then induced, and measures were repeated at 2, 5, 10, and 15 min. During 2 tw/s contractions, NOS inhibition reduced Q with and without ET(A)-receptor blockade. In both groups, OER increased in response to the fall in Q, with the result being no change in VO(2)/TD. NOS inhibition also decreased Q during 4 tw/s contractions, but OER did not increase, resulting in a reduction in VO(2)/TD 5 and 15 min after N(omega)-nitro-L-arginine methyl ester. These data indicated that 1) a reciprocal increase in ET-1 during NOS inhibition does not influence active hyperemia in skeletal muscle, and 2) during 4 tw/s contractions, the ischemia with NOS inhibition was associated with either an O(2) limitation or an alteration in the efficiency of muscle contractions.

Animals↗

PubMed1993

The use of oximetry in determining intestinal blood flow.

The intraoperative evaluation of intestinal ischemia and viability is often subjective and unreliable. The results of recent reports of pulse and surface oximetry have suggested that these techniques may be useful in assessing intestinal blood flow. In the current study, we evaluated and compared the ability of intestinal tissue oxygen saturation (as measured by pulse oximetry) and intestinal surface oxygen tension (as measured by surface oximetry) to determine the actual intestinal tissue blood flow (as measured with a radiolabeled microsphere technique). In five dogs, tissue oxygen saturation, surface oxygen tension and blood flow of the proximal and distal parts of the small intestine were measured under basal conditions. A clamp placed around the root of the superior mesenteric artery was then tightened to decrease the blood flow through this artery (as measured by an ultrasonic flow probe) by 50 percent and then by 75 percent, repeating all measurements after each reduction. The two consecutive reductions in superior mesenteric artery blood flow resulted in an average 54 and 76 percent reduction in tissue blood flow, respectively. As a result of these reductions in tissue blood flow, the average intestinal tissue oxygen saturation (percentage), as determined by pulse oximetry, decreased significantly from a basal value of 93 +/- 1 to 83 +/- 1 (p < 0.05) and then to 76 +/- 1 (p < 0.05) with the two progressive blood flow reductions. Intestinal surface oxygen tension decreased more steeply, from a basal value of 97 +/- 1 to 80 +/- 6 (p < 0.05) and then to 64 +/- 7 millimeters of mercury (p < 0.05) with the same two reductions in tissue blood flow. Both techniques were capable of estimating tissue blood flow, but pulse oximetry was quicker and simpler to use. We conclude that the pulse oximeter has the potential to be of value in the intraoperative assessment of intestinal blood flow.

Animals↗

PubMed1992

The role of angiotensin in the intestinal vascular response to hypotension in a canine model.

It was previously shown that the vasoconstrictory response to hypotension was similar in the mucosa of the small bowel and the colon but was significantly higher in the muscularis of the latter than that of the former. To understand the mechanism of this differential response of the muscularis of the small bowel and the colon, the present study investigated the effect of an angiotensin II inhibitor (saralasin) on the hypotension-induced vasoconstriction of the mucosa and the muscularis of these two locations of the gastrointestinal tract. Dogs were used. Hypotension was induced by hemorrhage to reduce blood pressure by 40 mm Hg. Blood flow was measured by 15-microns radiolabeled microspheres. Saralasin was infused intravenously for 20 minutes at a rate of 0.05 mg.kg-1 bolus followed by 1 microgram.kg-1.min-1. Saralasin had no effect on the basal blood flow of the mucosa or the muscularis of the small bowel or on the hypotension-induced vasoconstriction of these two layers of the small bowel. In contrast, saralasin decreased blood flow to the mucosa (-28%; P less than 0.001) and increased blood flow to the muscularis (+140%; P less than 0.001) of the colon under basal conditions and also reduced the hypotension-induced vasoconstriction of the colonic muscularis (P less than 0.01). These and supplementary data indicate that there is a difference between the small bowel and the colon in local activity of vascular angiotensin system and that this system is most active in the colonic muscularis where it plays a significant role in the vasoconstrictory response to hypotension.

Angiotensin II↗

PubMed1990

A randomized prospective trial comparing oral sodium phosphate with standard polyethylene glycol-based lavage solution (Golytely) in the preparation of patients for colonoscopy.

One hundred and two patients were randomized to receive either oral sodium phosphate or standard polyethylene glycol-based lavage solution (Golytely) prior to colonoscopy in order to establish whether the much smaller volume of the former agent enhanced patient tolerance while maintaining or improving effectiveness and safety. Overall, patients found sodium phosphate preparation much easier to complete. In 37 patients who had had a previous colonoscopy prepared with Golytely, 100% of those now receiving sodium phosphate found it easier to complete and over 90% felt it caused less discomfort, compared with their previous experience with Golytely. Colonoscopists, unaware of the type of lavage solution used, scored the degree of colonic cleansing significantly higher for sodium phosphate-prepared colons compared with colons prepared with Golytely. Serial measurements of blood tests and postural pulse and blood pressure changes did not reveal any clinically significant changes in intravascular volume. Hyperphosphatemia was noted with sodium phosphate, but was transient, and no concomitant decrease in calcium was seen. Histological assessment for possible preparation-induced changes revealed no difference between the two agents. Sodium phosphate is significantly less expensive than Golytely. We conclude that, in the group of patients studied, sodium phosphate is a safe colonic cleansing agent that is better tolerated and more effective than Golytely.

Colonoscopy↗

PubMedDate not supplied

Anastomotic and regional blood flow following esophagogastrectomy in an opossum model.

Adenocarcinoma of the esophagus is increasing in incidence. The primary treatment is surgical resection, which is associated with considerable risk of anastomotic dehiscence and stricture. Decreased blood flow has been suggested as one of the factors contributing to these anastomotic failures. Our hypothesis was that anastomotic blood flow was decreased secondary to gastric and esophageal mobilization and would be increased by endogenous nitric oxide. Five opossums underwent esophagogastrectomy. Gastric and esophageal blood flow was measured following laparotomy, esophageal and gastric mobilization, esophagogastric resection and anastomosis, and L-arginine infusion. Radioactive microspheres were used to measure blood flow in the mucosa and muscularis of the esophagogastric anastomosis, esophagus, and stomach. Contrary to our hypothesis, blood flow in the anastomosis was maintained if not increased following esophagogastrectomy. However, the blood flow to the gastric mucosa adjacent to the anastomosis may be decreased. This suggests a possible redistribution of gastric blood flow to supply the anastomosis. If prolonged, this may contribute to poor anastomotic healing. L-Arginine infusion had no effect on blood flow at the anastomosis.

Anastomosis, Surgical↗