The association between pre-operative variables, including blood pressure, and postoperative kidney function.

We used multivariate analyses to assess the association of pre-operative variables with kidney function in 41,523 adults after scheduled surgery in a single large academic hospital. Eight variables were independently associated with a reduction in postoperative estimated glomerular filtration rate: pre-operative renal function; age; ASA physical status; cardiac failure; anaemia; cancer; type of surgery; and the lowest quartile of pre-operative mean arterial blood pressure (< 71 mmHg). The estimated glomerular filtration rate fell by a mean (95% CI) of 2.7 (0.04-5.40) ml.min-1 .1.73 m-2 for patients with a pre-operative mean arterial pressure < 71 mmHg, p = 0.047. The same variables and male sex were associated with postoperative acute kidney injury. The odds ratio (95% CI) for acute postoperative kidney injury was 1.9 (1.2-2.9) for patients with a pre-operative mean arterial blood pressure < 71 mmHg, p = 0.005.

New bradykinin analogs in contraction of rat uterus.

In this study, we evaluated 20 of our previously synthesized peptides on isolated rat uterus by Holton's procedure with minor modifications, and compared their activity with that assessed previously by their ability to inhibit vasodepressor response to exogenous bradykinin (BK) in conscious rats. We used [D-Arg(0), Hyp(3), Thi(5, 8), (D-Phe)(7)]BK, the B(2) antagonist of Vavrek and Stewart as a model when designing our analogs. We observed that, in the case of the rat uterus test, the activity of peptides modified by acylation of the N-terminus with various bulky groups depends substantially on the chemical character of the substituent. We also learned that, contrary to previous examples, acylation of the N-terminus of antagonists, which contain a sterically restricted fragment in the C-terminal part, may not improve their antagonistic potencies. Besides an improved characterization of a series BK analogs, our studies have provided new information on the structure-activity relationship, which in turn may be of value in the design of more potent and selective bradykinin antagonists. The results of our studies appear to support the hypothesis of others about the presence of different subtypes of B(2) receptors in rat uterus and blood vessels.

Nitric oxide inhibition of IGF-1 stimulated proteoglycan synthesis: role of cGMP.

Insulin-like growth factor (IGF-1) is critical for normal development and maintenance of cartilage, however arthritic cartilage responds poorly to IGF-1; part of this insensitivity is mediated by nitric oxide (NO). These studies test if cGMP is responsible for NO dependent insensitivity to IGF-1 in chondrocytes in situ in organ culture and in monolayer culture. Lapine cartilage and chondrocytes in monolayer culture and cartilage from osteoarthritic human knees were used. Tissues were exposed to NO from iNOS induced by IL-1, and proteoglycan synthesis in response to IGF-1 was evaluated in the presence and absence of cGMP dependent protein kinase (PKG) inhibitors. PKG activators inhibited IGF-1 responses in cartilage but not chondrocytes in monolayer. IL-1 stimulated cGMP synthesis in both monolayer and organ cultures. However, PKG inhibitors in cartilage slices but not in monolayer cultures restored response to IGF-1. PKG activity was detected in both fresh and monolayer chondrocytes, confirming this part of the cGMP signal cascade is intact in both of the preparations evaluated. Arthritic cartilage response to IGF-1 was restored by both N(G)-monomethyl-L-arginine inhibition of NO synthesis and PKG inhibitors. The data suggests that cGMP mediated effects are critical to NO actions on chondrocytes in situ in the cartilage matrix and supports a role for cGMP in the pathophysiologic effects of NO in osteoarthritis.

Analogues of arginine vasopressin modified in position 2 or 3 with naphthylalanine: selective antagonists of oxytocin in-vitro.

In this study we describe the synthesis and some pharmacological properties of six new analogues of arginine vasopressin (AVP). Five of the peptides were substituted in position 2 with L-1-naphthylalanine (L-1-Nal) or D-1-naphthylalanine (D-1-Nal); one had D-1-Nal in position 3. All analogues were tested in bioassays for pressor and antidiuretic activity. We also tested the uterotonic activity of the peptides in-vitro. Two of the new peptides were moderately potent V1a and oxytocin antagonists. The modifications proposed resulted in a drop or the removal of antidiuretic activity and in the removal of pressor activity, or conversion into moderate antagonists. Two peptides ([Mpa1, (L-1-Nal)2]AVP and [Mpal, (D-1-Nal)2]AVP) which appear not to interact with V1a and V2 receptors were exceptionally selective oxytocin antagonists in vitro. These compounds with selective oxytocin antagonistic activity may be promising candidates for the development of potential tocolytic agents for the prevention of pre-term labour.

A morphometrical study of human fetal thymus.

A morphometrical study was made of the thymus lobules in the cortical and medullary layers of male and female fetuses, 16 to 31 weeks old, divided into the age groups 16 to 19, 20 to 23, 24 to 27 and 28 to 31 weeks of intrauterine life. Results were correlated with body and thymus weights; the lobular, cortical and medullary volumes, as obtained using a histometrical method, were proportional to thymus, but not body weight increase. No differences were noted in the volumes and weights investigated as a function of fetal sex.

New analogues of bradykinin containing a conformationally restricted dipeptide fragment in their molecules.

The present paper describes the synthesis and some pharmacological properties of two new bradykinin analogues containing the ethylene-bridged dipeptide Phe-Phe in their molecules. In a further two peptides this modification was combined with acylation of the N-terminus with 1-adamantaneacetic acid. Finally, we synthesized four analogues by removing the Ser6 residue from the four peptides mentioned above. The activity of the new analogues was assayed on isolated rat uterus (RUT) and in rat blood pressure tests (BPT). The results clearly indicate that the proposed modification, alone or in combination with other changes, resulted in either a drop in antiuterotonic activity or even in conversion to an agonism. Although this tendency is not so distinct in blood pressure assays, the antagonistic potency of the new analogues is also diminished. Nevertheless, it was demonstrated that the D-amino acid in position 7 which, until recently, was considered necessary for antagonism, may be replaced, together with the amino acid occupying position 8, by a suitable, sterically restricted L,L-dipeptide unit.