No abstract

The characterization and localization of endothelin A (ETA) and endothelin B (ETB) receptors have been determined in tissue sections of the human atrioventricular conducting system, surrounding regions of atrial and ventricular myocardium, and the left ventricular free wall by use of radioligand binding, polymerase chain reaction, and in situ hybridization. Selective ETA (BQ123) and ETB (BQ3020) compounds in conjunction with [125I]endothelin-1 revealed the presence of ETA and ETB receptors in the left ventricular free wall (BQ123: 57 +/- 5% ETA, 43 +/- 2% ETB, n = 3; BQ3020: 67 +/- 3% ETA, 33 +/- 3% ETB, n = 3). Autoradiography using [125I]endothelin-1 in the absence or presence of BQ3020, BQ123, or endothelin-1 showed ETA and ETB receptors localized to atrial and ventricular myocardium, the atrioventricular conducting system, and endocardial cells. There was a higher proportion of ETB receptors in the atrioventricular node and the penetrating and branching bundles of His than in the surrounding interventricular and interatrial septa (p < 0.0001). There was a lower density of ETB receptors in the interventricular septum compared with the interatrial septum and the atrioventricular conducting system (p = 0.009) and a lower density of ETA receptors in the atrioventricular conducting system compared with interatrial and interventricular septa (p = 0.008). Isolated right atrial myocytes showed a higher proportion of ETA receptors (91 +/- 12%, n = 3). Amplification of left ventricular free wall cDNA by polymerase chain reaction revealed the presence of ETA and ETB receptor mRNA. mRNA for both subtypes was detected in isolated atrial myocytes. In situ hybridization showed ETA and ETB receptor mRNA localization to atrial and ventricular myocardium, the atrioventricular conducting system, and endocardial cells. These studies demonstrate the presence of ETA and ETB receptors in human myocardium and the atrioventricular conducting system.

Objectives-Rotator cuff tendinitis and lateral epicondylitis are common in clinical practice but the underlying pathology is poorly understood. The study examined both normal and biopsy tendon specimens histologically, to determine the mechanisms involved in tendon degeneration. Methods-Rotator cuff tendons from 83 cadavers aged 11-94 and tendon biopsy specimens from 20 patients with lateral epicondylitis aged 27-56 years were examined histologically. Results-The microscopic changes found in the tendon biopsies from the elbow were similar to those found in the cadaveric rotator cufftendons. Abnormalities ranged from minor blood vessel wall changes and loss of tenocytes to calcification. The most frequent abnormality was glycosaminoglycan infiltration and fibrocartilaginous transformation. There appeared to be some sequence in the changes observed which were milder in younger patients. Only 17% of cadaver tendons, below the age of 39 were abnormal but abnormalities increase in later life to around 40-50%. Conclusions-There was an increasing incidence of degenerative changes in tendons with age. The changes observed in biopsy samples of common extensor tendons were the same as those seen in aged supraspinatus tendons, but these changes were not seen in control common extensor tendons. ( poor.4 In the absence of operative material, a study of changes in the rotator cuff with age would at least give insight into changes that occur which might predispose individuals to symptomatic lesions. Studies on cadavers have described changes within the rotator cuff and also at their insertion. It is probable that changes within the tendon itself are of most relevance to clinical symptoms. Rupture of the cuff and calcification is usually seen within the substance of the tendon, 1-2 cm from the insertion. As this area is the 'watershed zone' of blood supply from muscle and bone it is relatively avascular making it prone to ischaemic stress and has been called the critical zone. However, a recent qualitative study5 on the number and size of blood vessels in this region suggests that there is little difference between the supraspinatus and infraspinatus tendons. As most problems occur in the supraspinatus tendon, other factors in addition to blood supply most predispose this tendon to degenerate.Rotator cuff degeneration has had limited study. An early investigation by Lindblom in 1939,6 was followed by an extensive study on 125 cases by Wilson and Duff in 19437 who attempted to grade the severity of changes and looked at the effects of age. A later paper by Brewer on just three tendons8 included some electron microscopy studies and most recently an investigation by Clark9 emphasised the interdependance of the individual components of the rotator cuff. These studies are descriptive and it is often unclear how frequently changes were found and at what age.

1 Daily administration of 1 nmol substance P or 3 pmol recombinant human interleukin-1 alpha (IL-la) caused intense neovascularization in a rat sponge model of angiogenesis. Lower doses of substance P (10 pmol) or IL-lh (0.3 pmol) were ineffective when given alone. When combined at these low doses, substance P and IL-lo interacted to produce an enhanced neovascular response.2 By use of selective tachykinin NK,, NK2 and NK3 receptor agonists, ([Sar9,Met(02)' ]substance P, [P-Ala8]neurokinin A(4-10), Succ-[Asp6,MePhe8]substance P(6-11) (senktide), respectively), it was established that the activation of NK, receptors is most likely to mediate the angiogenic response to substance P in this model.3 The angiogenic activity of substance P and IL-lh (10 pmol and 0.3 pmol day-', respectively) was abolished by co-administration of (i) the selective peptide NK, receptor antagonist, L-668, 169 (1 nmol day-'), (ii) the selective non-peptide NK, receptor antagonists, RP 67580 and (±)-CP-96,345 (both at 1 nmol day-') or (iii) the IL-1 receptor antagonist, IL-Ira, (50 g day-'). In contrast, the selective NK2 receptor antagonist, L-659,874 (1 nmol day-') was ineffective. 4 The angiogenic action of substance P and IL-lh was resistant to modification by mepyramine (1 nmol day-') and/or cimetidine (10 nmol day-'), indomethacin (7 nmol day-') or the plateletactivating factor (PAF) antagonist, WEB-2086 (22 nmol day-'), indicating that histamine, prostaglandins and PAF are not likely to be involved in this neovascular response.5 The inhibition of the substance P/IL-I angiogenic response by selective NK, receptor antagonists or by an IL-1 receptor antagonist demonstrates that angiosuppression can be achieved by blocking the activity of angiogenic factors at the receptor level.