The regulation of pulmonary vascular tone

Abstract

1 The ability to manipulate pharmacologically pulmonary vascular tone independent of effects on systemic blood vessels is a desirable objective. Elucidation of the biochemical mechanisms underlying hypoxia-induced pulmonary vasoconstriction ( HPV) may permit preferential targeting of the pulmonary circulation. 2 Here we review our studies of the role of locally synthesized candidate vasoactive factors in HPV. In addition, we present data demonstrating an attenuated pressor response to hypoxia in the pulmonary circulation of Fischer 344 rats compared with the Wistar-Kyoto ( WKY) rat strain. 3 We propose that a systematic genome-wide search using the HPV phenotype and a panel of highly informative microsatellite markers will elucidate the genetic loci underlying the difference in susceptibility to HPV in these two rat strains and provide a valuable and novel insight into the factors that determine the HPV response. Keywords hypoxia vasoactive factors genetics rat strainsThe clinical problem optimal. There are obvious practical difficulties with the chronic infusion of compounds and there are concerns about the toxicity of chronic nitric oxide administration. The normal adult pulmonary circulation is a lowpressure, low-resistance system with little or no resting Clearly, the treatment of pulmonary hypertension would benefit from a more comprehensive range of drugs that vascular tone. Pulmonary artery pressure may be increased, however, in a number of clinical situations, target selectively the pulmonary circulation. such as in patients with chronic hypoxic lung disease or a left-to-right intracardiac shunt, and, less frequently, as a primary event. In the long-term, pulmonary hypertension leads to right ventricular hypertrophy, heart failure Hypoxia-induced pulmonary vasoconstriction (HPV ) and premature death.The current treatment of pulmonary hypertension is Oxygen tension is a major regulator of pulmonary vascular tone. Ventilation of lungs with an hypoxic unsatisfactory [1,2]. Oxygen is an effective pulmonary vasodilator in pulmonary hypertension secondary to gaseous mixture (i.e. decreasing PO 2 from~130 to 30-40 mmHg) leads to acute pulmonary vasoconstricchronic obstructive lung disease [3 ] and has been reported to be beneficial in other forms of pulmonary tion, most pronounced in precapillary arterioles [9 ]. Constriction is also observed in isolated pulmonary hypertension [4, 5 ], but it is inconvenient to administer, relatively expensive and has to be given for at least 12 h arteries (the degree of vasoconstriction correlating inversely with diminishing vessel size) [10][11][12] and per day. A number of more conventional vasodilators have been examined, but the doses required to reduce isolated pulmonary vascular smooth muscle cells [11 ] perfused at low oxygen tension (~40 mmHg). the elevated pulmonary artery pressure are usually so high that they are associated with symptomaticIn contrast, systemic vessels in the intact rat [13 ], mesenteric resistance vessels perfused in situ [ 14] and and unacceptab...

Recent insights into the pathogenesis and therapeutics of pulmonary hypertension

“…The pulmonary vascular and cardiac response to hypoxia is reduced markedly in the Fischer 344 rat strain compared with the Wistar-Kyoto strain [53], and a similar strain-related difference has been reported between Fischer 344 and Sprague-Dawley rats [54]. The differential response breeds true, and cannot be explained by differences in pulmonary vascular architecture.…”

Vascular remodeling and ET-1 expression in rat strains with different responses to chronic hypoxia

“…Previous studies with isolated perfused lung preparations have shown that the pressor response to acute hypoxia in the F-344 rat pulmonary circulation is ϳ50% of that produced in the WKY rat (25) and markedly reduced compared with outbred Sprague-Dawley rats (8). The F-344 rat pulmonary vascular response to other pressor stimuli such as angiotensin II, however, is similar to that observed in the WKY rat (25), and others (8) have found that pulmonary artery rings from F-344 rats contract as well as those from Sprague-Dawley rats to phorbol 12-myristate 13acetate, a protein kinase C activator. Taken together with our histological findings, the attenuated response of the F-344 rat to hypoxic pulmonary vasoconstriction does not appear to be due to a relative paucity of pulmonary vascular smooth muscle.…”

“…Taken together with our histological findings, the attenuated response of the F-344 rat to hypoxic pulmonary vasoconstriction does not appear to be due to a relative paucity of pulmonary vascular smooth muscle. Likewise, the comparable rise in hematocrit in F-344 and WKY rats during chronic exposure to hypoxia (25) would argue against a generalized abnormality of perception of oxygen tension.…”

Knockdown of Arginase I Restores NO Signaling in the Vasculature of Old Rats

“…It is well established that there are significant differences in the vascular biology of these different rat strains. 34,35 Furthermore, there are differences in the vascular phenotype expression with aging between the strains. 36 One of the seminal features of the aging vasculature is an increase in arterial stiffness, which is additionally exacerbated by hypertension and diabetes.…”