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All vertebrate cardiac muscle responds intrinsically to mechanical stimulation which can lead to changes in both the inotropic and chronotropic state of the heart. However the magnitude and physiological relevance of these mechanically-induced responses differ between vertebrate classes. This review will discuss the differences and similarities in the response of vertebrate hearts to stretch. It will focus on responses to mechanical stimulation that have been well characterised in mammals, and discuss what is known about them in non-mammalian vertebrates. Specifically we focus on the Frank- Starling response or length-tension relationship, stretch acceleration of heart rate (the Bainbridge effect) and mechanically-induced effects on cardiac rhythm. Although they have not been categorically studied, these three basic mechanical and electrical responses to stretch are likely present in all vertebrate classes. For example, in a manner similar to mammals, one of the earliest vertebrates, the hagfish (Myxine glutinosa), shows a remarkable increase (up to 150%) in heart rate in response to cardiac stretch and in amphibian hearts, modification of action potential profiles and mechanically triggered action potentials have been observed. These commonalities are interesting given the differences in whole heart, cellular and sub-cellular morphology and working environments between early and later vertebrates. These differences may have led to fundamental differences in cardiovascular design between classes. For instance, the exquisite sensitivity of the Starling response in the heart of the rainbow trout (Oncorhynchus mykiss) may explain why fish increase predominantly stroke volume rather than heart rate when modulating cardiac output. We speculate that despite the variety of vertebrate hearts, mechanosensitivity is fundamentally similar, if subtly different, across classes. Shared mechanisms, such as mechanosensitive channels (possibly TRP), make early vertebrate hearts useful models for the study of cardiac mechanosensitivity. Finally, given that early vertebrates are known to rely on intrinsic regulation to a greater extent than later vertebrates they may provide useful systems in which to study the role of mechanosensitivity in the evolution of cardiac function and cardiac regulation. [ABSTRACT FROM AUTHOR]

Overproduction or underregulation of the proinflammatory complement component C5a has been implicated in numerous immune and inflammatory conditions. Therefore, targeting the C5a receptor (C5aR) has become an innovative strategy for antiinflammatory drug development. The novel cyclic peptide C5aR antagonist, AcF-[OP(D-Cha)WR] (PMX53), attenuates injury in numerous animal models of inflammation following intravenous, subcutaneous, intraperitoneal, and oral administration. In the present study the transdermal pharmacology of PMX53 and three analogs designed with increased lipophilicity, hydrocinnamate-[OP(D-Cha)WCit] (PMX200), AcF-[OP(D-Cha)WCit] (PMX201) and hydrocinnamate-[OP(D-Cha)WR] (PMX205), have been examined in order to assess their transdermal permeability and inhibitory effect on C5a-mediated lipopolysaccharide (LPS)-induced systemic responses. In the rat, PMX53, PMX201, and PMX205, were bioavailable following topical dermal administration (10 mg/50 cm2 site/rat). All analogs functionally antagonized neutropenia and hypotension induced by systemic challenge with LPS (1 mg/kg i.v.). Interestingly, PMX200 attenuated LPS-induced neutropenia more effectively than other analogs, despite undetectable (<5 ng/ml) circulating levels following topical administration. In conclusion, we have demonstrated that cyclic peptide C5aR antagonists can penetrate transdermally sufficiently to have systemic effects. However, increasing lipophilicity in these compounds did not result in increased blood levels. Nonetheless, topical application of C5aR antagonists produced circulating levels of the drugs that antagonized the LPS-induced systemic responses of neutropenia and hypotension. This suggests that these small-molecule C5aR antagonists may be developed for topical administration for the treatment of local and systemic inflammatory conditions in the human and veterinary pharmaceutical markets. [ABSTRACT FROM AUTHOR]

The forty-third chapter of the book "Earl of Rochester: The Critical Heritage," edited by David Farley-Hills is presented. The article offers an excerpt from the book "Lives of the Poets," by Robert Shiels, under the name "Mr. Cibber." The excerpt focuses on the writings of John Wilmot, Earl of Rochester, whom Shiels calls wicked despite a talent for satire.